WO2019094053A1 - Disulfiram and copper salt dosing regimen - Google Patents

Disulfiram and copper salt dosing regimen Download PDF

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Publication number
WO2019094053A1
WO2019094053A1 PCT/US2017/061362 US2017061362W WO2019094053A1 WO 2019094053 A1 WO2019094053 A1 WO 2019094053A1 US 2017061362 W US2017061362 W US 2017061362W WO 2019094053 A1 WO2019094053 A1 WO 2019094053A1
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cancer
copper
therapeutically effective
effective amount
administration
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PCT/US2017/061362
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French (fr)
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Daniel James GEORGE
Tian Zhang
Stephen Marcus
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Duke University
Cantex Pharmaceuticals, Inc.
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Priority to PCT/US2017/061362 priority Critical patent/WO2019094053A1/en
Publication of WO2019094053A1 publication Critical patent/WO2019094053A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • Disulfiram or Bis(diethylthiocarbamyl) disulfide (DSF) is a drug long used for treatment of alcohol abuse. More recently, disulfiram and copper have been shown to form active complexes that are effective in vitro in killing neoplastic cells of various cancers, see, e.g., U.S. Pat. Nos. 6,548,540; 6,589,987; and 7,816,403. In addition, preclinical studies in xenograft models have shown that disulfiram is effective at inhibiting prostate cancer minor growth in mice when administered with copper but not without the co-administration of copper, see Denoyer et al, Oncoiargel; 2016, 7(24): 37064-37080.
  • the methods comprise administering to a patient with cancer a first therapeutically effective amount of copper salt by intravenous administration; and administering to the patient a therapeutically effective amount of disulfiram by oral administration; wherein the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle.
  • the methods further comprise the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration.
  • the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCk).
  • the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
  • the first therapeutically effective amount of copper salt is administered as one or more bolus injections.
  • the bolus injection is 0.1 mg-30 mg CuCh.
  • the bolus injection of CuCh is selected from the group consisting of 1 mg, 3 mg, 5 mg, and 7 mg.
  • the first therapeutically effective amount of copper salt is administered as a continuous infusion.
  • the first therapeutically effective amount of copper salt is administered as a bolus followed or preceded by a continuous infusion.
  • the first therapeutically effective amount of copper salt is administered weekly.
  • ceruloplasmin levels in the patient are determined prior to administration of the first therapeutically effective amount of copper salt, for at least one cycle.
  • ceruloplasmin levels are detected after administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper.
  • the ceruloplasmin levels are used to determine a dose of the first therapeutically effective amount of copper salt.
  • 64 Cu PET imaging is performed on the patient. In certain embodiments, 64 Cu PET imaging is performed prior to the administration of the first therapeutically effective amount of copper salt. In certain embodiments, 64 Cu PET imaging is performed following the administration of the first therapeutically effective amount of copper salt. In certain embodiments, 64 Cu PET imaging is performed within 4 hours and at 24 hours after administration of 64 Cu. In certain embodiments, increased uptake of 64 Cu in neoplastic tissue as compared to one or more non-neoplastic tissues identifies a patient requiring treatment or a patient responsive to treatment.
  • the first therapeutically effective amount of copper salt is administered 12-48 hours prior to the administration of the disulfiram.
  • the first therapeutically effective amount of copper salt is administered one day prior to the administration of the disulfiram.
  • the disulfiram is administered at a total dose of 10 mg-500 mg.
  • the disulfiram is administered at a total dose of 10 mg-500 mg, TID.
  • the disulfiram is administered at a total dose of 120 mg TID, wherein each divided dose is 40 mg.
  • the disulfiram is administered at a total dose of 240 mg TID, wherein each divided dose is 80 mg.
  • the disulfiram is administered without food.
  • the second therapeutically effective amount of copper salt is copper glycinate. In certain embodiments, the second therapeutically effective amount of copper salt is copper gluconate. In certain embodiments, second therapeutically effective amount of copper salt is administered at a total dose of 0.1 mg-30 mg. In certain
  • the second therapeutically effective amount of copper salt is administered at a total dose of 1.5 mg-5 mg. In certain embodiments, the second therapeutically effective amount of copper salt is administered at a divided dose of 1.5 mg. In certain embodiments, second therapeutically effective amount of copper salt is administered TID. In certain embodiments, the second therapeutically effective amount of copper salt is administered at a divided dose of 0.5 mg-3 mg, TID. In certain embodiments, the second therapeutically effective amount of copper salt is administered at a divided dose of 1.5 mg, TID. In certain embodiments, the second therapeutically effective amount of copper salt is administered not within one hour of disulfiram. In certain embodiments, the second therapeutically effective amount of copper salt is administered at least one hour after the administration of disulfiram. In certain embodiments, the second therapeutically effective amount of copper salt is administered at least one hour before the administration of disulfiram. In certain
  • the administration of the second therapeutically effective amount of copper salt is administered 24 hours to 16 days after the administration of disulfiram. In certain embodiments, the administration of the second therapeutically effective amount of copper salt is administered 14-16 days after the administration of disulfiram.
  • the administration of the second therapeutically effective amount of copper salt is performed by administration of a single oral dosage form configured to temporally stagger release of copper and disulfiram in the patient.
  • the cancer is copper-avid.
  • the copper avidity of the cancer is determined by comparing an amount of 64 Cu present in neoplastic tissue determined by 64 Cu PET imaging to an amount of 64 Cu present in nonneoplastic tissue determined by 64 Cu PET imaging; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue compared to 64 Cu present in non-neoplastic tissue.
  • the copper avidity of the cancer is determined by comparing a baseline amount of 64 Cu present in neoplastic tissue determined by 64 CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of 64 Cu present in neoplastic tissue determined by 64 CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64 Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt.
  • the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; and wherein the cancer is copper avid if there is increased 64 Cu in the tumor compared to a predetermined threshold.
  • the cancer has elevated expression or elevated activity of DNA methyltransferase.
  • the cancer is one in which DNA
  • methyltransferase contributes to disease etiology.
  • the cancer is one in which inhibition of DNA methyltransferase is therapeutically effective.
  • the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
  • GBM glioblastoma multiforme
  • astrocytoma oligodendroglioma
  • the cancer is prostate cancer.
  • the cancer is metastatic prostate cancer.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
  • the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
  • the prostate cancer is CRPC after treatment with chemotherapy.
  • the prostate cancer is chemotherapy-naive mCRPC.
  • the prostate cancer is neuroendocrine prostate cancer (NEPC).
  • the prostate cancer is progressing on other treatments. In certain embodiments, the prostate cancer is progressing on androgen deprivation treatment. In certain embodiments, the androgen deprivation treatment comprises a CYP17 inhibitor. In certain embodiments, the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700, and combinations thereof. In certain embodiments, the CYP17 inhibitor is abiraterone. In certain embodiments, the androgen deprivation treatment comprises an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is aminoglutethimide.
  • the androgen deprivation treatment comprises an androgen receptor inhibitor.
  • the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof.
  • the androgen deprivation treatment is enzalutamide.
  • the androgen deprivation treatment comprises a luteinizing hormone releasing hormone (LHRH) antagonist.
  • the LHRH antagonist is degarelix.
  • the androgen deprivation treatment comprises a LHRH agonist.
  • the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof.
  • the prostate cancer is progressing on first line chemotherapy.
  • the chemotherapy is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estamustine, and combinations thereof.
  • the prostate cancer is progressing after primary tumor surgical removal.
  • the cancer is GBM. In certain embodiments, the cancer is GBM, and wherein the copper salt or disulfiram are administered in combination with temozolomide. In certain embodiments, the cancer is medulloblastoma.
  • the cancer is pancreatic cancer. In certain embodiments, the pancreatic cancer is metastatic. In certain embodiments, the cancer is pancreatic cancer, and wherein the copper salt or disulfiram are administered in combination with gemcitabine and nab-paclitaxel. In certain embodiments, the copper salt or disulfiram are administered in combination with gemcitabine, nab-paclitaxel and 2-0, 3-0 desulfated heparinoid (ODSH).
  • ODSH desulfated heparinoid
  • the cancer is rectal cancer. In certain embodiments, the rectal cancer is locally advanced. In certain embodiments, the cancer is rectal cancer and wherein the copper salt or disulfiram are administered in combination with
  • the cancer is lung cancer.
  • the lung cancer is locally advanced.
  • the cancer is lung cancer and the copper salt or disulfiram are administered in combination with the at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, paclitaxel, an immunomodulator, and combinations thereof.
  • the at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, paclitaxel, an immunomodulator, and combinations thereof.
  • the at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, paclitaxel, an immunomodulator, and combinations thereof.
  • immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
  • the cancer is glioma.
  • the cancer is glioma and wherein the copper salt or disulfiram are administered in combination with at least one additional anti-cancer agent selected from the group consisting of radiation, temozolomide, nitrosourea, an immunomodulator, and combinations thereof.
  • the nitrosourea is bis-chloroethylnitrosourea (BCNU), l-(2-chloroethyl)-3- cyclohexyl-1 -nitrosourea (CCNU), or combinations thereof.
  • the immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
  • the cancer is head and neck cancer. In certain embodiments, the head and neck cancer is locally advanced. In certain embodiments, the cancer is head and neck cancer and wherein the copper salt or disulfiram are administered in combination with at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, carboplatin, 5-fluorouracil, and combinations thereof.
  • the cancer is breast cancer.
  • the breast cancer is metastatic.
  • the breast cancer is triple-negative breast cancer.
  • the copper salt or disulfiram are administered in combination with a second antineoplastic treatment regimen.
  • the second antineoplastic treatment regimen comprises chemotherapy.
  • the second antineoplastic treatment regimen comprises radiation therapy.
  • the second antineoplastic treatment regimen comprises immune therapy.
  • the cancer is a hormone-responsive cancer and the second antineoplastic treatment regimen is a hormone therapy.
  • the hormone-responsive cancer is prostate cancer.
  • the hormone therapy is androgen deprivation therapy.
  • the androgen deprivation therapy comprises orchiectomy.
  • the androgen deprivation therapy comprises a CYP17 inhibitor.
  • the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700, and combinations thereof.
  • the CYP17 inhibitor is abiraterone.
  • the androgen deprivation therapy comprises an aromatase inhibitor.
  • the aromatase inhibitor is aminoglutethimide.
  • the androgen deprivation therapy comprises an androgen receptor inhibitor.
  • the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof.
  • the androgen deprivation therapy is enzalutamide.
  • the androgen deprivation therapy comprises a luteinizing hormone releasing hormone (LHRH) antagonist.
  • the LHRH antagonist is degarelix.
  • the androgen deprivation treatment comprises a LHRH agonist.
  • the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof.
  • the second antineoplastic treatment regimen comprises ODSH.
  • an improved method of treating cancer with disulfiram and copper comprising administering, for at least one treatment cycle, at least one of copper and disulfiram by a parenteral route of administration.
  • the parenteral route of administration is intravenous administration.
  • the copper is administered by intravenous administration.
  • the copper is administered by intravenous administration and the disulfiram is administered orally.
  • the copper is administered by intravenous administration prior to the administration of disulfiram.
  • the disulfiram is administered by intravenous administration.
  • the copper is copper chloride (CuCh).
  • the method further comprises the step of administering a therapeutically effective amount of copper salt by oral administration.
  • the therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
  • the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, meso
  • the cancer is prostate cancer.
  • the cancer is metastatic prostate cancer.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
  • the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
  • the prostate cancer is CRPC after treatment with chemotherapy.
  • the prostate cancer is chemotherapy-naive mCRPC.
  • the prostate cancer is neuroendocrine prostate cancer ( EPC).
  • the prostate cancer is progressing on other treatments. In certain embodiments, wherein the prostate cancer is progressing on androgen deprivation treatment.
  • a method of treating copper-avid cancers comprising determining that a patient's cancer is copper-avid by performing Cu 64 PET imaging on the patient; administering to the patient with a copper-avid cancer a first therapeutically effective amount of copper salt by intravenous administration; and
  • the copper avidity of the cancer is determined by comparing an amount of 64 Cu present in tumors determined by 64 CuPET imaging to an amount of 64 Cu present in non-neoplastic tissue determined by 64 CuPET imaging; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue compared to 64 Cu present in nonneoplastic tissue.
  • copper avidity of the cancer is determined by comparing a baseline amount of 64 Cu present in tumors determined by 64 CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of 64 Cu present in tumors determined by 64 CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64 Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt.
  • the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; and wherein the cancer is copper avid if there is increased Cu in the tumor compared to a predetermined threshold.
  • the methods further comprise the step of determining ceruloplasmin levels in the patient prior to the administration of the first therapeutically effective amount of copper salt, for at least one cycle. In certain embodiments, the methods further comprise the step of determining ceruloplasmin levels after the administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper. In certain embodiments, the ceruloplasmin levels in the patient are used to determine a dose of the first therapeutically effective amount of copper salt.
  • the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh).
  • the methods comprise the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration.
  • the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
  • an amount of 64 Cu within neoplastic tissue is determined to be elevated compared to an amount of 64 Cu within non-neoplastic tissue, additional administrations are performed of the first therapeutically effective amount of copper salt, the therapeutically effective amount of disulfiram, the second therapeutically effective amount of copper salt, or combinations thereof.
  • a dosage is increased of the additional administrations of the first therapeutically effective amount of copper salt, the therapeutically effective amount of disulfiram, the second therapeutically effective amount of copper salt, or combinations thereof.
  • the patient is administered at least one additional chemotherapeutic agent.
  • the patient will be administered a different at least one additional chemotherapeutic agent.
  • the copper-avid cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
  • GBM glioblastoma multiforme
  • astrocytoma astrocytoma
  • the cancer is prostate cancer.
  • the cancer is metastatic prostate cancer.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
  • the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
  • the prostate cancer is CRPC after treatment with chemotherapy.
  • the prostate cancer is chemotherapy-naive mCRPC.
  • the prostate cancer is neuroendocrine prostate cancer ( EPC).
  • the prostate cancer is progressing on other treatments.
  • the prostate cancer is progressing on androgen deprivation treatment.
  • a method of identifying a cancer that will be responsive to split-route treatment with copper and disulfiram comprising performing 64 Cu PET imaging on the patient; and determining that the cancer is copper-avid and thus will be responsive, wherein the split-route treatment regimen comprises
  • the copper avidity of the cancer is determined by comparing an amount of 64 Cu present in neoplastic tissue determined by 64 CuPET imaging to an amount of 64 Cu present in non-neoplastic tissue determined by 64 CuPET imaging; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue compared to 64 Cu present in non-neoplastic tissue.
  • the copper avidity of the cancer is determined by comparing a baseline amount of 64 Cu present in neoplastic tissue determined by 64 CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of Cu present in neoplastic tissue determined by CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64 Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt.
  • the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; wherein the cancer is copper avid if there is increased 64 Cu in the tumor compared to a predetermined threshold.
  • the methods further comprise the step of determining ceruloplasmin levels in the patient prior to the administration of the first therapeutically effective amount of copper salt, for at least one cycle. In certain embodiments, the methods further comprise the step of determining ceruloplasmin levels after the administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper. In certain embodiments, the ceruloplasmin levels are used to determine a dose of the first therapeutically effective amount of copper salt.
  • the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh).
  • the treatment regimen further comprises the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration.
  • the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
  • the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
  • GBM glioblastoma multiforme
  • astrocytoma oligodendroglioma
  • the cancer is prostate cancer.
  • the cancer is metastatic prostate cancer.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
  • the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
  • the prostate cancer is CRPC after treatment with chemotherapy.
  • the prostate cancer is chemotherapy-naive mCRPC.
  • the prostate cancer is neuroendocrine prostate cancer ( EPC).
  • the prostate cancer is progressing on other treatments.
  • the prostate cancer is progressing on androgen deprivation treatment.
  • a method of treating prostate cancer comprising, administering to a patient a first therapeutically effective amount of CuCh by intravenous administration; administering to a patient a therapeutically effective amount of disulfiram by oral administration; and administering to a patient a second therapeutically effective amount of copper gluconate by oral administration; wherein the administration of the first therapeutically effective amount of CuCh by intravenous administration is performed prior to the administration of disulfiram; wherein the DSF is administered at a dose of 80 mg, TDD; wherein the second therapeutically effective amount of copper gluconate is
  • Figure 1 schematizes the clinical trial protocol for treatment of metastatic prostate cancer comprising split-route administration of copper salt and disulfiram.
  • Disulfiram forms complexes with metals, such as copper; the dithiocarbamate metal complexes have been shown to be effective in vitro and in animal models to inhibit cancer cell growth and/or survival. Described herein are methods for the administration of disulfiram (DSF) and copper for the treatment of cancer. Also disclosed herein are methods for the identification of patients with cancer that will be responsive to disulfiram and copper treatment.
  • DSF disulfiram
  • copper for the treatment of cancer.
  • methods for the identification of patients with cancer that will be responsive to disulfiram and copper treatment.
  • copper refers to copper in either the elemental form or in the form of a copper salt (e.g., copper chloride, copper gluconate or copper glycinate).
  • a copper salt e.g., copper chloride, copper gluconate or copper glycinate
  • mg Cu or “mg copper”, refers to the mass of elemental copper in the form of copper chloride, copper gluconate or copper glycinate.
  • Copper avidity of a cancer or “copper-avid cancer” refers to a cancer, tumor or neoplastic tissue that exhibits increased content of copper upon administration of copper compared to (i) non-neoplastic tissues or (ii) a baseline value, wherein the baseline value is determined prior to administration of copper or compared to a pre-determined value determined from historical data or control samples.
  • Ceuloplasmin levels refers to an amount of ceruloplasmin protein in a sample of plasma.
  • DSF disulfiram, bis(diethylthiocarbamoyl) disulfide or tetraethylthiuram disulfide.
  • DSF copper complex refers to a copper 1, 1-dithiolato complex.
  • Performing 64 Cu PET imaging refers to administering compositions comprising radioactive 64 Cu isotopes to a patient by intravenous injection of the composition comprising 64 Cu, followed by whole body PET/CT imaging at one or more time points after the administration of the 64 Cu.
  • Split-route treatment refers to administering at least two of a plurality of therapeutic agents by different routes of administration (e.g., oral and intravenous administration).
  • Effective amount or “therapeutically effective amount” or “sufficient amount” refers to an amount sufficient to produce a desired effect, e.g., an amount sufficient to reduce tumor burden or reduce disease or stabilize disease or reduce disease symptoms in a subject or an amount that is effective to ameliorate a symptom of a disease.
  • Treating cancer specifically refers to administering therapeutic agents to a patient diagnosed with cancer, i.e., having established cancer in the patient, to inhibit the further growth or spread of the malignant cells in the cancerous tissue and/or to cause the death of malignant cells, or a patient in whom a cancer has been previously treated with potentially curative surgery, radiation, or other treatments and in whom the goal of treatment is to reduce the risk of cancer recurrence, or a patient at known high risk of developing a new cancer for whom the goal is cancer prevention.
  • Cancer that is responsive to treatment or “responsiveness of a cancer to treatment” refers to cancers or neoplastic tissue that, following treatment with an anti-cancer agent, exhibits reduced growth, reduced size, reduced mass, and/or reduced cancer cell proliferation, or that following treatment, results in increased progression free survival or over survival in a patient with the cancer.
  • Preventing cancer refers to administering to a subject with a therapeutic agent for the purpose of inhibiting the onset of cancer or for the purpose of preventing the recurrence of cancer in a patient previously diagnosed with cancer.
  • the subject may be a patient that has been determined to have a higher than average probability of developing cancer than individuals of similar age.
  • the subject may have undergone any diagnostic procedure known in the art for determining the probability of developing cancer.
  • the subject may have undergone prior cancer treatment. For example, the subject may have undergone cancer treatment with an anti-cancer agent, surgery or combinations thereof.
  • Anti-cancer agent refers to any agent or therapeutic used in the art for the treatment of cancer and/or cancer-related conditions.
  • anti-cancer agents include, but are not limited to, radiation, chemotherapeutics such as, but not limited to:
  • platinum compounds ⁇ e.g., cisplatin or carboplatin
  • alkylating agents ⁇ e.g., temozolomide
  • antitumor antibiotics taxanes ⁇ e.g., paclitaxel
  • antimetabolites nucleoside analogues ⁇ e.g., 5-fluorouracil and capecitabine
  • topoisomerase inhibitors hypomethylating agents
  • proteasome inhibitors epipodophyllotoxins
  • DNA synthesis inhibitors vinca alkaloids
  • targeted cancer therapeutics such as but not limited to, tyrosine kinase inhibitors, monoclonal antibodies, nitrosoureas (e.g., bis-chloroethylnitrosourea or l-(2-chloroethyl)-3-cyclohexyl-l- nitrosourea) , enzymes, biological agents ⁇ e.g., interferons and interleukins), hexamethylmelamine,
  • Temozolomide-resistant glioblastoma or "glioblastoma that is temozolomide- resistant” as used herein refer interchangeably to primary or secondary glioblastoma, astrocytoma or oligodendroglioma in which the subject harboring the cancer has completed a course of temozolomide treatment (either with or without concurrent radiation therapy) and has pathological verification of recurrent tumors.
  • Temporal staggered release or “staggered release” refers to the onset of release of one or more agents after or prior to the onset of release of another agent in a pharmaceutical composition.
  • DSF refers to disulfiram.
  • TID refers to administration of a pharmaceutical agent thrice or three times daily
  • IV refers to intravenous administration of a pharmaceutical agent
  • PET refers to positron emission tomography
  • CRPC refers to castration resistant prostate cancer
  • EPC refers to neuroendocrine prostate cancer
  • ADV refers to androgen deprivation therapy
  • LHRH refers to luteinizing hormone releasing hormone.
  • methods of treating hyperproliferative disorders such as cancer
  • the methods comprise administering to a subject with cancer, a hyperproliferative disorder or other condition, or administering to a subject suspected of having a high probability of developing cancer, a hyperproliferative disorder or other condition, an effective amount of DSF and an effective amount of copper on a dosage schedule wherein at least one of DSF and copper is administered by a parenteral route of administration.
  • the methods comprise administering an effective amount of an oral dosage form comprising DSF preceded by or followed by intravenous administration an effective amount of copper.
  • the methods comprise administering an effective amount of an oral dosage form comprising DSF preceded by intravenous administration an effective amount of copper. In certain currently preferred embodiments, the methods comprise administering an effective amount of an oral dosage form comprising DSF preceded by intravenous administration an effective amount of copper and followed by oral administration of an effective amount of copper. In certain embodiments, the copper oral dosage form is administered not less than one hour before the administration of the DSF oral dosage form. In certain embodiments, the copper oral dosage form is administered not less than one hour after the administration of the DSF oral dosage form.
  • a therapeutically effective amount of DSF is administered.
  • the therapeutically effective amount of DSF is 0.01- 0.1 mg, 0.1-1 mg, 1.0-10.0 mg, 10.0-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-150 mg, 150-200 mg, 200-300 mg, 300- 400 mg, 400-500 mg or 500-1,000 mg.
  • the therapeutically effective amount of DSF administered is 40 mg.
  • the therapeutically effective amount of DSF administered is 80 mg.
  • the therapeutically effective amount of DSF administered is 40 mg, thrice daily (TID), wherein the total therapeutically effective amount of DSF administered per day is 120 mg.
  • TID thrice daily
  • therapeutically effective amount of DSF administered is 80 mg, thrice daily (TID); wherein the total therapeutically effective amount of DSF administered per day is 240 mg.
  • a therapeutically effective amount of copper is administered by split-route treatment for at least one cycle.
  • the split route treatment comprises administration of copper by two distinct routes of administration.
  • the copper is in the form of copper chloride (CuCh), copper gluconate, copper sulfate or copper glycinate.
  • the copper is in the form of CuCh or copper gluconate.
  • the split-route treatment comprises administration of a first therapeutically effective amount of copper intravenously followed by administration of a second
  • the split-route treatment comprises administration of first therapeutically effective amount of CuCh intravenously followed by administration of a second therapeutically effective amount of copper gluconate orally. In certain embodiments, the split-route treatment comprises administration of a first therapeutically effective amount of copper orally followed by administration of a second therapeutically effective amount of copper intravenously. In certain embodiments, the split-route treatment comprises the administration of CuCh intravenously followed by administration of copper gluconate orally 24 hours-28 days after intravenous administration of CuCh. In certain embodiments, the split-route treatment comprises the administration of CuCh intravenously followed by administration of copper gluconate orally 14-16 days after intravenous administration of CuCh.
  • the split-route treatment of copper comprises intravenous administration of a first therapeutically effective amount of CuCh by one or more bolus injections, followed by oral administration of a second therapeutically effective amount of copper gluconate or gycinate.
  • the first therapeutically effective amount of CuCh is 0.1 mg- 30 mg CuCh. In certain embodiments, the first therapeutically effective amount of CuCh is 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 30 mg CuCh.
  • the second therapeutically effective amount of copper is 0.1 mg-30 mg copper gluconate or copper glycinate. In certain embodiments, the second therapeutically effective amount of copper is 0.01-0.1 mg, 0.1-1 mg, 1.0-10.0 mg, 10.0-20 mg, 20-30 mg, 30 ⁇ 0 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg or 90-100 mg copper gluconate or copper glycinate. In certain embodiments, a second therapeutically effective amount of copper gluconate is administered orally.
  • the second therapeutically effective amount of copper is 0.01-0.1 mg, 0.1-1 mg, 1.0-10.0 mg, 10.0-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg and 90-100 mg copper gluconate.
  • the therapeutically effective amount of copper gluconate is 0.1 mg-30 mg.
  • the second therapeutically effective amount of copper gluconate is 0.5 mg-5 mg. In an embodiment, the second therapeutically effective amount of copper gluconate is 1.5 mg. In an embodiment, the second therapeutically effective amount of copper gluconate is 4.5 mg.
  • the DSF is administered orally once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly or monthly.
  • the copper is administered orally once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly or monthly.
  • the copper gluconate is administered orally once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly, bi-weekly or monthly.
  • the DSF and copper are orally administered
  • the DSF and copper gluconate are orally administered simultaneously once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly, bi-weekly or monthly.
  • the copper and DSF are administered for at least one cycle; wherein a cycle is anywhere from one week to 12 weeks in duration.
  • the copper and DSF are administered for at least one cycle, wherein each cycle is 28 days in duration.
  • copper is administered intravenously weekly on day one
  • DSF is administered daily beginning on day 2 of a 28 days cycle.
  • copper is administered intravenously weekly on day one; DSF is administered TID beginning on day 2, and copper gluconate is administered TID beginning on day 16 of a 28 days cycle.
  • DSF and/or copper are administered without food or administered to a fasting patient. In some embodiments, DSF and/or copper are administered in the fasting state. In some embodiments, DSF and/or copper are administered with food or shortly after the subject has eaten a meal, or within 1 hour before or after the subject ingests food. In certain embodiments, the oral dosage forms comprising DSF and/or copper are administered without food or when the subject has an empty stomach, or greater than 2 hours after the subject has ingested food.
  • the methods include administering to the patient a therapeutically effective amount of DSF and an intracellular copper ion stimulant, which can enhance the intracellular level of the above described heavy metal ions in the patient.
  • Intracellular heavy metal ion carriers are known.
  • ceruloplasmin can be administered to the patient to enhance the intracellular copper level.
  • Other copper ion carriers known in the art may also be used.
  • copper and/or DSF can be used in combination with an additional conventional anti-cancer therapy.
  • the method can be complemented by a conventional radiation therapy or chemotherapy.
  • the method comprises administering to a patient DSF and copper and an additional anti-cancer agent.
  • the additional anti-cancer agent may be administered prior to, concurrently or after administration of the DSF and copper.
  • a "target" cell is contacted with one or more compositions described herein.
  • at least one additional agent can be administered in combination with disulfiram and/or copper.
  • the additional agent is an anti-cancer agent.
  • anti-cancer agents include, but are not limited to, radiation, platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine ), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, dactinomycin), taxanes (e.g., paclitaxel, « ⁇ -paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, flox
  • immunotheapeutics e.g., PD1 antagonists, PDL-1 antagonists, or any combination thereof.
  • the methods described herein improve the efficacy of chemotherapy and radiotherapy.
  • One approach involves administration of DSF and copper by the methods described herein in combination with use of chemo or therapeutic or radiotherapeutic intervention.
  • This treatment option may offer a synergistic therapeutic effect along with the disulfiram and copper complex.
  • any of the treatments with DSF and/or copper compositions or dosage forms may precede or follow the other agent treatment by intervals ranging from minutes to weeks.
  • the other agent and any of the DSF and/or copper may precede or follow the other agent treatment by intervals ranging from minutes to weeks.
  • compositions or dosage forms described herein are applied separately to the cell, a significant period of time should not expire between the time of each delivery, such that the agent and DSF copper complex would still be able to exert an advantageously combined (e.g., synergistic) effect on the cell.
  • the cell can be contacted with both the other agent, DSF and copper within about 12-24 h, or from about 6-12 h of each other, with a delay time of up to about 12 h.
  • the methods described herein can be combined with therapies that induce DNA damage when applied to a cell.
  • Such therapies include radiation such as, for example, y-irradiation, X-ray, UV-irradiation, microwave, electronic emissions, and the like.
  • the method described in the application result in reduced tumor burden, increased overall survival, increased progression-free survival and/or decreased disease symptoms in the patient.
  • the present application describes effective methods for treating or preventing various types of hyperproliferative conditions and cancers of adults and children, including but not limited to: prostate cancer, glioblastoma (glioblastoma, astrocytoma or oligodendroglioma), medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
  • glioblastoma glioblast
  • the present application describes effective methods for treating primary malignant brain tumors, such as, but not limited to, malignant glioma.
  • the present invention is effective in treating prostate cancer, glioblastoma, medulloblastoma, rectal cancer, pancreatic cancer, head and neck cancer, lung cancer, and triple-negative breast cancer.
  • the methods are used for the treatment of prostate cancer.
  • the cancer is metastatic prostate cancer.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
  • the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
  • the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
  • the prostate cancer is CRPC after treatment with chemotherapy.
  • the prostate cancer is chemotherapy-naive mCRPC.
  • the prostate cancer is neuroendocrine prostate cancer ( EPC).
  • the prostate cancer is progressing on other treatments. In certain embodiments, the prostate cancer is progressing on androgen deprivation treatment. In certain embodiments, the androgen deprivation treatment comprises a CYP17 inhibitor. In certain embodiments, the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700, and combinations thereof. In certain embodiments, the CYP17 inhibitor is abiraterone. In certain embodiments, the androgen deprivation treatment comprises an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is aminoglutethimide.
  • the androgen deprivation treatment comprises an androgen receptor inhibitor.
  • the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof.
  • the androgen deprivation treatment is enzalutamide.
  • the androgen deprivation treatment comprises a luteinizing hormone releasing hormone (LHRH) antagonist.
  • the LHRH antagonist is degarelix.
  • the androgen deprivation treatment comprises a LHRH agonist.
  • the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof.
  • the prostate cancer is progressing on first line chemotherapy.
  • the chemotherapy is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estamustine, and combinations thereof.
  • the prostate cancer is progressing after primary tumor surgical removal.
  • the methods of the application are used for the treatment of primary malignant brain tumors. In certain embodiments, the methods are used for the treatment of glioblastoma. In certain embodiments, the methods are used for the treatment of temozolomide-resistant glioblastoma. In certain embodiments, the methods of the application are used for the treatment of malignant glioma. In certain embodiments, the methods of the application are used for the treatment of pancreatic cancer. In certain embodiments, the methods of the application are used for the treatment of rectal cancer. In certain
  • the methods of the application are used for the treatment of head and neck cancer. In certain embodiments, the methods of the application are used for the treatment of lung cancer. In certain embodiments, the methods of the application are used for the treatment of metastatic pancreatic cancer. In certain embodiments, the methods of the application are used for the treatment of inflammatory breast cancer. In certain
  • the methods of the application are used for the treatment of Her2 positive breast cancer. In certain embodiments, the methods of the application are used for the treatment of castration-resistant prostate cancer. In certain embodiments, the methods of the application are used for the treatment of acute myelogenous leukemia (AML). In certain embodiments, the methods of the application are used for the treatment of acute
  • the methods of the application are used for the treatment of esophageal cancer. In certain embodiments, the methods of the application are used for the treatment of mesothelioma.
  • the cancer is recurrent cancer that has failed one or more prior anti-cancer treatments. In certain embodiments, the subject has unresectable brain metastases. In certain embodiments, the subject has not yet undergone a prior anti-cancer treatment. In certain embodiments, the cancer is a pediatric cancer.
  • the cancer is a pediatric brain tumor including, but not limited to, glioma, medulloblastoma, pituitary adenoma, atypical teratoid or rhabdoid tumor or ependymoma.
  • DSF and copper are administered with temozolomide for the treatment of glioblastoma.
  • DSF and copper are administered with Paclitaxel for the treatment of breast cancer, including triple-negative breast cancer.
  • DSF and copper are administered with a chemotherapeutic and/or targeted anti-cancer agent for the treatment of cancer, including, but not limited to, prostate cancer, glioblastoma, pancreatic cancer, rectal cancer, colon cancer, head and neck cancer, kidney cancer, bladder cancer, lung cancer, meduloblastoma and breast cancer.
  • a chemotherapeutic and/or targeted anti-cancer agent for the treatment of cancer including, but not limited to, prostate cancer, glioblastoma, pancreatic cancer, rectal cancer, colon cancer, head and neck cancer, kidney cancer, bladder cancer, lung cancer, meduloblastoma and breast cancer.
  • the methods of the application are used for the treatment of rectal cancer.
  • described herein are methods of treating rectal cancer, comprising administering to a patient with locally advanced rectal cancer a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF.
  • 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF.
  • a second therapeutically effective amount of copper is administered orally.
  • the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper.
  • at least one anti-cancer agent is selected from the group consisting of, 5-fluorouracil, capecitabine, radiation, and combinations thereof.
  • the methods of the application are used for the treatment of head and neck cancer.
  • described herein are methods of treating head and neck cancer, comprising administering to a patient with locally advanced head and neck cancer a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF.
  • 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF.
  • a second therapeutically effective amount of copper is administered orally.
  • the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper.
  • at least one anti-cancer agent is selected from the group consisting of radiation, cisplatin, carboplatin, 5-fluorouracil, and combinations thereof.
  • the methods of the application are used for the treatment of lung cancer.
  • described herein are methods of treating lung cancer, comprising administering to a patient with locally advanced lung cancer a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF.
  • 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF.
  • a second therapeutically effective amount of copper is administered orally.
  • the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper.
  • the at least one additional anti-cancer agent is selected from the group consisting of radiation, cisplatin, paclitaxel, immunotherapy, PD-1 antagonists, PDL-1 antagonists, and combinations thereof.
  • the methods of the application are used for the treatment of primary malignant brain tumors.
  • described herein are methods of treating malignant glioma or other primary malignant brain tumors, comprising administering to a patient with malignant glioma a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF.
  • 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF.
  • a second therapeutically effective amount of copper is administered orally.
  • the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper.
  • the at least one additional anti-cancer agent is selected from the group consisting of radiation, temozolomide, a nitrosourea including, an immunomodulator, and combinations thereof.
  • the nitrosourea is bis- chloroethylnitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l -nitrosourea (CCNU), or combinations thereof.
  • the immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
  • the methods of the application are used for the treatment of pancreatic cancer.
  • the methods of pancreatic cancer comprise administering to a patient with malignant glioma a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF.
  • 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF.
  • DSF and copper are administered in combination with Na ⁇ -paclitaxel and gemcitabine for the treatment of metastatic pancreatic cancer.
  • DSF and copper are administered in combination with ⁇ -paclitaxel and gemcitabine for the treatment of metastatic pancreatic cancer in patients that have previously received combination chemotherapy comprising 5-Fluorouracil, leucovorin, irinotecan and oxaliplatin.
  • methods of treating disorders or conditions that would benefit from the treatment of DSF and copper are presented.
  • the condition is an infection.
  • the methods described herein comprise administering DSF and copper for the treatment of tuberculosis.
  • the methods described herein comprise administering DSF and copper for the treatment of leishmaniasis.
  • the present application provides methods of treating cancer wherein copper and disulfiram are administered to a patient with cancer in pharmaceutical compositions.
  • Disulfiram has been used clinically in the treatment of alcohol abuse, in which disulfiram inhibits hepatic aldehyde dehydrogenase. Disulfiram has the following formula.
  • Rl , R2 , R3 , and R4 are all ethyl.
  • the thiolate anion derivative of disulfiram is diethyldithiocarbamate anion, the sodium salt of which has the following formula:
  • Copper 1, 1- dithiolato complex The copper complex of diethyldithiocarbamate is shown below as Copper 1, 1- dithiolato complex, in the following formula:
  • the DSF copper complex refers to the Copper 1,1-dithiolato complex.
  • Copper ions can be administered separately as an aqueous solution in a
  • copper ions are administered separately to form a chelate after ingestion in which the ions are complexed with thiuram disulfide compounds.
  • the amount of copper to be used advantageously is proportional to the amount of thiuram disulfide compound to be administered based on the molar ratio between a copper and thiuram disulfide compound in the chelate.
  • oral dosage forms are presented that comprise
  • the oral dosage forms used in the methods described herein may comprise disulfiram without copper, copper without disulfiram, or disulfiram and copper.
  • the copper can be in the form of, but is not limited to, copper gluconate. In certain embodiments, the copper is in the form of copper gluconate. In certain aspects, the oral dosage forms comprise DSF and copper gluconate.
  • oral dosage forms can comprise, in addition to disulfiram and/or copper, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on, for example, the dosage of active DSF copper complex needed for effective treatment, timing and location of release of the DSF and/or copper, solubility and stability of DSF, copper and/or DSF copper complex, dosages of DSF and copper required for formation of the DSF copper complex, absorption characteristics of the DSF, copper and/or DSF copper complex.
  • the oral dosage forms described herein can be tablet, capsule, powder or liquid forms.
  • a tablet can include a solid carrier such as gelatin or an adjuvant.
  • Liquid dosage forms generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.
  • the DSF and/or copper can be delivered orally in enclosed gelatin capsules (e.g., hard gelatin or soft gelatin) or compressed tablets.
  • Capsules and tablets can be prepared using any conventional techniques.
  • the active compounds can be incorporated into a formulation which includes pharmaceutically acceptable carriers, such as excipients (e.g., starch, lactose), binders (e.g., gelatin, cellulose, gum), disintegrating agents (e.g.,
  • croscarmellose sodium, crospovidone, alginate, Primogel, and corn starch e.g., lubricants (e.g., magnesium stearate, silicon dioxide), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint).
  • Possible excipients include those that have been previously used in FDA-approved products such as, microcrystalline cellulose (MCC), and lactose anhydrous, as fillers; croscarmellose sodium, and crospovidone as disintegrants; colloidal silicon dioxide as glidant; magnesium stearate and talc as lubricants and anti -adherents.
  • Suitable excipients include, colloidal silicon dioxide, anhydrous lactose, sodium starch glycolate, and stearic acid.
  • Various coatings can also be prepared for the capsules and tablets to modify the flavors, tastes, colors, and shapes of the capsules and tablets.
  • liquid carriers such as fatty oil can also be included in capsules.
  • enteric-coated capsules that are impervious to stomach acid but dissolve in the alkaline environment of the intestines or colon, in order to prevent release of carbon disulfide from dithiocarbamates in the acid environment of the stomach, and to preserve the integrity of the DSF.
  • the compounds for administration of copper, it is desirable to administer the compounds as enteric-coated capsules that are impervious to stomach acid but dissolve in the alkaline environment of the intestines or colon.
  • oral formulations such as chewing gum, suspension, syrup, wafer, elixir, and the like can also be prepared containing the active compounds used in this invention.
  • Various modifying agents for flavors, tastes, colors, and shapes of the special forms can also be included.
  • the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle, such as olive oil, corn oil, and safflower oil.
  • the DSF and/or copper are administered in combination with other therapeutic agents that treat or prevent another disease or symptom in the subject treated.
  • other therapeutic agents should not interfere with or adversely affect the effects of the active compounds of this invention on the cancer being treated.
  • Such other therapeutic agents include, but are not limited to, anticancer agents, antiviral agents, antibiotics, antifungal agents, anti-inflammation agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, hypertension drugs, and the like.
  • anti-cancer agents include, but are not limited to, radiation, platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine ), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, dactinomycin), taxanes (e.g., paclitaxel, « ⁇ -paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguan
  • Additional anti-cancer agents include, but are not limited to, prednisone, docetaxel, cabazitaxel, mitoxantrone, estamustine, bicalutamide, etoposide, doxorubicin, ixabepilone, satraplatin, cisplatin, carboplatin, picoplatin, oxaliplatin, paclitaxel, tesetaxel, gemcitabine, cytarabine; carmustine, sorafenib, temsirolimus, revlimid, custirsen, orteronel, temsirolimus, everolimus, patupilone, phenoxodiol, vorinostat, orteronel, enzastaurin, tasquinimod, triapine, arsenic trioxide, sabarubicin, perifosine, selinexor, suramin, fenreti
  • the additional anti-cancer agent is a heparinoid.
  • the heparinoid is a PF-4-interacting heparinoid.
  • the heparinoid is substantially desulfated at the 2-0 and/or 3-0 position (ODSH).
  • the cancer is a hormone responsive cancer and the anticancer agent is a hormonal agent.
  • the hormonal agent is an androgen deprivation agent for the treatment of prostate cancer.
  • hormonal agents include, but are not limited to, a CYP17 inhibitor (e.g., abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700), aromatase inhibitor (e.g., aminoglutethimide), an androgen receptor inhibitor (e.g., enzalutamide, flutamide, bicalutamide, nilutamide), a luteinizing hormone releasing hormone (LHRH) antagonist (e.g., degarelix), and a LHRH agonist (e.g., leuprolide, goserelin, triptorelin, histrelin).
  • LHRH luteinizing hormone releasing hormone
  • compositions containing copper described herein comprise a therapeutically effective amount of copper salt. In certain embodiments, pharmaceutical compositions containing copper described herein are configured for parenteral or oral administration of copper. [00106] In certain embodiments, the pharmaceutical composition containing copper is configured for intravenous administration of copper salt. In certain embodiments, the pharmaceutical composition containing copper are configured for intravenous administration of copper chloride (CuCh).
  • CuCh copper chloride
  • dosage forms for intravenous administration can comprise, in addition to copper, one or more pharmaceutically acceptable excipients, carrier, buffers, stabilizers or other materials well known to those skilled in the art.
  • the dosage forms containing copper for intravenous administration are configured for administration as one or more bolus injections.
  • the dosage form for bolus injection contains 0.1 mg-30 mg copper chloride.
  • the dosage form for bolus injection contain 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 gm, 9 gm, 10 mg, 15 mg, 20 mg, 30 mg copper chloride.
  • the dosage forms containing copper for intravenous administration are configured for administration as a continuous infusion.
  • the pharmaceutical composition containing copper is configured for oral administration of copper salt. In certain embodiments, the pharmaceutical composition containing copper is an oral dosage form for administration of copper gluconate or copper glycinate.
  • compositions comprising copper can be formulated as pharmaceutical dosage forms for oral administration.
  • These oral dosage forms can comprise, in addition to copper, one or more pharmaceutically acceptable excipients, carrier, buffers, stabilizers or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on, for example, the dosage of copper needed for effective treatment, timing and location of release of the copper, solubility and stability of copper, dosages of copper, and/or absorption characteristics of the copper.
  • the one or more excipients are colloidal silicon dioxide, anhydrous lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, stearic acid, anhydrous lactose, sodium croscarmellose, crospovidone, colloidal silicon dioxide, magnesium stearate, talc, or combinations thereof.
  • each of the copper oral dosage forms contain 0.1 mg copper, 0.2 mg copper, 0.25 mg copper, 0.3 mg copper, 0.4 mg copper, 0.5 mg copper, 0.75 mg copper, 1 mg copper, 1.5 mg copper, 2 mg copper, 2.5 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg copper.
  • the copper can also be delivered orally in enclosed gelatin capsules (e.g., hard gelatin or soft gelatin) or compressed tablets.
  • Capsules and tablets can be prepared using any conventional techniques.
  • Various coatings can also be prepared for the capsules and tablets to modify the flavors, tastes, colors, and shapes of the capsules and tablets.
  • liquid carriers such as fatty oil can also be included in capsules.
  • the oral dosage form is a tablet containing copper.
  • the oral dosage form containing copper is a capsule containing one or more copper tablets.
  • the capsule contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more copper tablets.
  • the oral dosage forms containing copper can be configured for controlled release or protection including microcapsules and nanocapsules generally known in the art, and hydrogels described above can all be utilized in oral administration of the copper.
  • the oral dosage forms containing copper are coated external to the dosage form with a coating.
  • the coating is a pH-sensitive or a pH-insensitive coating.
  • Another preferable delivery form comprises liposomes as carriers. Liposomes are micelles formed from various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. The copper can be enclosed within such micelles.
  • the copper is formulated to be released immediately upon ingestion. In certain embodiments, the copper is formulated to be released between 1 min and 5 min, 5 min and 30 min, 30 min and 45 min, 45 min and 1 h, 1 h and 2 h, 2h and 3 h, 1 h and 3 h, 1 h and 4 h, 1 h and 5 h, 2 h and 4 h, 2 h and 5 h, or 3h and 8 h after ingestion.
  • compositions containing DSF 4.4.2.
  • compositions containing disulfiram of the invention include a therapeutically effective amount of DSF.
  • the pharmaceutical compositions containing disulfiram of the invention include a therapeutically effective amount of DSF.
  • compositions containing disulfiram are configured for oral or parenteral administration of DSF.
  • the pharmaceutical compositions containing disulfiram are an oral dosage form.
  • the pharmaceutical composition containing DSF is for parenteral administration of DSF.
  • the pharmaceutical composition containing DSF is configured for intravenous administration of DSF.
  • compositions comprising DSF can be formulated in pharmaceutical dosage forms for oral administration.
  • oral dosage forms can comprise, in addition to DSF, one or more pharmaceutically acceptable excipients, carriers, buffers, stabilizers or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on, for example, the dosage of active DSF needed for effective treatment, the timing and location of release of the DSF and/or DSF copper complex, the solubility and stability of DSF and/or DSF copper complex, the dosages of DSF, and the absorption characteristics of the DSF and/or DSF copper complex.
  • the one or more excipients are colloidal silicon dioxide, anhydrous lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, stearic acid, anhydrous lactose, sodium croscarmellose, crospovidone, colloidal silicon dioxide, magnesium stearate, talc, or combinations thereof.
  • the oral dosage form containing DSF contains 20 mg
  • DSF 30 mg DSF, 40 mg DSF, 50 mg DSF, 60 mg DSF, 70 mg DSF, 80 mg DSF, 90 mg DSF, 100 mg DSF, or 120 mg DSF.
  • the DSF can be delivered orally in enclosed gelatin capsules (e.g., hard gelatin or soft gelatin) or compressed tablets.
  • Capsules and tablets can be prepared using any conventional techniques.
  • Various coatings can also be prepared for the capsules and tablets to modify the flavors, tastes, colors, and shapes of the capsules and tablets.
  • liquid carriers such as fatty oil can also be included in capsules.
  • the oral dosage form is a tablet containing DSF.
  • the oral dosage form containing DSF is a capsule containing one or more DSF tablets.
  • the capsule contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more DSF tablets.
  • the DSF can also be conjugated, i.e., covalently linked, to a water soluble non-immunogenic high molecular weight polymer to form a polymer conjugate.
  • such polymers e.g., polyethylene glycol
  • the DSF in the conjugate when administered to a patient can have a longer half-life in the body, and exhibit better efficacy.
  • the oral dosage forms containing DSF can be configured for controlled release or protection including microcapsules and nanocapsules generally known in the art, and hydrogels described above can all be utilized in oral administration of the DSF.
  • the oral dosage forms containing DSF are coated external to the dosage form with a coating.
  • the coating is a pH-sensitive or a pH-insensitive coating.
  • Another preferable delivery form comprises liposomes as carriers. Liposomes are micelles formed from various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. The DSF can be enclosed within such micelles.
  • the DSF is formulated to be released immediately upon ingestion. In certain embodiments, the DSF is formulated to be released between 1 min and 5 min, 5 min and 30 min, 30 min and 45 min, 45 min and 1 h, 1 h and 2 h, 2h and 3 h, 1 h and 3 h, 1 h and 4 h, 1 h and 5 h, 2 h and 4 h, 2 h and 5 h, or 3h and 8 h after ingestion.
  • the pharmaceutically useful compounds according to the present invention are administered preferably in a "therapeutically effective amount” or “prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual.
  • a "therapeutically effective amount” or “prophylactically effective amount” as the case can be, although prophylaxis can be considered therapy.
  • prophylaxis can be considered therapy
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of cancer or
  • hyperproliferative disorder being treated Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16 th edition, Osol, A. (ed.), 1980.
  • a pharmaceutical composition or dosage form are administered alone or in combination with other treatments, either simultaneously or sequentially, depending upon the condition to be treated.
  • the methods described herein include methods of identifying a cancer that will be responsive to treatment with copper and disulfiram.
  • the methods for identifying a cancer responsive to treatment comprise performing 64 Cu PET imaging on the patient; and determining that the cancer is copper-avid and thus will be responsive to treatment.
  • 64 Cu PET imaging can be performed prior to and/or following parenteral or oral administration of a copper salt.
  • determination of the copper avidity of a cancer can be performed by comparing an amount of 64 Cu present in neoplastic tissue determined by 64 CuPET imaging to an amount of 64 Cu present in non-neoplastic tissue determined by 64 CuPET imaging; wherein the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue compared to 64 Cu present in non-neoplastic tissue.
  • the copper avidity of the cancer is determined by comparing a baseline amount of 64 Cu present in neoplastic tissue determined by 64 CuPET imaging prior to the
  • the cancer is copper-avid if there is increased 64 Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64 Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt.
  • the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; wherein the cancer is copper avid if there is increased 64 Cu in the tumor compared to a predetermined threshold.
  • 64 Cu PET imaging is performed by administering compositions comprising radioactive 64 Cu isotopes to a patient.
  • the administration is performed by intravenous injection of the composition comprising 64 Cu, followed by whole body PET/CT imaging at one or more time points after the administration of the 64 Cu.
  • the PET imaging is performed at 2-4 hours following the
  • the dose of 64 Cu administered is 1-20 mCi of 64 Cu chloride. In certain embodiments, the dose of 64 Cu administered is 8-12 mCi of 64 Cu chloride. In certain embodiments, the dose of 64 Cu administered is 10 mCi of 64 Cu chloride.
  • non-radioactive nickel and other trace metals are present in the composition comprising 64 Cu for intravenous administration; however, the total maximum mass dose of all metals is 1 microgram or less.
  • whole body PET/CT imaging is performed within 35 days prior to cycle 1 day 1. In certain embodiments, whole body PET/CT imaging is performed within 35 days prior to cycle 1 day 1 and every 3 cycles thereafter.
  • 64 Cu PET imaging is performed during treatment to monitor copper avidity of a cancer and/or cancer responsiveness to treatment with disulfiram and copper.
  • whole body PET/CT imaging is performed.
  • CT scan with contrast of chest, abdomen and pelvis is performed.
  • a CT scan without contrast, Na P 18 PET or MRI may be substituted for the CT scan with contrast.
  • tumor biopsies are taken to identify cancers responsive to treatment with disulfiram and copper and copper levels within the biopsied tumor tissue is assessed and compared to either a baseline value or a pre-determined value from historical data or control tissues from the same patient or other individuals.
  • Tumor biopsies may be performed on primary tumors, metastatic tumor lesions, lymph nodes or any neoplastic tissue.
  • methods of identification of a cancer that will be responsive to treatment with copper and disulfiram comprise determining ceruloplasmin levels in the patient prior to and/or following the administration of a therapeutically effective amount of copper salt.
  • ceruloplasmin levels are compared to a baseline value wherein the baseline value is determined in the patient with the cancer prior to administration of copper or is determined based on a pre-determined value from historical data or control samples from the same patient or other individuals.
  • increased ceruloplasmin levels prior to and/or following administration of copper indicates that a cancer will be responsive to treatment with disulfiram and copper.
  • Copper 0.4 mg/mL (Cupric Chloride Injection, USP) contains 0.4 mg copper/mL and is administered intravenously only after dilution.
  • a total dose of 1 mg of copper chloride (dose level 1) is added to 250 ml of D5W and infused via peripheral intravenous route over approximately 2 hours, lmg is the physiologic dose added to a 24- hour infusion of total parenteral nutrition.
  • 3mg, 5mg, and 7mg of copper chloride is added to 250 mL of D5W and infused peripherally over 2 hours.
  • Subjects are then treated on open-label DSF (80 mg three times a day, starting on cycle 1, day 2).
  • DSF is administered by the subject at a dose of 80 mg three times a day orally in 4-week cycles throughout the treatment period.
  • Subjects are instructed to take the dose of DSF one hour before all three meals, around the same time each day.
  • DSF is taken with approximately 8 ounces of water and consumed over as short a time as possible.
  • the DSF total daily dose is 240 mg.
  • Oral copper gluconate is administered 1.5 mg three times a day, starting cycle
  • Each treatment cycle consists of 28 consecutive days. Subjects commence DSF treatment on cycle 1 day 2. Subjects take DSF until radiographic disease progression and/or unequivocal clinical progression, at which time study treatment is discontinued. If the subject had radiographic progression but no unequivocal clinical progression, and alternate treatment is not initiated, the subject continues on the study treatment at the Investigator's discretion.
  • the first 3 subjects at each dose level of intravenous CuCh will have DSF PKs drawn on cycle 1, day 1.
  • the subjects are administered the first dose of DSF on cycle 1, day 2, followed by PK samples drawn at 2h, 4h, 6h, and 8h after first dose, and then resume DSF for the afternoon dose (only 2 doses for cycle 1, day 2).
  • Subjects then resume TID dosing of DSF on cycle 1, day3. If one of these subjects is unable to complete the PK studies, then that subject is replaced by a subsequent subject treated at the same dose level.
  • Group A EPC
  • Group B EPC
  • adenocarcinoma CRPC with non-liver/peritoneal metastases (lymph nodes, bone, or lung)
  • Group C adenocarcinoma CRPC with liver and/or peritoneal metastases.
  • DLT dose limiting toxicity
  • the second stage allocates eligible subjects based upon a continual reassessment method. Additional subjects are not accrued until a stopping rule is triggered or the minimum required time frame has elapsed. Subjects are followed for a minimum of 28 days from the start of treatment for assessment of DLTs.
  • the initial stage accrues subjects in cohorts of two on each dose level until a subject experiences a DLT.
  • two eligible subjects are entered onto dose level 1 (Table 1).
  • this event triggers the second stage and initiates the continual reassessment method (CRM).
  • each group if both subjects on dose level 1 experience a DLT, then enrollment to the group will be stopped. If 0 subjects experience a DLT, then the next cohort is treated at the next higher dose level. Subject allocation to higher dose levels occurs if the minimum follow-up period has been satisfied and no DLT has been observed. The allocation strategy is followed for accrual to increasing dose levels until a subject experiences a DLT or a stopping rule is triggered. Once a DLT has been observed, the 2 -Stage using CRM modeling begins. In the absence of DLT's, escalation continues until dose level 4 is reached. Subjects continue to be entered on dose level 4 until a DLT occurs or until a stopping rule is triggered.
  • Subjects undergo Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64 Cu injection. Following completion of the first CuCh infusion(s), subjects undergo another 64 Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after 64 Cu injection.
  • the use of copper radionuclides in nuclear medicine has a long established record of patient safety.
  • For the effective dose of 0.0338 mSv/MBq a 10 mCi (370 MBq) administered activity results in an effective dose Of 1.25 rem (12.5 mSv). This is comparable to the effective dose of 8.0 mSv for an oncologic 18F-FDG study, assuming 12 mCi administered and 0.018 mSv/MBq.
  • An optional image-guided lymph node biopsy is performed for subjects who consent to the biopsy, have lymph node disease accessible by core biopsy or locally recurrent tumor accessible by transrectal ultrasound (TRUS) and whose cycle 1 day 2 schedule is permissive of the biopsy. Core biopsies of these lesions are obtained, provided have not been exposed to prior irradiation. In the event that a subject's only accessible tumor tissue for biopsy is in their bone marrow, a CT or MRI- guided bone biopsy may be substituted for the lymph node or TRUS biopsy.
  • TRUS transrectal ultrasound
  • Ceruloplasmin levels are measured at baseline and prior to each IV CuCh infusion in order to determine the concentrations following saturation of plasma binding and to correlate with any unforeseen toxicity. Ceruloplasmin levels following IV CuCh infusion is associated with response to DSF.
  • Serum copper PK is drawn before and 1 hour after infusion of CuCh on cycle
  • Histologic variants of prostate cancer including neuroendocrine features and small cell carcinoma of the prostate are included. If neuroendocrine prostate cancer is not biopsy proven, clinical evidence of neuroendocrine prostate cancer is acceptable for stratification into group A. Subjects have radiographic evidence of metastatic disease. Subjects being treatment with ongoing androgen deprivation therapy (ADT) using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed or screening serum testosterone must be ⁇ 50 ng/dl.
  • ADT ongoing androgen deprivation therapy
  • Subjects exhibit evidence of disease progression on ADT as evidenced by one of the following: 2 consecutive PSA levels 50% or greater above the PSA nadir achieved on ADT and separated at least 1 week apart, or CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to PCWG3 criteria or RECIST 1.1 criteria, or at least 1 new bone scan lesion as compared to the most immediate prior radiologic studies, or absolute rise in PSA of 2.0ng/mL or greater, minimum 2 consecutive rising PSA levels with an interval of > 1 week between each PSA level.
  • Subjects have a minimum of 2 weeks elapsed off of antiandrogen therapy prior to registration (i.e.
  • Subjects have a minimum of 4 weeks from prior chemotherapy, including but not limited to, docetaxel, cabazitaxel, mitoxantrone, carboplatinum, cisplatin, or estramustine; if applicable. Subjects have a minimum of 4 weeks from any major surgery prior to registration.
  • a phase II, multicenter, open-label, single-arm study is performed to confirm the safety, tolerability, and efficacy of a staggered oral dosing regimen of disulfiram and copper gluconate for treatment of recurrent, temozolomide-resistant, glioblastoma.
  • TMZ temozolomide
  • results of the clinical trial demonstrate that a dosing regimen in which disulfiram and copper gluconate are administered on a split-route dosing schedule is capable of resensitizing temozolomide-resistant recurrent glioblastoma to temozolomide.
  • a phase II, open label, randomized study with two study arms is performed to confirm the anti-cancer effect of DSF and copper in combination with gemcitabine and nab- Paclitaxel in patients with metastatic pancreatic cancer.
  • the objectives of the study are to evaluate progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines Version 1.1, to evaluate changes in plasma levels of CA19-9 from baseline as a marker of tumor response, to evaluate the safety and tolerability of gemcitabine + « ⁇ -paclitaxel with or without DSF-Cu in this patient population, to evaluate the objective tumor response according to RECIST guidelines, to evaluate overall survival, and to evaluate changes from baseline for serum albumin and body weight.
  • PFS progression-free survival
  • RECIST Response Evaluation Criteria in Solid Tumors
  • Na ⁇ -paclitaxel + gemcitabine + DSF-CU 25 subjects receive Na ⁇ -paclitaxel + gemcitabine + DSF-CU.
  • Na ⁇ -paclitaxel 125 mg/m 2 is administered by IV over 30 minutes followed by administration of gemcitabine by IV infusion at 1000 mg/m 2 over 30 minutes.
  • Na ⁇ -paclitaxel + gemcitabine is given weekly for 3 weeks followed by one week of rest.
  • day one subjects are administered copper chloride intravenously.
  • Subjects undergo 64 Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64 Cu injection. Following completion of the first CuCh infusion(s), subjects undergo another 64 Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after Cu injection.
  • patients take 80 mg DSF TID with approximately 8 ounces of water at least one hour before food.
  • copper gluconate is taken at a dose of 1.5 mg with meals TID and not within one hour of DSF.
  • Nab-paclitaxel + gemcitabine 25 subjects receive Nab-paclitaxel + gemcitabine.
  • Nab-paclitaxel 125 mg/m2 is administered by IV over 30 minutes followed by administration of gemcitabine by IV infusion at 1000 mg/m 2 over 30 minutes.
  • Na ⁇ -paclitaxel + gemcitabine will be given weekly for 3 weeks followed by one week of rest.
  • FOLFIRINOX regimen Patients may not have received a second line chemotherapy regimen after developing progressive disease or intolerance to the FOLFIRINOX regimen.
  • Patients have one or more metastatic tumors measurable by CT scan.
  • Patients have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
  • Patients are male or non-pregnant and non-lactating female and > 18 to ⁇ 80 years of age.
  • the primary objective is to confirm an antitumor effect of DSF and Copper in combination with chemoradiotherapy as determined by the incidence of pathologic complete response (no evidence of residual cancer) at the time of surgery.
  • Secondary Objectives are to determine evidence of an antitumor effect of DSF and Copper in combination with chemoradiotherapy as determined by: safety of DSF and Copper in combination with chemoradiotherapy as determined by toxicity assessment according to NCI CTCAE V.4.0, tumor down staging, tumor regression, R0 resection rate; negative circumferential resection rate, and rate of sphincter-sparing surgery.
  • Subjects with locally advanced (T3 or T4 or node positive) rectal adenocarcinoma are enrolled into the study and receive chemoradiotherapy consistent with the institutional standard of care. During a run-in period, 10 subjects are enrolled to receive
  • chemoradiotherapy + DSF and Cu to assess compatibility of the combination and then 50 subjects are randomized to an open label, controlled period with two arms at a ratio of 1 : 1 to receive: chemoradiotherapy + DSF and Cu, or chemoradiotherapy without DSF and Cu.
  • data from the 10 subjects enrolled in the study are reviewed by the investigators that enrolled the subjects in the study as well as Cantex management (Dr. Stephen Marcus) to assess the safety of the administration of chemoradiation + DSF-Cu and recommend whether continuation with the Randomized Period of the study is indicated.
  • Treatment A Treatment A
  • Chemoradiotherapy is administered in accordance with the institutional standard of care along with DSF and copper by intravenous and oral administration.
  • day one subjects are administered copper chloride intravenously.
  • Subjects undergo 64 Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64 Cu injection.
  • subjects undergo another 64 Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after 64 Cu injection.
  • patients take 80 mg DSF TID with approximately 8 ounces of water at least one hour before food.
  • copper gluconate is taken at a dose of 1.5 mg with meals TID and not within one hour of DSF.
  • DSF at 80 mg TID and 1.5 mg of Cu TID.
  • the DSF and copper doses are administered sequentially, with each DSF dose administered at least one hour before the administration of copper.
  • Chemoradiotherapy is administered in accordance with the institutional standard of care without DSF and Copper.
  • Patients must have histologically confirmed adenocarcinoma of the rectum with pathologic material reviewed by the Department of Pathology at MDACC.
  • the clinical stage must be T3, T4, or node positive Tl or 2.
  • Patients must have no evidence of metastatic disease.
  • Patient is Male or a non-pregnant and non-lactating female and > 18 to ⁇ 80 years of age.
  • Patient has adequate biological parameters as demonstrated by the following blood counts at Screening (obtained ⁇ 14 days prior to randomization) and at Baseline-Day 0: Absolute neutrophil count (ANC) > 1.5 x 10 9 /L; Platelet count > 100,000/mm 3 (100 ⁇ 10 9 /L);
  • Patient has the following blood chemistry levels at Screening (obtained ⁇ 14 days prior to randomization) and at Baseline-Day 0: AST (SGOT), ALT (SGPT) ⁇ 2.5 x upper limit of normal range (ULN), unless liver metastases are present, then ⁇ 5 x ULN is allowed.
  • Total bilirubin ⁇ 1.5 ⁇ ULN.
  • Patient has ECOG performance status from 0 to 2. Patient has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent Form (ICF) prior to participation in any study-related activities.
  • ICF Informed Consent Form
  • results of the clinical trial demonstrate that an oral dosing regimen in which disulfiram and copper gluconate are administered on a split-route dosing schedule in combination with chemoradiotherapy is capable of increasing progression-free survival in patients with locally advanced rectal cancer.

Abstract

This application relates to methods and compositions for the administration of disulfiram (DSF) and copper salt for the treatment and prevention of medical conditions, such as cancer. DSF and copper form active complexes that have been shown to be effective in the treatment of cancers. Included herein are improved methods for the adminstration of DSF and copper, wherein at least one of DSF or copper are adminstered by a parenteral route of adminstration.

Description

DISULFIRAM AND COPPER SALT DOSING REGIMEN
1. BACKGROUND
[0001] Disulfiram or Bis(diethylthiocarbamyl) disulfide (DSF) is a drug long used for treatment of alcohol abuse. More recently, disulfiram and copper have been shown to form active complexes that are effective in vitro in killing neoplastic cells of various cancers, see, e.g., U.S. Pat. Nos. 6,548,540; 6,589,987; and 7,816,403. In addition, preclinical studies in xenograft models have shown that disulfiram is effective at inhibiting prostate cancer minor growth in mice when administered with copper but not without the co-administration of copper, see Denoyer et al, Oncoiargel; 2016, 7(24): 37064-37080.
[0002] Despite this promise, however, combination therapy with disulfiram and copper has not yet been proven to be effective in human cancer patients. There is a continuing need for methods that allow the preclinical efficacy of combination therapy with disulfiram and copper to be translated into effective human therapies.
2. SUMMARY
[0003] Disclosed herein are methods for the administration of DSF and copper for the treatment of hyperproliferative disorders, including cancer. In a first aspect, the methods comprise administering to a patient with cancer a first therapeutically effective amount of copper salt by intravenous administration; and administering to the patient a therapeutically effective amount of disulfiram by oral administration; wherein the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle. In certain embodiments, the methods further comprise the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration. In certain
embodiments, the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCk).
[0004] In certain embodiments, the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate. In certain embodiments, the first therapeutically effective amount of copper salt is administered as one or more bolus injections. In certain embodiments, the bolus injection is 0.1 mg-30 mg CuCh. In certain embodiments, the bolus injection of CuCh is selected from the group consisting of 1 mg, 3 mg, 5 mg, and 7 mg. In certain embodiments, the first therapeutically effective amount of copper salt is administered as a continuous infusion. In certain embodiments, the first therapeutically effective amount of copper salt is administered as a bolus followed or preceded by a continuous infusion. In certain embodiments, the first therapeutically effective amount of copper salt is administered weekly.
[0005] In certain embodiments, ceruloplasmin levels in the patient are determined prior to administration of the first therapeutically effective amount of copper salt, for at least one cycle. In certain embodiments, ceruloplasmin levels are detected after administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper. In certain embodiments, the ceruloplasmin levels are used to determine a dose of the first therapeutically effective amount of copper salt.
[0006] In certain embodiments, 64Cu PET imaging is performed on the patient. In certain embodiments, 64Cu PET imaging is performed prior to the administration of the first therapeutically effective amount of copper salt. In certain embodiments, 64Cu PET imaging is performed following the administration of the first therapeutically effective amount of copper salt. In certain embodiments, 64Cu PET imaging is performed within 4 hours and at 24 hours after administration of 64Cu. In certain embodiments, increased uptake of 64Cu in neoplastic tissue as compared to one or more non-neoplastic tissues identifies a patient requiring treatment or a patient responsive to treatment.
[0007] In certain embodiments, the first therapeutically effective amount of copper salt is administered 12-48 hours prior to the administration of the disulfiram. In certain
embodiments, the first therapeutically effective amount of copper salt is administered one day prior to the administration of the disulfiram. In certain embodiments, the disulfiram is administered at a total dose of 10 mg-500 mg. In certain embodiments the disulfiram is administered at a total dose of 10 mg-500 mg, TID. In certain embodiments the disulfiram is administered at a total dose of 120 mg TID, wherein each divided dose is 40 mg. In certain embodiments, the disulfiram is administered at a total dose of 240 mg TID, wherein each divided dose is 80 mg. In certain embodiments, the disulfiram is administered without food.
[0008] In certain embodiments, the second therapeutically effective amount of copper salt is copper glycinate. In certain embodiments, the second therapeutically effective amount of copper salt is copper gluconate. In certain embodiments, second therapeutically effective amount of copper salt is administered at a total dose of 0.1 mg-30 mg. In certain
embodiments, the second therapeutically effective amount of copper salt is administered at a total dose of 1.5 mg-5 mg. In certain embodiments, the second therapeutically effective amount of copper salt is administered at a divided dose of 1.5 mg. In certain embodiments, second therapeutically effective amount of copper salt is administered TID. In certain embodiments, the second therapeutically effective amount of copper salt is administered at a divided dose of 0.5 mg-3 mg, TID. In certain embodiments, the second therapeutically effective amount of copper salt is administered at a divided dose of 1.5 mg, TID. In certain embodiments, the second therapeutically effective amount of copper salt is administered not within one hour of disulfiram. In certain embodiments, the second therapeutically effective amount of copper salt is administered at least one hour after the administration of disulfiram. In certain embodiments, the second therapeutically effective amount of copper salt is administered at least one hour before the administration of disulfiram. In certain
embodiments, the administration of the second therapeutically effective amount of copper salt is administered 24 hours to 16 days after the administration of disulfiram. In certain embodiments, the administration of the second therapeutically effective amount of copper salt is administered 14-16 days after the administration of disulfiram.
[0009] In certain embodiments, the administration of the second therapeutically effective amount of copper salt is performed by administration of a single oral dosage form configured to temporally stagger release of copper and disulfiram in the patient.
[0010] In certain embodiments, the cancer is copper-avid. In certain embodiments, the copper avidity of the cancer is determined by comparing an amount of 64Cu present in neoplastic tissue determined by 64Cu PET imaging to an amount of 64Cu present in nonneoplastic tissue determined by 64Cu PET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in non-neoplastic tissue. In certain embodiments, the copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt. In certain embodiments , the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; and wherein the cancer is copper avid if there is increased 64Cu in the tumor compared to a predetermined threshold.
[0011] In certain embodiments, the cancer has elevated expression or elevated activity of DNA methyltransferase. In certain embodiments, the cancer is one in which DNA
methyltransferase contributes to disease etiology. In certain embodiments, the cancer is one in which inhibition of DNA methyltransferase is therapeutically effective.
[0012] In certain embodiments, the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
[0013] In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is metastatic prostate cancer. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer is castration resistant prostate cancer (CRPC). In certain embodiments, the prostate cancer is CRPC after treatment with chemotherapy. In certain embodiments, the prostate cancer is chemotherapy-naive mCRPC. In certain embodiments, the prostate cancer is neuroendocrine prostate cancer (NEPC).
[0014] In certain embodiments, the prostate cancer is progressing on other treatments. In certain embodiments, the prostate cancer is progressing on androgen deprivation treatment. In certain embodiments, the androgen deprivation treatment comprises a CYP17 inhibitor. In certain embodiments, the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700, and combinations thereof. In certain embodiments, the CYP17 inhibitor is abiraterone. In certain embodiments, the androgen deprivation treatment comprises an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is aminoglutethimide. In certain embodiments, the androgen deprivation treatment comprises an androgen receptor inhibitor. In certain embodiments, the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof. In certain embodiments, the androgen deprivation treatment is enzalutamide. In certain embodiments, the androgen deprivation treatment comprises a luteinizing hormone releasing hormone (LHRH) antagonist. In certain embodiments, the LHRH antagonist is degarelix. In certain embodiments, the androgen deprivation treatment comprises a LHRH agonist. In certain embodiments, the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof. In certain embodiments, the prostate cancer is progressing on first line chemotherapy. In certain embodiments, the chemotherapy is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estamustine, and combinations thereof. In certain embodiments, the prostate cancer is progressing after primary tumor surgical removal.
[0015] In certain embodiments, the cancer is GBM. In certain embodiments, the cancer is GBM, and wherein the copper salt or disulfiram are administered in combination with temozolomide. In certain embodiments, the cancer is medulloblastoma.
[0016] In certain embodiment, the cancer is pancreatic cancer. In certain embodiments, the pancreatic cancer is metastatic. In certain embodiments, the cancer is pancreatic cancer, and wherein the copper salt or disulfiram are administered in combination with gemcitabine and nab-paclitaxel. In certain embodiments, the copper salt or disulfiram are administered in combination with gemcitabine, nab-paclitaxel and 2-0, 3-0 desulfated heparinoid (ODSH).
[0017] In certain embodiments, the cancer is rectal cancer. In certain embodiments, the rectal cancer is locally advanced. In certain embodiments, the cancer is rectal cancer and wherein the copper salt or disulfiram are administered in combination with
chemoradiotherapy.
[0018] In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is locally advanced. In certain embodiments, the cancer is lung cancer and the copper salt or disulfiram are administered in combination with the at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, paclitaxel, an immunomodulator, and combinations thereof. In certain embodiments, the
immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
[0019] In certain embodiments, the cancer is glioma. In certain embodiments, the cancer is glioma and wherein the copper salt or disulfiram are administered in combination with at least one additional anti-cancer agent selected from the group consisting of radiation, temozolomide, nitrosourea, an immunomodulator, and combinations thereof. In certain embodiments, the nitrosourea is bis-chloroethylnitrosourea (BCNU), l-(2-chloroethyl)-3- cyclohexyl-1 -nitrosourea (CCNU), or combinations thereof. In certain embodiments, the immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
[0020] In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the head and neck cancer is locally advanced. In certain embodiments, the cancer is head and neck cancer and wherein the copper salt or disulfiram are administered in combination with at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, carboplatin, 5-fluorouracil, and combinations thereof.
[0021] In certain embodiments, the cancer is breast cancer. In certain embodiments, the breast cancer is metastatic. In certain embodiments, the breast cancer is triple-negative breast cancer.
[0022] In certain embodiments, the copper salt or disulfiram are administered in combination with a second antineoplastic treatment regimen. In certain embodiments, the second antineoplastic treatment regimen comprises chemotherapy. In certain embodiments, the second antineoplastic treatment regimen comprises radiation therapy. In certain
embodiments, the second antineoplastic treatment regimen comprises immune therapy.
[0023] In certain embodiments, the cancer is a hormone-responsive cancer and the second antineoplastic treatment regimen is a hormone therapy. In certain embodiments, the hormone-responsive cancer is prostate cancer. In certain embodiments, the hormone therapy is androgen deprivation therapy. In certain embodiments, the androgen deprivation therapy comprises orchiectomy. In certain embodiments, the androgen deprivation therapy comprises a CYP17 inhibitor. In certain embodiments, the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700, and combinations thereof. In certain embodiments, the CYP17 inhibitor is abiraterone. In certain embodiments, the androgen deprivation therapy comprises an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is aminoglutethimide. In certain embodiments, the androgen deprivation therapy comprises an androgen receptor inhibitor. In certain embodiments, the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof. In certain embodiments, the androgen deprivation therapy is enzalutamide. In certain embodiments, the androgen deprivation therapy comprises a luteinizing hormone releasing hormone (LHRH) antagonist. In certain embodiments, the LHRH antagonist is degarelix. In certain embodiments, the androgen deprivation treatment comprises a LHRH agonist. In certain embodiments, the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof. In certain embodiments, the second antineoplastic treatment regimen comprises ODSH.
[0024] In a further aspect, described herein is an improved method of treating cancer with disulfiram and copper, the improvement comprising administering, for at least one treatment cycle, at least one of copper and disulfiram by a parenteral route of administration. In certain embodiments, the parenteral route of administration is intravenous administration. In certain embodiments, the copper is administered by intravenous administration. In certain embodiments, the copper is administered by intravenous administration and the disulfiram is administered orally. In certain embodiments, the copper is administered by intravenous administration prior to the administration of disulfiram. In certain embodiments, the disulfiram is administered by intravenous administration. In certain embodiments, the copper is copper chloride (CuCh). In certain embodiments, the method further comprises the step of administering a therapeutically effective amount of copper salt by oral administration. In certain embodiments, the therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate. In certain embodiments, the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
[0025] In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is metastatic prostate cancer. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer is castration resistant prostate cancer (CRPC). In certain embodiments, the prostate cancer is CRPC after treatment with chemotherapy. In certain embodiments, the prostate cancer is chemotherapy-naive mCRPC. In certain embodiments, the prostate cancer is neuroendocrine prostate cancer ( EPC). In certain embodiments, the prostate cancer is progressing on other treatments. In certain embodiments, wherein the prostate cancer is progressing on androgen deprivation treatment.
[0026] In an aspect, disclosed herein is a method of treating copper-avid cancers, the method comprising determining that a patient's cancer is copper-avid by performing Cu64 PET imaging on the patient; administering to the patient with a copper-avid cancer a first therapeutically effective amount of copper salt by intravenous administration; and
administering to the patient a therapeutically effective amount of disulfiram by oral administration, wherein the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle.
[0027] In certain embodiments, the copper avidity of the cancer is determined by comparing an amount of 64Cu present in tumors determined by 64CuPET imaging to an amount of 64Cu present in non-neoplastic tissue determined by 64CuPET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in nonneoplastic tissue. In certain embodiments, copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in tumors determined by 64CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of 64Cu present in tumors determined by 64CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt. In certain embodiments, the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; and wherein the cancer is copper avid if there is increased Cu in the tumor compared to a predetermined threshold.
[0028] In certain embodiments, the methods further comprise the step of determining ceruloplasmin levels in the patient prior to the administration of the first therapeutically effective amount of copper salt, for at least one cycle. In certain embodiments, the methods further comprise the step of determining ceruloplasmin levels after the administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper. In certain embodiments, the ceruloplasmin levels in the patient are used to determine a dose of the first therapeutically effective amount of copper salt.
[0029] In certain embodiments, the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh). In certain embodiments, the methods comprise the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration. In certain embodiments, the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
[0030] In certain embodiments, if an amount of 64Cu within neoplastic tissue is determined to be elevated compared to an amount of 64Cu within non-neoplastic tissue, additional administrations are performed of the first therapeutically effective amount of copper salt, the therapeutically effective amount of disulfiram, the second therapeutically effective amount of copper salt, or combinations thereof. In certain embodiments, if an amount of 64Cu within neoplastic tissue is determined to be elevated compared to an amount of 64Cu within nonneoplastic tissue, a dosage is increased of the additional administrations of the first therapeutically effective amount of copper salt, the therapeutically effective amount of disulfiram, the second therapeutically effective amount of copper salt, or combinations thereof. In certain embodiments, the patient is administered at least one additional chemotherapeutic agent. In certain embodiments, if an amount of 64Cu within tumor tissues is determined not to be elevated compared to an amount of 64Cu within non-neoplastic tissue, the patient will be administered a different at least one additional chemotherapeutic agent.
[0031] In certain embodiments, the copper-avid cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is metastatic prostate cancer. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer is castration resistant prostate cancer (CRPC). In certain embodiments, the prostate cancer is CRPC after treatment with chemotherapy. In certain embodiments, the prostate cancer is chemotherapy-naive mCRPC. In certain embodiments, the prostate cancer is neuroendocrine prostate cancer ( EPC). In certain embodiments, the prostate cancer is progressing on other treatments. In certain embodiments, the prostate cancer is progressing on androgen deprivation treatment.
[0032] In certain aspects, described herein is a method of identifying a cancer that will be responsive to split-route treatment with copper and disulfiram, the method comprising performing 64Cu PET imaging on the patient; and determining that the cancer is copper-avid and thus will be responsive, wherein the split-route treatment regimen comprises
administering to a patient with cancer a first therapeutically effective amount of copper salt by intravenous administration; and administering to the patient a therapeutically effective amount of disulfiram by oral administration; wherein the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle. In certain embodiments, the copper avidity of the cancer is determined by comparing an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging to an amount of 64Cu present in non-neoplastic tissue determined by 64CuPET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in non-neoplastic tissue. In certain embodiments, the copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of Cu present in neoplastic tissue determined by CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt. In certain embodiments, the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; wherein the cancer is copper avid if there is increased 64Cu in the tumor compared to a predetermined threshold.
[0033] In certain embodiments, the methods further comprise the step of determining ceruloplasmin levels in the patient prior to the administration of the first therapeutically effective amount of copper salt, for at least one cycle. In certain embodiments, the methods further comprise the step of determining ceruloplasmin levels after the administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper. In certain embodiments, the ceruloplasmin levels are used to determine a dose of the first therapeutically effective amount of copper salt.
[0034] In certain embodiments, the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh). In certain embodiments, the treatment regimen further comprises the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration. In certain embodiments, the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
[0035] In certain embodiments, the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is metastatic prostate cancer. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer is castration resistant prostate cancer (CRPC). In certain embodiments, the prostate cancer is CRPC after treatment with chemotherapy. In certain embodiments, the prostate cancer is chemotherapy-naive mCRPC. In certain embodiments, the prostate cancer is neuroendocrine prostate cancer ( EPC). In certain embodiments, the prostate cancer is progressing on other treatments. In certain embodiments, the prostate cancer is progressing on androgen deprivation treatment.
[0036] In yet another aspect, disclosed herein is a method of treating prostate cancer comprising, administering to a patient a first therapeutically effective amount of CuCh by intravenous administration; administering to a patient a therapeutically effective amount of disulfiram by oral administration; and administering to a patient a second therapeutically effective amount of copper gluconate by oral administration; wherein the administration of the first therapeutically effective amount of CuCh by intravenous administration is performed prior to the administration of disulfiram; wherein the DSF is administered at a dose of 80 mg, TDD; wherein the second therapeutically effective amount of copper gluconate is
administered at a dose of 1.5 mg, TID; and wherein the second therapeutically effective amount of copper gluconate is administered not within one hour of administration of DSF.
3. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0037] These and other features, embodiments, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawing where:
[0038] Figure 1 schematizes the clinical trial protocol for treatment of metastatic prostate cancer comprising split-route administration of copper salt and disulfiram.
4. DETAILED DESCRIPTION
4.1. Advantages and utility
[0039] Disulfiram forms complexes with metals, such as copper; the dithiocarbamate metal complexes have been shown to be effective in vitro and in animal models to inhibit cancer cell growth and/or survival. Described herein are methods for the administration of disulfiram (DSF) and copper for the treatment of cancer. Also disclosed herein are methods for the identification of patients with cancer that will be responsive to disulfiram and copper treatment.
4.2. Definitions
[0040] Unless otherwise defined herein, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains. The following terms are defined as set forth below.
[0041] Unless stated otherwise, as used herein, the term "copper" refers to copper in either the elemental form or in the form of a copper salt (e.g., copper chloride, copper gluconate or copper glycinate).
[0042] Unless stated otherwise, the term, "mg Cu" or "mg copper", refers to the mass of elemental copper in the form of copper chloride, copper gluconate or copper glycinate.
[0043] "Copper avidity" of a cancer or "copper-avid cancer" refers to a cancer, tumor or neoplastic tissue that exhibits increased content of copper upon administration of copper compared to (i) non-neoplastic tissues or (ii) a baseline value, wherein the baseline value is determined prior to administration of copper or compared to a pre-determined value determined from historical data or control samples.
[0044] "Ceruloplasmin levels" refers to an amount of ceruloplasmin protein in a sample of plasma.
[0045] "DSF" refers to disulfiram, bis(diethylthiocarbamoyl) disulfide or tetraethylthiuram disulfide.
[0046] "DSF copper complex" refers to a copper 1, 1-dithiolato complex.
[0047] "Performing 64Cu PET imaging" refers to administering compositions comprising radioactive 64Cu isotopes to a patient by intravenous injection of the composition comprising 64Cu, followed by whole body PET/CT imaging at one or more time points after the administration of the 64Cu.
[0048] "Split-route treatment", as used herein, refers to administering at least two of a plurality of therapeutic agents by different routes of administration (e.g., oral and intravenous administration).
[0049] "Effective amount" or "therapeutically effective amount" or "sufficient amount" refers to an amount sufficient to produce a desired effect, e.g., an amount sufficient to reduce tumor burden or reduce disease or stabilize disease or reduce disease symptoms in a subject or an amount that is effective to ameliorate a symptom of a disease.
[0050] "Treating cancer" as used herein, specifically refers to administering therapeutic agents to a patient diagnosed with cancer, i.e., having established cancer in the patient, to inhibit the further growth or spread of the malignant cells in the cancerous tissue and/or to cause the death of malignant cells, or a patient in whom a cancer has been previously treated with potentially curative surgery, radiation, or other treatments and in whom the goal of treatment is to reduce the risk of cancer recurrence, or a patient at known high risk of developing a new cancer for whom the goal is cancer prevention.
[0051] "Cancer that is responsive to treatment" or "responsiveness of a cancer to treatment" refers to cancers or neoplastic tissue that, following treatment with an anti-cancer agent, exhibits reduced growth, reduced size, reduced mass, and/or reduced cancer cell proliferation, or that following treatment, results in increased progression free survival or over survival in a patient with the cancer.
[0052] "Preventing cancer" as used herein, refers to administering to a subject with a therapeutic agent for the purpose of inhibiting the onset of cancer or for the purpose of preventing the recurrence of cancer in a patient previously diagnosed with cancer. The subject may be a patient that has been determined to have a higher than average probability of developing cancer than individuals of similar age. The subject may have undergone any diagnostic procedure known in the art for determining the probability of developing cancer. The subject may have undergone prior cancer treatment. For example, the subject may have undergone cancer treatment with an anti-cancer agent, surgery or combinations thereof.
[0053] "Anti-cancer agent" as used herein, refers to any agent or therapeutic used in the art for the treatment of cancer and/or cancer-related conditions. Examples of anti-cancer agents include, but are not limited to, radiation, chemotherapeutics such as, but not limited to:
platinum compounds {e.g., cisplatin or carboplatin), alkylating agents {e.g., temozolomide), antitumor antibiotics, taxanes {e.g., paclitaxel), antimetabolites, nucleoside analogues {e.g., 5-fluorouracil and capecitabine), topoisomerase inhibitors, hypomethylating agents, proteasome inhibitors, epipodophyllotoxins, DNA synthesis inhibitors, vinca alkaloids, targeted cancer therapeutics, such as but not limited to, tyrosine kinase inhibitors, monoclonal antibodies, nitrosoureas (e.g., bis-chloroethylnitrosourea or l-(2-chloroethyl)-3-cyclohexyl-l- nitrosourea) , enzymes, biological agents {e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors, steroids, hormonal agents (e.g., androgen receptor antagonists), aromatase inhibitors, PARP inhibitors, arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, immunomodulator (e.g., PD1 antagonists or PDL-1 antagonists), or any combination thereof.
[0054] "Temozolomide-resistant glioblastoma" or "glioblastoma that is temozolomide- resistant" as used herein refer interchangeably to primary or secondary glioblastoma, astrocytoma or oligodendroglioma in which the subject harboring the cancer has completed a course of temozolomide treatment (either with or without concurrent radiation therapy) and has pathological verification of recurrent tumors.
[0055] "Temporally staggered release" or "staggered release" refers to the onset of release of one or more agents after or prior to the onset of release of another agent in a pharmaceutical composition.
[0056] Abbreviations used in this application include the following: DSF, refers to disulfiram.; TID refers to administration of a pharmaceutical agent thrice or three times daily; IV refers to intravenous administration of a pharmaceutical agent; PET refers to positron emission tomography; CRPC refers to castration resistant prostate cancer; EPC refers to neuroendocrine prostate cancer; ADV refers to androgen deprivation therapy, and LHRH refers to luteinizing hormone releasing hormone.
[0057] Recitation of ranges herein includes the recited endpoints and all points there between.
[0058] It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.
4.3. Dosing regimens
[0059] In a first aspect, methods of treating hyperproliferative disorders, such as cancer, are presented. The methods comprise administering to a subject with cancer, a hyperproliferative disorder or other condition, or administering to a subject suspected of having a high probability of developing cancer, a hyperproliferative disorder or other condition, an effective amount of DSF and an effective amount of copper on a dosage schedule wherein at least one of DSF and copper is administered by a parenteral route of administration. [0060] In certain embodiments, the methods comprise administering an effective amount of an oral dosage form comprising DSF preceded by or followed by intravenous administration an effective amount of copper. In certain embodiments, the methods comprise administering an effective amount of an oral dosage form comprising DSF preceded by intravenous administration an effective amount of copper. In certain currently preferred embodiments, the methods comprise administering an effective amount of an oral dosage form comprising DSF preceded by intravenous administration an effective amount of copper and followed by oral administration of an effective amount of copper. In certain embodiments, the copper oral dosage form is administered not less than one hour before the administration of the DSF oral dosage form. In certain embodiments, the copper oral dosage form is administered not less than one hour after the administration of the DSF oral dosage form.
[0061] In the methods described herein, a therapeutically effective amount of DSF is administered. In certain embodiments, the therapeutically effective amount of DSF is 0.01- 0.1 mg, 0.1-1 mg, 1.0-10.0 mg, 10.0-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-150 mg, 150-200 mg, 200-300 mg, 300- 400 mg, 400-500 mg or 500-1,000 mg. In an embodiment, the therapeutically effective amount of DSF administered is 40 mg. In an embodiment, the therapeutically effective amount of DSF administered is 80 mg. In an embodiment, the therapeutically effective amount of DSF administered is 40 mg, thrice daily (TID), wherein the total therapeutically effective amount of DSF administered per day is 120 mg. In an embodiment, the
therapeutically effective amount of DSF administered is 80 mg, thrice daily (TID); wherein the total therapeutically effective amount of DSF administered per day is 240 mg.
[0062] In preferred embodiments of the methods described herein, a therapeutically effective amount of copper is administered by split-route treatment for at least one cycle. In certain embodiments, the split route treatment comprises administration of copper by two distinct routes of administration. In typical embodiments, the copper is in the form of copper chloride (CuCh), copper gluconate, copper sulfate or copper glycinate. In currently preferred embodiments, the copper is in the form of CuCh or copper gluconate. In certain
embodiments, the split-route treatment comprises administration of a first therapeutically effective amount of copper intravenously followed by administration of a second
therapeutically effective amount of copper orally. In certain embodiments, the split-route treatment comprises administration of first therapeutically effective amount of CuCh intravenously followed by administration of a second therapeutically effective amount of copper gluconate orally. In certain embodiments, the split-route treatment comprises administration of a first therapeutically effective amount of copper orally followed by administration of a second therapeutically effective amount of copper intravenously. In certain embodiments, the split-route treatment comprises the administration of CuCh intravenously followed by administration of copper gluconate orally 24 hours-28 days after intravenous administration of CuCh. In certain embodiments, the split-route treatment comprises the administration of CuCh intravenously followed by administration of copper gluconate orally 14-16 days after intravenous administration of CuCh.
[0063] In certain embodiments, the split-route treatment of copper comprises intravenous administration of a first therapeutically effective amount of CuCh by one or more bolus injections, followed by oral administration of a second therapeutically effective amount of copper gluconate or gycinate.
[0064] In certain embodiments, the first therapeutically effective amount of CuCh is 0.1 mg- 30 mg CuCh. In certain embodiments, the first therapeutically effective amount of CuCh is 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 30 mg CuCh.
[0065] In certain embodiments, the second therapeutically effective amount of copper is 0.1 mg-30 mg copper gluconate or copper glycinate. In certain embodiments, the second therapeutically effective amount of copper is 0.01-0.1 mg, 0.1-1 mg, 1.0-10.0 mg, 10.0-20 mg, 20-30 mg, 30^0 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg or 90-100 mg copper gluconate or copper glycinate. In certain embodiments, a second therapeutically effective amount of copper gluconate is administered orally. In certain embodiments, the second therapeutically effective amount of copper is 0.01-0.1 mg, 0.1-1 mg, 1.0-10.0 mg, 10.0-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg and 90-100 mg copper gluconate. In an embodiment, the therapeutically effective amount of copper gluconate is 0.1 mg-30 mg.
[0066] In an embodiment, the second therapeutically effective amount of copper gluconate is 0.5 mg-5 mg. In an embodiment, the second therapeutically effective amount of copper gluconate is 1.5 mg. In an embodiment, the second therapeutically effective amount of copper gluconate is 4.5 mg.
[0067] In certain embodiments, the DSF is administered orally once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly or monthly. In certain embodiments, the copper is administered orally once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly or monthly. In certain embodiments, the copper gluconate is administered orally once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly, bi-weekly or monthly. In certain embodiments, the DSF and copper are orally administered
simultaneously once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly or monthly. In certain embodiments, the DSF and copper gluconate are orally administered simultaneously once daily, twice daily, thrice daily, 4 times daily, 5 times daily, every other day, 2 times per week, weekly, bi-weekly or monthly.
[0068] In certain embodiments, the copper and DSF are administered for at least one cycle; wherein a cycle is anywhere from one week to 12 weeks in duration. In certain
embodiments, the copper and DSF are administered for at least one cycle, wherein each cycle is 28 days in duration. In certain, copper is administered intravenously weekly on day one, and DSF is administered daily beginning on day 2 of a 28 days cycle. In certain
embodiments, copper is administered intravenously weekly on day one; DSF is administered TID beginning on day 2, and copper gluconate is administered TID beginning on day 16 of a 28 days cycle.
[0069] In certain embodiments, DSF and/or copper are administered without food or administered to a fasting patient. In some embodiments, DSF and/or copper are administered in the fasting state. In some embodiments, DSF and/or copper are administered with food or shortly after the subject has eaten a meal, or within 1 hour before or after the subject ingests food. In certain embodiments, the oral dosage forms comprising DSF and/or copper are administered without food or when the subject has an empty stomach, or greater than 2 hours after the subject has ingested food.
[0070] In accordance with an aspect of the methods described herein for treating cancer in a subject, the methods include administering to the patient a therapeutically effective amount of DSF and an intracellular copper ion stimulant, which can enhance the intracellular level of the above described heavy metal ions in the patient. Intracellular heavy metal ion carriers are known. For example, ceruloplasmin can be administered to the patient to enhance the intracellular copper level. Other copper ion carriers known in the art may also be
administered in accordance with this aspect of the invention. The copper ion carriers and the DSF and/or copper can be administered together or separately. [0071] In accordance with an aspect of the methods described in this application, copper and/or DSF can be used in combination with an additional conventional anti-cancer therapy. For example, the method can be complemented by a conventional radiation therapy or chemotherapy. Thus, in an embodiment, the method comprises administering to a patient DSF and copper and an additional anti-cancer agent. The additional anti-cancer agent may be administered prior to, concurrently or after administration of the DSF and copper.
[0072] In order to inhibit cell growth, induce cell differentiation, induce apoptosis, inhibit MDR phenotype, inhibit metastasis, inhibit angiogenesis or otherwise reverse or reduce the malignant phenotype of tumor cells using the methods and compositions of the present application, a "target" cell is contacted with one or more compositions described herein. In certain embodiments of the methods, at least one additional agent can be administered in combination with disulfiram and/or copper. In certain embodiments, the additional agent is an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, radiation, platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine ), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, dactinomycin), taxanes (e.g., paclitaxel, «αέ-paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, and methotrexate ), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine, gemcitabine, 5-flurouracil), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine ), proteasome inhibitors (e.g., bortezomib ), epipodophyllotoxins (e.g., etoposide and teniposide ), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine ), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab, ozogamicin, bevacizumab ), nitrosoureas (e.g., carmustine, fotemustine, and lomustine ), enzymes (e.g., L- Asparaginase ), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide, bicalutamide, granisetron, flutamide, androgen receptor antagonists), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX-2) inhibitors, PARP inhibitors,
immunotheapeutics (e.g., PD1 antagonists, PDL-1 antagonists), or any combination thereof.
[0073] In certain embodiments, the methods described herein improve the efficacy of chemotherapy and radiotherapy. One approach involves administration of DSF and copper by the methods described herein in combination with use of chemo or therapeutic or radiotherapeutic intervention. This treatment option may offer a synergistic therapeutic effect along with the disulfiram and copper complex.
[0074] Alternatively, any of the treatments with DSF and/or copper compositions or dosage forms may precede or follow the other agent treatment by intervals ranging from minutes to weeks. In embodiments where the other agent and any of the DSF and/or copper
compositions or dosage forms described herein are applied separately to the cell, a significant period of time should not expire between the time of each delivery, such that the agent and DSF copper complex would still be able to exert an advantageously combined (e.g., synergistic) effect on the cell. In an embodiment, the cell can be contacted with both the other agent, DSF and copper within about 12-24 h, or from about 6-12 h of each other, with a delay time of up to about 12 h. In some situations, it may be desirable to extend the duration of treatment with just the therapeutic agent, for example, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective
administrations.
[0075] In certain embodiments, the methods described herein can be combined with therapies that induce DNA damage when applied to a cell. Such therapies include radiation such as, for example, y-irradiation, X-ray, UV-irradiation, microwave, electronic emissions, and the like.
[0076] In certain embodiments, the method described in the application result in reduced tumor burden, increased overall survival, increased progression-free survival and/or decreased disease symptoms in the patient.
4.3.1. Cancers
[0077] The present application describes effective methods for treating or preventing various types of hyperproliferative conditions and cancers of adults and children, including but not limited to: prostate cancer, glioblastoma (glioblastoma, astrocytoma or oligodendroglioma), medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma. The present application describes effective methods for treating primary malignant brain tumors, such as, but not limited to, malignant glioma. In particular, the present invention is effective in treating prostate cancer, glioblastoma, medulloblastoma, rectal cancer, pancreatic cancer, head and neck cancer, lung cancer, and triple-negative breast cancer.
[0078] In certain embodiments, the methods are used for the treatment of prostate cancer. In certain embodiments, the cancer is metastatic prostate cancer. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof. In certain embodiments, the metastatic prostate cancer is castration resistant prostate cancer (CRPC). In certain embodiments, the prostate cancer is CRPC after treatment with chemotherapy. In certain embodiments, the prostate cancer is chemotherapy-naive mCRPC. In certain embodiments, the prostate cancer is neuroendocrine prostate cancer ( EPC).
[0079] In certain embodiments, the prostate cancer is progressing on other treatments. In certain embodiments, the prostate cancer is progressing on androgen deprivation treatment. In certain embodiments, the androgen deprivation treatment comprises a CYP17 inhibitor. In certain embodiments, the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700, and combinations thereof. In certain embodiments, the CYP17 inhibitor is abiraterone. In certain embodiments, the androgen deprivation treatment comprises an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is aminoglutethimide. In certain embodiments, the androgen deprivation treatment comprises an androgen receptor inhibitor. In certain embodiments, the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof. In certain embodiments, the androgen deprivation treatment is enzalutamide. In certain embodiments, the androgen deprivation treatment comprises a luteinizing hormone releasing hormone (LHRH) antagonist. In certain embodiments, the LHRH antagonist is degarelix. In certain embodiments, the androgen deprivation treatment comprises a LHRH agonist. In certain embodiments, the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof. In certain embodiments, the prostate cancer is progressing on first line chemotherapy. In certain embodiments, the chemotherapy is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estamustine, and combinations thereof. In certain embodiments, the prostate cancer is progressing after primary tumor surgical removal.
[0080] In certain embodiments, the methods of the application are used for the treatment of primary malignant brain tumors. In certain embodiments, the methods are used for the treatment of glioblastoma. In certain embodiments, the methods are used for the treatment of temozolomide-resistant glioblastoma. In certain embodiments, the methods of the application are used for the treatment of malignant glioma. In certain embodiments, the methods of the application are used for the treatment of pancreatic cancer. In certain embodiments, the methods of the application are used for the treatment of rectal cancer. In certain
embodiments, the methods of the application are used for the treatment of head and neck cancer. In certain embodiments, the methods of the application are used for the treatment of lung cancer. In certain embodiments, the methods of the application are used for the treatment of metastatic pancreatic cancer. In certain embodiments, the methods of the application are used for the treatment of inflammatory breast cancer. In certain
embodiments, the methods of the application are used for the treatment of Her2 positive breast cancer. In certain embodiments, the methods of the application are used for the treatment of castration-resistant prostate cancer. In certain embodiments, the methods of the application are used for the treatment of acute myelogenous leukemia (AML). In certain embodiments, the methods of the application are used for the treatment of acute
lymphoblastic leukemia (ALL). In certain embodiments, the methods of the application are used for the treatment of esophageal cancer. In certain embodiments, the methods of the application are used for the treatment of mesothelioma. In certain embodiments, the cancer is recurrent cancer that has failed one or more prior anti-cancer treatments. In certain embodiments, the subject has unresectable brain metastases. In certain embodiments, the subject has not yet undergone a prior anti-cancer treatment. In certain embodiments, the cancer is a pediatric cancer. In certain embodiments, the cancer is a pediatric brain tumor including, but not limited to, glioma, medulloblastoma, pituitary adenoma, atypical teratoid or rhabdoid tumor or ependymoma. [0081] In certain embodiments, DSF and copper are administered with temozolomide for the treatment of glioblastoma. In certain embodiments, DSF and copper are administered with Paclitaxel for the treatment of breast cancer, including triple-negative breast cancer.
[0082] In certain embodiments, DSF and copper are administered with a chemotherapeutic and/or targeted anti-cancer agent for the treatment of cancer, including, but not limited to, prostate cancer, glioblastoma, pancreatic cancer, rectal cancer, colon cancer, head and neck cancer, kidney cancer, bladder cancer, lung cancer, meduloblastoma and breast cancer.
[0083] In an aspect, the methods of the application are used for the treatment of rectal cancer. In certain embodiments, described herein are methods of treating rectal cancer, comprising administering to a patient with locally advanced rectal cancer a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF. In certain embodiments, 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF. In certain embodiments a second therapeutically effective amount of copper is administered orally. In certain embodiments, the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper. In certain embodiments, at least one anti-cancer agent is selected from the group consisting of, 5-fluorouracil, capecitabine, radiation, and combinations thereof.
[0084] In an aspect, the methods of the application are used for the treatment of head and neck cancer. In certain embodiments, described herein are methods of treating head and neck cancer, comprising administering to a patient with locally advanced head and neck cancer a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF. In certain embodiments, 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF. In certain embodiments a second therapeutically effective amount of copper is administered orally. In certain embodiments, the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper. In certain embodiments, at least one anti-cancer agent is selected from the group consisting of radiation, cisplatin, carboplatin, 5-fluorouracil, and combinations thereof.
[0085] In an aspect, the methods of the application are used for the treatment of lung cancer. In certain embodiments, described herein are methods of treating lung cancer, comprising administering to a patient with locally advanced lung cancer a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF. In certain embodiments, 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF. In certain embodiments a second therapeutically effective amount of copper is administered orally. In certain embodiments, the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper. In certain embodiments, the at least one additional anti-cancer agent is selected from the group consisting of radiation, cisplatin, paclitaxel, immunotherapy, PD-1 antagonists, PDL-1 antagonists, and combinations thereof.
[0086] In an aspect, the methods of the application are used for the treatment of primary malignant brain tumors. In certain embodiments, described herein are methods of treating malignant glioma or other primary malignant brain tumors, comprising administering to a patient with malignant glioma a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF. In certain embodiments, 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF. In certain embodiments, a second therapeutically effective amount of copper is administered orally. In certain embodiments, the patient is administered at least one additional anti-cancer agent over a period of 2-8 weeks concurrent with administration of the DSF and copper. In certain embodiments, the at least one additional anti-cancer agent is selected from the group consisting of radiation, temozolomide, a nitrosourea including, an immunomodulator, and combinations thereof. In certain embodiments, the nitrosourea is bis- chloroethylnitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l -nitrosourea (CCNU), or combinations thereof. In certain embodiments, the immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
[0087] In certain embodiments, the methods of the application are used for the treatment of pancreatic cancer. In certain embodiments, the methods of pancreatic cancer comprise administering to a patient with malignant glioma a first therapeutically effective amount of copper salt by intravenous administration and administering an effective amount of DSF. In certain embodiments, 40 mg-80 mg of DSF are administered TID, wherein the total daily dose of DSF is 120-240 mg DSF. In certain embodiments, DSF and copper are administered in combination with Na^-paclitaxel and gemcitabine for the treatment of metastatic pancreatic cancer. In certain embodiments, DSF and copper are administered in combination with ώ-paclitaxel and gemcitabine for the treatment of metastatic pancreatic cancer in patients that have previously received combination chemotherapy comprising 5-Fluorouracil, leucovorin, irinotecan and oxaliplatin.
[0088] In certain aspects, methods of treating disorders or conditions that would benefit from the treatment of DSF and copper are presented. In certain embodiments, the condition is an infection. In certain embodiments, the methods described herein comprise administering DSF and copper for the treatment of tuberculosis. In certain embodiments, the methods described herein comprise administering DSF and copper for the treatment of leishmaniasis.
4.4. Pharmaceutical compositions
[0089] The present application provides methods of treating cancer wherein copper and disulfiram are administered to a patient with cancer in pharmaceutical compositions.
[0090] Disulfiram has been used clinically in the treatment of alcohol abuse, in which disulfiram inhibits hepatic aldehyde dehydrogenase. Disulfiram has the following formula.
S s
Figure imgf000026_0001
(I)
where Rl , R2 , R3 , and R4 are all ethyl.
[0091] The thiolate anion derivative of disulfiram is diethyldithiocarbamate anion, the sodium salt of which has the following formula:
jj ^CHsCHs
Na+ "S C N
\
CH2CH3
(Π)
[0092] The copper complex of diethyldithiocarbamate is shown below as Copper 1, 1- dithiolato complex, in the following formula:
Figure imgf000027_0001
(III)
wherein R2 , R3 are ethyl, and An is an anion of low molecular weight. As used herein, the DSF copper complex refers to the Copper 1,1-dithiolato complex.
[0093] Copper ions can be administered separately as an aqueous solution in a
pharmaceutically suitable salt form. In an embodiment, copper ions are administered separately to form a chelate after ingestion in which the ions are complexed with thiuram disulfide compounds. Thus, the amount of copper to be used advantageously is proportional to the amount of thiuram disulfide compound to be administered based on the molar ratio between a copper and thiuram disulfide compound in the chelate.
[0094] In certain embodiments, oral dosage forms are presented that comprise
dithiocarbamate disulfides, thiocarbamate anions in combination with copper, thiocarbamate complexes with copper ions, and dithiocarbamate metal chelates as described in U.S. Patent No. 6,548,540 which is herein incorporated by reference in its entirely.
[0095] The oral dosage forms used in the methods described herein may comprise disulfiram without copper, copper without disulfiram, or disulfiram and copper. The copper can be in the form of, but is not limited to, copper gluconate. In certain embodiments, the copper is in the form of copper gluconate. In certain aspects, the oral dosage forms comprise DSF and copper gluconate.
[0096] These oral dosage forms can comprise, in addition to disulfiram and/or copper, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on, for example, the dosage of active DSF copper complex needed for effective treatment, timing and location of release of the DSF and/or copper, solubility and stability of DSF, copper and/or DSF copper complex, dosages of DSF and copper required for formation of the DSF copper complex, absorption characteristics of the DSF, copper and/or DSF copper complex. [0097] The oral dosage forms described herein can be tablet, capsule, powder or liquid forms. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid dosage forms generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.
[0098] The DSF and/or copper can be delivered orally in enclosed gelatin capsules (e.g., hard gelatin or soft gelatin) or compressed tablets. Capsules and tablets can be prepared using any conventional techniques. For example, the active compounds can be incorporated into a formulation which includes pharmaceutically acceptable carriers, such as excipients (e.g., starch, lactose), binders (e.g., gelatin, cellulose, gum), disintegrating agents (e.g.,
croscarmellose sodium, crospovidone, alginate, Primogel, and corn starch), lubricants (e.g., magnesium stearate, silicon dioxide), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). Possible excipients include those that have been previously used in FDA-approved products such as, microcrystalline cellulose (MCC), and lactose anhydrous, as fillers; croscarmellose sodium, and crospovidone as disintegrants; colloidal silicon dioxide as glidant; magnesium stearate and talc as lubricants and anti -adherents. Suitable excipients include, colloidal silicon dioxide, anhydrous lactose, sodium starch glycolate, and stearic acid.
[0099] Various coatings can also be prepared for the capsules and tablets to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules. In certain embodiments, for administration of DSF, it is desirable to administer the compounds as enteric-coated capsules that are impervious to stomach acid but dissolve in the alkaline environment of the intestines or colon, in order to prevent release of carbon disulfide from dithiocarbamates in the acid environment of the stomach, and to preserve the integrity of the DSF. In certain
embodiments, for administration of copper, it is desirable to administer the compounds as enteric-coated capsules that are impervious to stomach acid but dissolve in the alkaline environment of the intestines or colon.
[00100] Other forms of oral formulations such as chewing gum, suspension, syrup, wafer, elixir, and the like can also be prepared containing the active compounds used in this invention. Various modifying agents for flavors, tastes, colors, and shapes of the special forms can also be included. In addition, for convenient administration by enteral feeding tube in patients unable to swallow, the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle, such as olive oil, corn oil, and safflower oil.
[00101] In certain embodiments, the DSF and/or copper are administered in combination with other therapeutic agents that treat or prevent another disease or symptom in the subject treated. However, it is to be understood that such other therapeutic agents should not interfere with or adversely affect the effects of the active compounds of this invention on the cancer being treated. Such other therapeutic agents include, but are not limited to, anticancer agents, antiviral agents, antibiotics, antifungal agents, anti-inflammation agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, hypertension drugs, and the like.
[00102] Examples of anti-cancer agents include, but are not limited to, radiation, platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine ), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, dactinomycin), taxanes (e.g., paclitaxel, «αέ-paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, and methotrexate ), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine, gemcitabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine ), proteasome inhibitors (e.g., bortezomib ), epipodophyllotoxins (e.g., etoposide and teniposide ), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine ), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab, ozogamicin, bevacizumab ), nitrosoureas (e.g., carmustine, fotemustine, and lomustine ), enzymes (e.g., L- Asparaginase ), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide, bicalutamide, granisetron, flutamide), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal antiinflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX- 2) inhibitors, PARP inhibitors, or any combination thereof. Additional anti-cancer agents include, but are not limited to, prednisone, docetaxel, cabazitaxel, mitoxantrone, estamustine, bicalutamide, etoposide, doxorubicin, ixabepilone, satraplatin, cisplatin, carboplatin, picoplatin, oxaliplatin, paclitaxel, tesetaxel, gemcitabine, cytarabine; carmustine, sorafenib, temsirolimus, revlimid, custirsen, orteronel, temsirolimus, everolimus, patupilone, phenoxodiol, vorinostat, orteronel, enzastaurin, tasquinimod, triapine, arsenic trioxide, sabarubicin, perifosine, selinexor, suramin, fenretinide, vinorelbine tartrate, atrasentan hydrochloride, leflunomide, thalidomide, celecoxib, pantoprazole, aflibercept, fenretinide, tanespimycin, eribulin mesylate, oblimersen, lenalidomide, cyclophosphamide, perifosine, ribociclib, alisertib, ipatasertib, apalutamide, proxalutamide, hydroxychloroquine, alvocidib, GSK525762, G-202, E7389, OGX- 427, KX2-391, IMC-3G3, BI 836845, BIND-014, HE3235, PHA-739358, KX2-391, GTI-2040, AT-101, MOR209/ES414, GT0918, ZD4054, MLN0128, MDX-010, AZD5363, BAY1841788, ODM-201, ARN-509, ZD4054, ruxolitinib, sunitinib, talazoparib, carfilzomib, olaparib, cabozantinib, vatalanib, afatinib, bortezomib, bevacizumab, trastuzumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, pertuzumab, and cixutumumab.
[00103] In certain embodiments, the additional anti-cancer agent is a heparinoid. In certain embodiments the heparinoid is a PF-4-interacting heparinoid. In certain embodiments, the heparinoid is substantially desulfated at the 2-0 and/or 3-0 position (ODSH).
[00104] In certain embodiments, the cancer is a hormone responsive cancer and the anticancer agent is a hormonal agent. In certain embodiments the hormonal agent is an androgen deprivation agent for the treatment of prostate cancer. Examples of hormonal agents include, but are not limited to, a CYP17 inhibitor (e.g., abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK-001, TAK-700), aromatase inhibitor (e.g., aminoglutethimide), an androgen receptor inhibitor (e.g., enzalutamide, flutamide, bicalutamide, nilutamide), a luteinizing hormone releasing hormone (LHRH) antagonist (e.g., degarelix), and a LHRH agonist (e.g., leuprolide, goserelin, triptorelin, histrelin).
4.4.1. Pharmaceutical compositions containing copper
[00105] In certain embodiments, pharmaceutical compositions containing copper described herein comprise a therapeutically effective amount of copper salt. In certain embodiments, pharmaceutical compositions containing copper described herein are configured for parenteral or oral administration of copper. [00106] In certain embodiments, the pharmaceutical composition containing copper is configured for intravenous administration of copper salt. In certain embodiments, the pharmaceutical composition containing copper are configured for intravenous administration of copper chloride (CuCh).
[00107] These dosage forms for intravenous administration can comprise, in addition to copper, one or more pharmaceutically acceptable excipients, carrier, buffers, stabilizers or other materials well known to those skilled in the art.
[00108] In certain embodiments, the dosage forms containing copper for intravenous administration are configured for administration as one or more bolus injections. In certain embodiments, the dosage form for bolus injection contains 0.1 mg-30 mg copper chloride. In certain embodiments, the dosage form for bolus injection contain 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 gm, 9 gm, 10 mg, 15 mg, 20 mg, 30 mg copper chloride.
[00109] In certain embodiments, the dosage forms containing copper for intravenous administration are configured for administration as a continuous infusion.
[00110] In certain embodiments, the pharmaceutical composition containing copper is configured for oral administration of copper salt. In certain embodiments, the pharmaceutical composition containing copper is an oral dosage form for administration of copper gluconate or copper glycinate.
[00111] The pharmaceutical compositions comprising copper can be formulated as pharmaceutical dosage forms for oral administration. These oral dosage forms can comprise, in addition to copper, one or more pharmaceutically acceptable excipients, carrier, buffers, stabilizers or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on, for example, the dosage of copper needed for effective treatment, timing and location of release of the copper, solubility and stability of copper, dosages of copper, and/or absorption characteristics of the copper.
[00112] In certain embodiments, the one or more excipients are colloidal silicon dioxide, anhydrous lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, stearic acid, anhydrous lactose, sodium croscarmellose, crospovidone, colloidal silicon dioxide, magnesium stearate, talc, or combinations thereof. [00113] In certain embodiments, each of the copper oral dosage forms contain 0.1 mg copper, 0.2 mg copper, 0.25 mg copper, 0.3 mg copper, 0.4 mg copper, 0.5 mg copper, 0.75 mg copper, 1 mg copper, 1.5 mg copper, 2 mg copper, 2.5 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg copper.
[00114] The copper can also be delivered orally in enclosed gelatin capsules (e.g., hard gelatin or soft gelatin) or compressed tablets. Capsules and tablets can be prepared using any conventional techniques. Various coatings can also be prepared for the capsules and tablets to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules.
[00115] In certain embodiments, the oral dosage form is a tablet containing copper. In certain embodiments, the oral dosage form containing copper is a capsule containing one or more copper tablets. In certain embodiments, the capsule contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more copper tablets.
[00116] In certain embodiments, the oral dosage forms containing copper can be configured for controlled release or protection including microcapsules and nanocapsules generally known in the art, and hydrogels described above can all be utilized in oral administration of the copper. In certain embodiments, the oral dosage forms containing copper are coated external to the dosage form with a coating. In certain embodiments, the coating is a pH-sensitive or a pH-insensitive coating. Another preferable delivery form comprises liposomes as carriers. Liposomes are micelles formed from various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. The copper can be enclosed within such micelles.
[00117] In certain embodiments, the copper is formulated to be released immediately upon ingestion. In certain embodiments, the copper is formulated to be released between 1 min and 5 min, 5 min and 30 min, 30 min and 45 min, 45 min and 1 h, 1 h and 2 h, 2h and 3 h, 1 h and 3 h, 1 h and 4 h, 1 h and 5 h, 2 h and 4 h, 2 h and 5 h, or 3h and 8 h after ingestion.
4.4.2. Pharmaceutical compositions containing DSF
[00118] The pharmaceutical compositions containing disulfiram of the invention include a therapeutically effective amount of DSF. In certain embodiments, the
pharmaceutical compositions containing disulfiram are configured for oral or parenteral administration of DSF. In certain embodiments, the pharmaceutical compositions containing disulfiram are an oral dosage form. In certain embodiments, the pharmaceutical composition containing DSF is for parenteral administration of DSF. In certain embodiments, the pharmaceutical composition containing DSF is configured for intravenous administration of DSF.
[00119] The pharmaceutical compositions comprising DSF can be formulated in pharmaceutical dosage forms for oral administration. These oral dosage forms can comprise, in addition to DSF, one or more pharmaceutically acceptable excipients, carriers, buffers, stabilizers or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on, for example, the dosage of active DSF needed for effective treatment, the timing and location of release of the DSF and/or DSF copper complex, the solubility and stability of DSF and/or DSF copper complex, the dosages of DSF, and the absorption characteristics of the DSF and/or DSF copper complex.
[00120] In certain embodiments, the one or more excipients are colloidal silicon dioxide, anhydrous lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, stearic acid, anhydrous lactose, sodium croscarmellose, crospovidone, colloidal silicon dioxide, magnesium stearate, talc, or combinations thereof.
[00121] In certain embodiments, the oral dosage form containing DSF contains 20 mg
DSF, 30 mg DSF, 40 mg DSF, 50 mg DSF, 60 mg DSF, 70 mg DSF, 80 mg DSF, 90 mg DSF, 100 mg DSF, or 120 mg DSF.
[00122] The DSF can be delivered orally in enclosed gelatin capsules (e.g., hard gelatin or soft gelatin) or compressed tablets. Capsules and tablets can be prepared using any conventional techniques. Various coatings can also be prepared for the capsules and tablets to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules.
[00123] In certain embodiments, the oral dosage form is a tablet containing DSF. In certain embodiments, the oral dosage form containing DSF is a capsule containing one or more DSF tablets. In certain embodiments, the capsule contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more DSF tablets.
[00124] The DSF can also be conjugated, i.e., covalently linked, to a water soluble non-immunogenic high molecular weight polymer to form a polymer conjugate.
Advantageously, such polymers, e.g., polyethylene glycol, can impart solubility, stability, and reduced immunogenicity to the active compounds. As a result, the DSF in the conjugate when administered to a patient, can have a longer half-life in the body, and exhibit better efficacy.
[00125] In certain embodiments, the oral dosage forms containing DSF can be configured for controlled release or protection including microcapsules and nanocapsules generally known in the art, and hydrogels described above can all be utilized in oral administration of the DSF. In certain embodiments, the oral dosage forms containing DSF are coated external to the dosage form with a coating. In certain embodiments, the coating is a pH-sensitive or a pH-insensitive coating. Another preferable delivery form comprises liposomes as carriers. Liposomes are micelles formed from various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. The DSF can be enclosed within such micelles.
[00126] In certain embodiments, the DSF is formulated to be released immediately upon ingestion. In certain embodiments, the DSF is formulated to be released between 1 min and 5 min, 5 min and 30 min, 30 min and 45 min, 45 min and 1 h, 1 h and 2 h, 2h and 3 h, 1 h and 3 h, 1 h and 4 h, 1 h and 5 h, 2 h and 4 h, 2 h and 5 h, or 3h and 8 h after ingestion.
[00127] The pharmaceutically useful compounds according to the present invention are administered preferably in a "therapeutically effective amount" or "prophylactically effective amount" (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of cancer or
hyperproliferative disorder being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.), 1980.
[00128] In certain embodiments, a pharmaceutical composition or dosage form are administered alone or in combination with other treatments, either simultaneously or sequentially, depending upon the condition to be treated.
4.5. Methods for patient selection
[00129] In certain embodiments, the methods described herein include methods of identifying a cancer that will be responsive to treatment with copper and disulfiram. In certain embodiments, the methods for identifying a cancer responsive to treatment comprise performing 64Cu PET imaging on the patient; and determining that the cancer is copper-avid and thus will be responsive to treatment.
[00130] 64Cu PET imaging can be performed prior to and/or following parenteral or oral administration of a copper salt. In certain embodiments, determination of the copper avidity of a cancer can be performed by comparing an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging to an amount of 64Cu present in non-neoplastic tissue determined by 64CuPET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in non-neoplastic tissue. In certain
embodiments, the copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging prior to the
administration of the first therapeutically effective amount of copper salt to an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt. In certain embodiments, the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; wherein the cancer is copper avid if there is increased 64Cu in the tumor compared to a predetermined threshold.
[00131] 64Cu PET imaging is performed by administering compositions comprising radioactive 64Cu isotopes to a patient. In certain embodiments, the administration is performed by intravenous injection of the composition comprising 64Cu, followed by whole body PET/CT imaging at one or more time points after the administration of the 64Cu. In certain embodiments, the PET imaging is performed at 2-4 hours following the
administration of the 64Cu and at 24 hours following the administration of the 64Cu.
[00132] In certain embodiments, the dose of 64Cu administered is 1-20 mCi of 64Cu chloride. In certain embodiments, the dose of 64Cu administered is 8-12 mCi of 64Cu chloride. In certain embodiments, the dose of 64Cu administered is 10 mCi of 64Cu chloride.
In certain embodiments, non-radioactive nickel and other trace metals are present in the composition comprising 64Cu for intravenous administration; however, the total maximum mass dose of all metals is 1 microgram or less. [00133] In certain embodiments, whole body PET/CT imaging is performed within 35 days prior to cycle 1 day 1. In certain embodiments, whole body PET/CT imaging is performed within 35 days prior to cycle 1 day 1 and every 3 cycles thereafter. In certain embodiments, 64Cu PET imaging is performed during treatment to monitor copper avidity of a cancer and/or cancer responsiveness to treatment with disulfiram and copper.
[00134] In certain embodiments, whole body PET/CT imaging is performed. In certain embodiments, CT scan with contrast of chest, abdomen and pelvis is performed. In certain embodiments, a CT scan without contrast, Na P18 PET or MRI may be substituted for the CT scan with contrast.
[00135] In certain embodiments, tumor biopsies are taken to identify cancers responsive to treatment with disulfiram and copper and copper levels within the biopsied tumor tissue is assessed and compared to either a baseline value or a pre-determined value from historical data or control tissues from the same patient or other individuals. Tumor biopsies may be performed on primary tumors, metastatic tumor lesions, lymph nodes or any neoplastic tissue.
[00136] In certain embodiments, methods of identification of a cancer that will be responsive to treatment with copper and disulfiram comprise determining ceruloplasmin levels in the patient prior to and/or following the administration of a therapeutically effective amount of copper salt. In certain embodiments, ceruloplasmin levels are compared to a baseline value wherein the baseline value is determined in the patient with the cancer prior to administration of copper or is determined based on a pre-determined value from historical data or control samples from the same patient or other individuals. In certain embodiments, increased ceruloplasmin levels prior to and/or following administration of copper indicates that a cancer will be responsive to treatment with disulfiram and copper.
4.6. Examples
[00137] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.
[00138] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature.
4.6.1. Example 1: Clinical study of disulfiram and copper split-route dosing regimen for the treatment of metastatic prostate cancer
[00139] An open-label single arm, dose escalation study of intravenously administered CuCh followed by oral dosing of DSF in men with metastatic castration resistant prostate cancer (mCRPC) is performed to confirm the safety, tolerability, and efficacy of a DSF and copper split-route dosing regimen for the treatment of mCRPC. Subjects undergo 64Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64Cu injection. Subjects undergo an optional image-guided tumor biopsy of a lymph node to assess the level of androgen receptor (AR) expression and intratumoral copper levels.
[00140] On cycle one, day one, subjects are administered copper chloride
intravenously (Figure 1). Copper 0.4 mg/mL (Cupric Chloride Injection, USP) contains 0.4 mg copper/mL and is administered intravenously only after dilution. A total dose of 1 mg of copper chloride (dose level 1) is added to 250 ml of D5W and infused via peripheral intravenous route over approximately 2 hours, lmg is the physiologic dose added to a 24- hour infusion of total parenteral nutrition. At subsequent dose levels, 3mg, 5mg, and 7mg of copper chloride is added to 250 mL of D5W and infused peripherally over 2 hours.
[00141] Following completion of the first CuCh infusion(s), subjects undergo another
64Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after 64Cu injection.
[00142] Subjects are then treated on open-label DSF (80 mg three times a day, starting on cycle 1, day 2). DSF is administered by the subject at a dose of 80 mg three times a day orally in 4-week cycles throughout the treatment period. Subjects are instructed to take the dose of DSF one hour before all three meals, around the same time each day. DSF is taken with approximately 8 ounces of water and consumed over as short a time as possible. The DSF total daily dose is 240 mg.
[00143] Oral copper gluconate is administered 1.5 mg three times a day, starting cycle
1, day 16 until evidence of disease progression as defined by Prostate Cancer Working Group Two (PCWG3) definition or until two years at which point they will roll over to the standard of care at that time. Subjects are instructed to take copper gluconate at least one hour after DSF three times a day, at approximately the same time each day. Copper gluconate is taken with a glass of water and consumed over as short a time as possible.
[00144] Each treatment cycle consists of 28 consecutive days. Subjects commence DSF treatment on cycle 1 day 2. Subjects take DSF until radiographic disease progression and/or unequivocal clinical progression, at which time study treatment is discontinued. If the subject had radiographic progression but no unequivocal clinical progression, and alternate treatment is not initiated, the subject continues on the study treatment at the Investigator's discretion.
[00145] The first 3 subjects at each dose level of intravenous CuCh will have DSF PKs drawn on cycle 1, day 1. The subjects are administered the first dose of DSF on cycle 1, day 2, followed by PK samples drawn at 2h, 4h, 6h, and 8h after first dose, and then resume DSF for the afternoon dose (only 2 doses for cycle 1, day 2). Subjects then resume TID dosing of DSF on cycle 1, day3. If one of these subjects is unable to complete the PK studies, then that subject is replaced by a subsequent subject treated at the same dose level.
[00146] Subjects will be stratified into 3 groups: Group A: EPC, Group B:
adenocarcinoma CRPC with non-liver/peritoneal metastases (lymph nodes, bone, or lung), and Group C: adenocarcinoma CRPC with liver and/or peritoneal metastases. With each group, accrual to dose levels occurs in two stages. Within each group, the first stage accrues subjects on escalating dose level until a subject experiences a dose limiting toxicity (DLT). The second stage allocates eligible subjects based upon a continual reassessment method. Additional subjects are not accrued until a stopping rule is triggered or the minimum required time frame has elapsed. Subjects are followed for a minimum of 28 days from the start of treatment for assessment of DLTs.
[00147] The initial stage accrues subjects in cohorts of two on each dose level until a subject experiences a DLT. Within each group, two eligible subjects are entered onto dose level 1 (Table 1). Within each group, if one of the two subjects experiences a DLT, then this event triggers the second stage and initiates the continual reassessment method (CRM).
Within each group, if both subjects on dose level 1 experience a DLT, then enrollment to the group will be stopped. If 0 subjects experience a DLT, then the next cohort is treated at the next higher dose level. Subject allocation to higher dose levels occurs if the minimum follow-up period has been satisfied and no DLT has been observed. The allocation strategy is followed for accrual to increasing dose levels until a subject experiences a DLT or a stopping rule is triggered. Once a DLT has been observed, the 2 -Stage using CRM modeling begins. In the absence of DLT's, escalation continues until dose level 4 is reached. Subjects continue to be entered on dose level 4 until a DLT occurs or until a stopping rule is triggered.
[00148] Doses escalate according to IV CuCh dose in groups of 2 subjects per dose level until the subject experiences a DLT, at which time initiation of a continual reassessment model (CRM) for determination of dose escalation is performed. A dose expansion at the MTD will continue to accrue until a maximum of 36 subjects have been treated on study.
Table 1. Dosing Table
Figure imgf000039_0001
NOTE: Dose level -1 = 1 mg of IV CuCh, Disulfiram 80 mg TID and 1.5 mg Copper gluconate TID.
[00149] Subjects undergo Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64Cu injection. Following completion of the first CuCh infusion(s), subjects undergo another 64Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after 64Cu injection. The use of copper radionuclides in nuclear medicine has a long established record of patient safety. For the effective dose of 0.0338 mSv/MBq, a 10 mCi (370 MBq) administered activity results in an effective dose Of 1.25 rem (12.5 mSv). This is comparable to the effective dose of 8.0 mSv for an oncologic 18F-FDG study, assuming 12 mCi administered and 0.018 mSv/MBq. For the mass amount in a 10 mCi dose of 64Cu chloride, there is a maximum mass dose of 3 nanograms of 64Cu in the form of 64Cu chloride. The effective specific activity is 10 - 300 mCi / microgram of metal at calibration. Non-radioactive nickel and perhaps other trace metals are present; however, the total maximum mass dose of all metals will be 1 microgram or less. Thus, for a lOmCi 64Cu chloride dose administered intravenously, the effective radiation dose will be 0.98 rem, and the maximum mass dose of all metals is 1 microgram or less. An IV push of 64CuCl2 is performed over 1 minute, and whole body PET/ CT image acquisition is performed at 2-4 hours, and then again at 24 hours. Although previous animal studies have shown relatively modest uptake of 64CuCh (3% ID/gm at 1 hour) in prostate cancer models, tumors defined by co-registered CT permit region of interest (ROI) definition to quantify PET uptake. Known metastatic lesions defined identified on CT define ROIs which are superimposed on PET for quantified Standardized Uptake Values (SUV) corrected for lean body mass.
[00150] An optional image-guided lymph node biopsy is performed for subjects who consent to the biopsy, have lymph node disease accessible by core biopsy or locally recurrent tumor accessible by transrectal ultrasound (TRUS) and whose cycle 1 day 2 schedule is permissive of the biopsy. Core biopsies of these lesions are obtained, provided have not been exposed to prior irradiation. In the event that a subject's only accessible tumor tissue for biopsy is in their bone marrow, a CT or MRI- guided bone biopsy may be substituted for the lymph node or TRUS biopsy.
[00151] Ceruloplasmin levels are measured at baseline and prior to each IV CuCh infusion in order to determine the concentrations following saturation of plasma binding and to correlate with any unforeseen toxicity. Ceruloplasmin levels following IV CuCh infusion is associated with response to DSF.
[00152] Serum copper PK is drawn before and 1 hour after infusion of CuCh on cycle
1 day 1, and 1 hour after infusion of CuCh on cycle 1 day 8 and day 15.
Patient Inclusion Criteria
[00153] Subjects have histologically confirmed diagnosis of prostate cancer.
Histologic variants of prostate cancer, including neuroendocrine features and small cell carcinoma of the prostate are included. If neuroendocrine prostate cancer is not biopsy proven, clinical evidence of neuroendocrine prostate cancer is acceptable for stratification into group A. Subjects have radiographic evidence of metastatic disease. Subjects being treatment with ongoing androgen deprivation therapy (ADT) using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed or screening serum testosterone must be <50 ng/dl. Subjects exhibit evidence of disease progression on ADT as evidenced by one of the following: 2 consecutive PSA levels 50% or greater above the PSA nadir achieved on ADT and separated at least 1 week apart, or CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to PCWG3 criteria or RECIST 1.1 criteria, or at least 1 new bone scan lesion as compared to the most immediate prior radiologic studies, or absolute rise in PSA of 2.0ng/mL or greater, minimum 2 consecutive rising PSA levels with an interval of > 1 week between each PSA level. Subjects have a minimum of 2 weeks elapsed off of antiandrogen therapy prior to registration (i.e. flutamide, nilutamide, and bicalutamide) without evidence of an anti-androgen withdrawal response. For subjects in Groups B or C, subjects have previously used of at least one androgen pathway inhibitor (either abiraterone acetate or enzalutamide) for metastatic CRPC For subjects in Group A with EPC, subjects have previously used of at least one platinum- containing chemotherapy regimen. Subjects have a minimum of 4 weeks off of enzalutamide or abiraterone, if applicable. Subjects have a minimum of 4 weeks from prior chemotherapy, including but not limited to, docetaxel, cabazitaxel, mitoxantrone, carboplatinum, cisplatin, or estramustine; if applicable. Subjects have a minimum of 4 weeks from any major surgery prior to registration.
[00154] The results of the clinical trial demonstrate that a dosing regimen in which disulfiram and copper gluconate are administered on a split-route dosing schedule is safe and effective for the treatment of metastatic prostate cancer.
4.6.2. Example 2: Clinical study of disulfiram and copper split-route dosing regimen for the treatment of temozolomide - resistant glioblastoma
[00155] A phase II, multicenter, open-label, single-arm study is performed to confirm the safety, tolerability, and efficacy of a staggered oral dosing regimen of disulfiram and copper gluconate for treatment of recurrent, temozolomide-resistant, glioblastoma.
[00156] Patients with temozolomide ("TMZ")-resistant glioblastoma are treated with disulfiram and copper gluconate on a dosing regimen to assess re-sensitization of the glioblastoma to TMZ. TMZ is administered daily on days 1-5 of a 28 day cycle at a dose of
150-200 mg/m2 PO. On cycle one, day one, subjects are administered copper chloride intravenously. Subjects undergo 64Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64Cu injection. Following completion of the first CuCh infusion(s), subjects undergo another 64Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after 64Cu injection. Two capsules of 40 mg each of disulfiram are administered orally thrice daily ("TID") (total of 240 mg per day) approximately 4-8 hours apart beginning on cycle 1, day2 of a 28 day cycle. Beginning on cycle 1, day 16, a capsule of 1.5 mg copper gluconate is administered orally TID (total of 4.5 mg per day) with meals, and not within one hour of the oral administration of disulfiram, TID in a 28 day cycle.
[00157] The results of the clinical trial demonstrate that a dosing regimen in which disulfiram and copper gluconate are administered on a split-route dosing schedule is capable of resensitizing temozolomide-resistant recurrent glioblastoma to temozolomide.
4.6.3. Example 3: Clinical study of disulfiram and copper split-route dosing regimen for the treatment of metastatic pancreatic cancer
[00158] A phase II, open label, randomized study with two study arms is performed to confirm the anti-cancer effect of DSF and copper in combination with gemcitabine and nab- Paclitaxel in patients with metastatic pancreatic cancer.
Study Objectives:
[00159] The objectives of the study are to evaluate progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines Version 1.1, to evaluate changes in plasma levels of CA19-9 from baseline as a marker of tumor response, to evaluate the safety and tolerability of gemcitabine + «αέ-paclitaxel with or without DSF-Cu in this patient population, to evaluate the objective tumor response according to RECIST guidelines, to evaluate overall survival, and to evaluate changes from baseline for serum albumin and body weight.
[00160] Overall Study Design: Open label, randomized study with two study arms: Treatment A:
25 subjects receive Na^-paclitaxel + gemcitabine + DSF-CU. Na^-paclitaxel 125 mg/m2 is administered by IV over 30 minutes followed by administration of gemcitabine by IV infusion at 1000 mg/m2 over 30 minutes. Na^-paclitaxel + gemcitabine is given weekly for 3 weeks followed by one week of rest. On cycle one, day one, subjects are administered copper chloride intravenously. Subjects undergo 64Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64Cu injection. Following completion of the first CuCh infusion(s), subjects undergo another 64Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after Cu injection. Beginning on cycle 1, day 2, patients take 80 mg DSF TID with approximately 8 ounces of water at least one hour before food. Beginning on cycle 1, day 16, copper gluconate is taken at a dose of 1.5 mg with meals TID and not within one hour of DSF.
Treatment B:
25 subjects receive Nab-paclitaxel + gemcitabine. Nab-paclitaxel 125 mg/m2 is administered by IV over 30 minutes followed by administration of gemcitabine by IV infusion at 1000 mg/m2 over 30 minutes. Na^-paclitaxel + gemcitabine will be given weekly for 3 weeks followed by one week of rest.
Patient Inclusion Criteria
Patients enrolled in the study have histologically confirmed adenocarcinoma of the pancreas that is metastatic and for which potential curative measures, such as resection of an isolated metastasis, are not available. Patients have received FOLFIRINOX combination
chemotherapy and either have developed progressive disease or intolerance to the
FOLFIRINOX regimen. Patients may not have received a second line chemotherapy regimen after developing progressive disease or intolerance to the FOLFIRINOX regimen. Patients have one or more metastatic tumors measurable by CT scan. Patients have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. Patients are male or non-pregnant and non-lactating female and > 18 to < 80 years of age. Patients have adequate biological parameters as demonstrated by the following blood counts at Screening (obtained < 14 days prior to randomization) and at Baseline-Day 0: Absolute neutrophil count (ANC) > 1.5 x 109/L; Platelet count > 100,000/mm3 (100 x 109/L);
Hemoglobin (Hgb) > 9 g/dL. Patients have the following blood chemistry levels at Screening (obtained < 14 days prior to randomization) and at Baseline-Day 0: AST (SGOT), ALT (SGPT) < 2.5 x upper limit of normal range (ULN), unless liver metastases are present, then < 5 x ULN is allowed. Total bilirubin < 1.5 χ ULN. Patients have ECOG performance status from 0 to < 2.
[00161] The results of the clinical trial demonstrate that an oral dosing regimen in which disulfiram and copper gluconate are administered on a split-route dosing schedule is capable of increasing progression-free survival when added to the standard of care regimen of Na^-paclitaxel + gemcitabine.
4.6.4. Example 4: Clinical study of the efficacy of disulfiram and
copper split-route dosing regimen in combination with chemoradiotherapy in patients with locally advanced rectal cancer
[00162] A phase II, open label, randomized study, with two study arms is performed to confirm the anti-cancer effect of DSF and Copper in combination with chemoradiotherapy in patients with locally advanced rectal cancer.
STUDY OBJECTIVES
[00163] The primary objective is to confirm an antitumor effect of DSF and Copper in combination with chemoradiotherapy as determined by the incidence of pathologic complete response (no evidence of residual cancer) at the time of surgery. Secondary Objectives are to determine evidence of an antitumor effect of DSF and Copper in combination with chemoradiotherapy as determined by: safety of DSF and Copper in combination with chemoradiotherapy as determined by toxicity assessment according to NCI CTCAE V.4.0, tumor down staging, tumor regression, R0 resection rate; negative circumferential resection rate, and rate of sphincter-sparing surgery.
[00164] Overall Study Design: Open label, randomized study with two study arms:
Subjects with locally advanced (T3 or T4 or node positive) rectal adenocarcinoma are enrolled into the study and receive chemoradiotherapy consistent with the institutional standard of care. During a run-in period, 10 subjects are enrolled to receive
chemoradiotherapy + DSF and Cu to assess compatibility of the combination and then 50 subjects are randomized to an open label, controlled period with two arms at a ratio of 1 : 1 to receive: chemoradiotherapy + DSF and Cu, or chemoradiotherapy without DSF and Cu. After the 10th subject has been enrolled and has been followed up until one month post- surgery or the last dose of DSF and Cu + chemoradiotherapy, whichever is first, data from the 10 subjects enrolled in the study are reviewed by the investigators that enrolled the subjects in the study as well as Cantex management (Dr. Stephen Marcus) to assess the safety of the administration of chemoradiation + DSF-Cu and recommend whether continuation with the Randomized Period of the study is indicated. Treatment A
Chemoradiotherapy is administered in accordance with the institutional standard of care along with DSF and copper by intravenous and oral administration. On cycle one, day one, subjects are administered copper chloride intravenously. Subjects undergo 64Cu PET imaging at baseline to assess tumor copper uptake at 2-4 hours and 24 hours after 64Cu injection. Following completion of the first CuCh infusion(s), subjects undergo another 64Cu PET imaging to assess tumor copper uptake following IV CuCh saturation at 2-4 hours and 24 hours after 64Cu injection. Beginning on cycle 1, day 2, patients take 80 mg DSF TID with approximately 8 ounces of water at least one hour before food. Beginning on cycle 1, day 16, copper gluconate is taken at a dose of 1.5 mg with meals TID and not within one hour of DSF.
DSF at 80 mg TID and 1.5 mg of Cu TID. The DSF and copper doses are administered sequentially, with each DSF dose administered at least one hour before the administration of copper.
Treatment B
Chemoradiotherapy is administered in accordance with the institutional standard of care without DSF and Copper.
[00165] Ongoing Safety Assessment during the Treatment Period of the Study. If, at any point, there appears to be a 25% or greater increase in the expected/reported incidence of grade 3 or 4 toxicities, accrual is held, and dose modification or study discontinuation is considered.
[00166] Patient Inclusion Criteria
Patients must have histologically confirmed adenocarcinoma of the rectum with pathologic material reviewed by the Department of Pathology at MDACC. The clinical stage must be T3, T4, or node positive Tl or 2. Patients must have no evidence of metastatic disease.
Patient is Male or a non-pregnant and non-lactating female and > 18 to < 80 years of age. Patient has adequate biological parameters as demonstrated by the following blood counts at Screening (obtained < 14 days prior to randomization) and at Baseline-Day 0: Absolute neutrophil count (ANC) > 1.5 x 109/L; Platelet count > 100,000/mm3 (100 χ 109/L);
Hemoglobin (Hgb) > 9 g/dL. Patient has the following blood chemistry levels at Screening (obtained < 14 days prior to randomization) and at Baseline-Day 0: AST (SGOT), ALT (SGPT) < 2.5 x upper limit of normal range (ULN), unless liver metastases are present, then < 5 x ULN is allowed. Total bilirubin < 1.5 χ ULN. Patient has ECOG performance status from 0 to 2. Patient has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent Form (ICF) prior to participation in any study-related activities.
[00167] The results of the clinical trial demonstrate that an oral dosing regimen in which disulfiram and copper gluconate are administered on a split-route dosing schedule in combination with chemoradiotherapy is capable of increasing progression-free survival in patients with locally advanced rectal cancer.
[00168] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.
[00169] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

WHAT IS CLAIMED IS:
1. A method of treating cancer, comprising: administering to a patient with cancer a first therapeutically effective amount of copper salt by intravenous administration; and
administering to the patient a therapeutically effective amount of disulfiram by oral administration;
wherein the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle.
2. The method of claim 1, further comprising the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration.
3. The method of claim 1 or claim 2, wherein the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh).
4. The method of claim 2 or claim 3, wherein the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
5. The method of any one of claims 1-4, wherein the first therapeutically effective amount of copper salt is administered as one or more bolus injections.
6. The method of claim 5, wherein the bolus injection is 0.1 mg-30 mg CuCh.
7. The method of claim 6, wherein the bolus injection of CuCh is selected from the group consisting of 1 mg, 3 mg, 5 mg, and 7 mg.
8. The method of any one of claims 1-4 wherein the first therapeutically effective amount of copper salt is administered as a continuous infusion.
9. The method of any one of claims 1-8, wherein the first therapeutically effective amount of copper salt is administered as a bolus followed or preceded by a continuous infusion.
10. The method of any one of claims 1-9, wherein the first therapeutically effective amount of copper salt is administered weekly.
11. The method of any one of claim 1-10, wherein ceruloplasmin levels in the patient are determined prior to administration of the first therapeutically effective amount of copper salt, for at least one cycle.
12. The method of claim 11, wherein ceruloplasmin levels are detected after administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper.
13. The method of claim 11 or claim 12, wherein the ceruloplasmin levels are used to determine a dose of the first therapeutically effective amount of copper salt.
14. The method of any one of claim 1-13 wherein 64Cu PET imaging is performed on the patient.
15. The method of claim 14, wherein 64Cu PET imaging is performed prior to the administration of the first therapeutically effective amount of copper salt.
16. The method of claim 14 or claim 15, wherein 64Cu PET imaging is performed following the administration of the first therapeutically effective amount of copper salt.
17. The method of any one of claims 14-16, wherein 64Cu PET imaging is performed within 4 hours and at 24 hours after administration of 64Cu.
18. The method of any one of claims 14-17, wherein increased uptake of 64Cu in neoplastic tissue as compared to one or more non-neoplastic tissues identifies a patient requiring treatment or a patient responsive to treatment.
19. The method of any one of claims 1-18, wherein the first therapeutically effective amount of copper salt is administered 12-48 hours prior to the administration of the disulfiram.
20. The method of claim 19, wherein the first therapeutically effective amount of copper salt is administered one day prior to the administration of the disulfiram.
21. The method of any one of claims 1-20, wherein the disulfiram is administered at a total dose of 10 mg-500 mg.
22. The method of any one of claims 1-21, wherein the disulfiram is administered at a total dose of 10 mg-500 mg, administered as divided doses TID.
23. The method of claim 22, wherein the disulfiram is administered at a total dose of 120 mg, TID and wherein each divided dose is 40 mg.
24. The method of claim 22, wherein the disulfiram is administered at a total dose of 240 mg, administered as divided doses TID and wherein each divided dose is 80 mg.
25. The method of any one of claims 1-24, wherein the disulfiram is administered without food.
26. The method of any one of claims 2-25, wherein the second therapeutically effective amount of copper salt is copper glycinate.
27. The method of any one of claims 2-25, wherein the second therapeutically effective amount of copper salt is copper gluconate.
28. The method of any of claims 2-27, wherein the second therapeutically effective amount of copper salt is administered at a total dose of 0.1 mg-30 mg.
29. The method of claim 28, wherein the second therapeutically effective amount of copper salt is administered at a total dose of 1.5 mg-5 mg.
30. The method of claim 29, wherein the second therapeutically effective amount of copper salt is administered at a divided dose of 1.5 mg.
31. The method of any one of claims 2-30, wherein the second therapeutically effective amount of copper salt is administered TID.
32. The method of claim 31, wherein the second therapeutically effective amount of copper salt is administered at a divided dose of 0.5 mg-3 mg, TID.
33. The method of claim 32, wherein the second therapeutically effective amount of copper salt is administered at a divided dose of 1.5 mg, TID.
34. The method of any one of claims 2-33, wherein the second therapeutically effective amount of copper salt is administered not within one hour of disulfiram.
35. The method of claim 34, wherein the second therapeutically effective amount of copper salt is administered at least one hour after the administration of disulfiram.
36. The method of claim 34, wherein the second therapeutically effective amount of copper salt is administered at least one hour before the administration of disulfiram.
37. The method of any one of claims 2-35, wherein for each cycle, the
administration of the second therapeutically effective amount of copper salt is
administered 24 hours to 16 days after the administration of disulfiram.
38. The method of claim 37, wherein the administration of the second
therapeutically effective amount of copper salt is administered 14 to 16 days after the administration of disulfiram.
39. The method of any one of claims 2-38, wherein the administration of the second therapeutically effective amount of copper salt is performed by administration of a single oral dosage form configured to temporally stagger release of copper and disulfiram in the patient.
40. The method of any one of claims 1-39, wherein the cancer is copper-avid.
41. The method of claim 40, wherein the copper avidity of the cancer is determined by comparing an amount of 64Cu present in neoplastic tissue determined by
64CuPET imaging to an amount of 64Cu present in non-neoplastic tissue determined by
64CuPET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in non-neoplastic tissue.
42. The method of claim 40, wherein the copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt.
43. The method of claim 40, wherein the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; and wherein the cancer is copper avid if there is increased 64Cu in the tumor compared to a predetermined threshold.
44. The method of any one of claims 1-43, wherein the cancer has elevated expression or elevated activity of DNA methyltransferase.
45. The method of any one of claims 1-44, wherein the cancer is one in which DNA methyltransferase contributes to disease etiology.
46. The method on any one of claims 1-45, wherein the cancer is one in which inhibition of DNA methyltransferase is therapeutically effective.
47. The method of any one of claims 1-46, wherein the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
48. The method of claim 47, wherein the cancer is prostate cancer.
49. The method of claim 48, wherein the cancer is metastatic prostate cancer.
50. The method of claim 49, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
51. The method of claim 49, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone
metastases, lung metastases, and combinations thereof.
52. The method of any one of claims 49-51, wherein the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
53. The method of any one of claims 48-52, wherein the prostate cancer is CRPC after treatment with chemotherapy.
54. The method of any one of claims 48-52, wherein the prostate cancer is chemotherapy-naive mCRPC.
55. The method of any one of claims 48-54, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).
56. The method of any one of claims 48-55, wherein the prostate cancer is progressing on other treatments.
57. The method of claim 56, wherein the prostate cancer is progressing on androgen deprivation treatment.
58. The method of claim 57, wherein the androgen deprivation treatment comprises a CYP17 inhibitor.
59. The method of claim 58, wherein the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK- 001, TAK-700, and combinations thereof.
60. The method of claim 59, wherein the CYP17 inhibitor is abiraterone.
61. The method of claim 57, wherein the androgen deprivation treatment comprises an aromatase inhibitor.
62. The method of claim 61, wherein the aromatase inhibitor is
aminoglutethimide.
63. The method of claim 57, wherein the androgen deprivation treatment comprises an androgen receptor inhibitor.
64. The method of claim 63, wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof.
65. The method of claim 64, wherein the androgen deprivation treatment is enzalutamide.
66. The method of claim 57, wherein the androgen deprivation treatment comprises a luteinizing hormone releasing hormone (LHRH) antagonist.
67. The method of claim 66, wherein the LHRH antagonist is degarelix.
68. The method of claim 57, wherein the androgen deprivation treatment comprises a LHRH agonist.
69. The method of claim 68, wherein the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof.
70. The method of claim 56, wherein the prostate cancer is progressing on first line chemotherapy.
71. The method of claim 70, wherein the chemotherapy is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estamustine, and combinations thereof.
72. The method of claim 56, wherein the prostate cancer is progressing after primary tumor surgical removal.
73. The method of claim 47, wherein the cancer is GBM.
74. The method of claim 73, wherein the cancer is GBM, and wherein the copper salt or disulfiram are administered in combination with temozolomide.
75. The method of claim 47, wherein the cancer is medulloblastoma.
76. The method of claim 47, wherein the cancer is pancreatic cancer.
77. The method of claim 76, wherein the pancreatic cancer is metastatic.
78. The method of claim 76 or claim 77, wherein the cancer is pancreatic cancer, and wherein the copper salt or disulfiram are administered in combination with gemcitabine and nab-paclitaxel.
79. The method of claim 78, wherein the copper salt or disulfiram are
administered in combination with gemcitabine, nab-paclitaxel and 2-0, 3-0 desulfated heparinoid (ODSH).
80. The method of claim 47, wherein the cancer is rectal cancer.
81. The method of claim 80, wherein the rectal cancer is locally advanced.
82. The method of claim 80 or claim 81, wherein the cancer is rectal cancer and wherein the copper salt or disulfiram are administered in combination with
chemoradi otherapy .
83. The method of claim 47, wherein the cancer is lung cancer.
84. The method of claim 83, wherein the lung cancer is locally advanced.
85. The method of claim 83 or claim 84, wherein the cancer is lung cancer and the copper salt or disulfiram are administered in combination with the at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, paclitaxel, an immunomodulator, and combinations thereof.
86. The method of clam 85, wherein the immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
87. The method of claim 47, wherein the cancer is glioma.
88. The method of claim 87, wherein the cancer is glioma and wherein the copper salt or disulfiram are administered in combination with at least one additional anti-cancer agent selected from the group consisting of radiation, temozolomide, nitrosourea, an immunomodulator, and combinations thereof.
89. The method of claim 88, wherein the nitrosourea is bis-chloroethylnitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l -nitrosourea (CCNU), or combinations thereof.
90. The method of claim 88, wherein the immunomodulator is a PD-1 antagonist, a PDL-1 antagonist, or combinations thereof.
91. The method of claim 47, wherein the cancer is head and neck cancer.
92. The method of claim 91, wherein the head and neck cancer is locally advanced.
93. The method of claim 91 or 92, wherein the cancer is head and neck cancer and wherein the copper salt or disulfiram are administered in combination with at least one additional anti-cancer agent selected from the group consisting of radiation, cisplatin, carboplatin, 5-fluorouracil, and combinations thereof.
94. The method of claim 47, wherein the cancer is breast cancer.
95. The method of claim 94, wherein the breast cancer is metastatic.
96. The method of claim 94 or claim 95, wherein the breast cancer is triple- negative breast cancer.
97. The method of any one of claims 1-96, wherein the copper salt or disulfiram are administered in combination with a second antineoplastic treatment regimen.
98. The method of claim 97, wherein the second antineoplastic treatment regimen comprises chemotherapy.
99. The method of claim 97, wherein the second antineoplastic treatment regimen comprises radiation therapy.
100. The method of claim 97, wherein the second antineoplastic treatment regimen comprises immune therapy.
101. The method of claim 97, wherein the cancer is a hormone-responsive cancer and the second antineoplastic treatment regimen is a hormone therapy.
102. The method of claim 101, wherein the hormone-responsive cancer is prostate cancer.
103. The method of claim 102, wherein the hormone therapy is androgen deprivation therapy.
104. The method of claim 103, wherein the androgen deprivation therapy comprises orchiectomy.
105. The method of claim 103, wherein the androgen deprivation therapy comprises a CYP17 inhibitor.
106. The method of claim 105, wherein the CYP17 inhibitor is selected from the group consisting of abiraterone, galeterone, orteronel, ketoconazole, seviteronal, TOK- 001, TAK-700, and combinations thereof.
107. The method of claim 106, wherein the CYP17 inhibitor is abiraterone.
108. The method of claim 103, wherein the androgen deprivation therapy comprises an aromatase inhibitor.
109. The method of claim 108, wherein the aromatase inhibitor is
aminoglutethimide.
110. The method of claim 103, wherein the androgen deprivation therapy comprises an androgen receptor inhibitor.
111. The method of claim 110, wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, flutamide, bicalutamide, nilutamide, and combinations thereof.
112. The method of claim 111, wherein the androgen deprivation therapy is enzalutamide.
113. The method of claim 103, wherein the androgen deprivation therapy comprises a luteinizing hormone releasing hormone (LHRH) antagonist.
114. The method of claim 113, wherein the LHRH antagonist is degarelix.
115. The method of claim 103, wherein the androgen deprivation treatment comprises a LHRH agonist.
116. The method of claim 115, wherein the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, and combinations thereof.
117. The method of claim 97, wherein the second antineoplastic treatment regimen comprises ODSH.
118. An improved method of treating cancer with disulfiram and copper, the improvement comprising: administering, for at least one treatment cycle, at least one of copper and disulfiram by a parenteral route of administration.
119. The method of claim 118, wherein the parenteral route of administration is intravenous administration.
120. The method of claim 119, wherein the copper is administered by intravenous administration.
121. The method of claim 120, wherein the copper is administered by intravenous administration and the disulfiram is administered orally.
122. The method of claim 121, wherein the copper is administered by intravenous administration prior to the administration of disulfiram.
123. The method of claim 118, wherein the disulfiram is administered by intravenous administration.
124. The method of any one of claims 120, wherein the copper is copper chloride (CuCk).
125. The method of claim 122, wherein the method further comprises the step of administering a therapeutically effective amount of copper salt by oral administration.
126. The method of claim 125, wherein the therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
127. The method of any one of claims 118-126, wherein the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
128. The method of claim 127, wherein the cancer is prostate cancer.
129. The method of claim 128, wherein the cancer is metastatic prostate cancer.
130. The method of claim 129, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
131. The method of claim 129, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
132. The method of any one of claims 129-131, wherein the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
133. The method of any one of claims 128-132, wherein the prostate cancer is CRPC after treatment with chemotherapy.
134. The method of any one of claims 128-132, wherein the prostate cancer is chemotherapy-naive mCRPC.
135. The method of any one of claims 128-134, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).
136. The method of any one of claims 128-135, wherein the prostate cancer is progressing on other treatments.
137. The method of claim 136, wherein the prostate cancer is progressing on androgen deprivation treatment.
138. A method of treating copper-avid cancers, the method comprising: determining that a patient's cancer is copper-avid by performing Cu64 PET imaging on the patient;
administering to the patient with a copper-avid cancer a first therapeutically effective amount of copper salt by intravenous administration; and
administering to the patient a therapeutically effective amount of disulfiram by oral administration,
wherein the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle.
139. The method of claim 138, wherein the copper avidity of the cancer is determined by comparing an amount of 64Cu present in tumors determined by 64Cu PET imaging to an amount of 64Cu present in non-neoplastic tissue determined by 64CuPET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in non-neoplastic tissue.
140. The method of claim 138, wherein the copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in tumors determined by 64CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of Cu present in tumors determined by CuPET imaging after the administration of the first therapeutically effective amount of copper salt;
wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to 64Cu present in neoplastic tissue at baseline prior to administration of the first
therapeutically effective amount of copper salt.
141. The method of claim 138, wherein the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; and wherein the cancer is copper avid if there is increased 64Cu in the tumor compared to a predetermined threshold.
142. The method of any one of claims 138-141, further comprising the step of determining ceruloplasmin levels in the patient prior to the administration of the first therapeutically effective amount of copper salt, for at least one cycle.
143. The method of claim 142, further comprising the step of determining ceruloplasmin levels after the administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased ceruloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper.
144. The method of claim 142 or claim 143, wherein the ceruloplasmin levels in the patient are used to determine a dose of the first therapeutically effective amount of copper salt.
145. The method of any one of claims 138-144, wherein the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh).
146. The method of any one of claims 138-145, further comprising the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration.
147. The method of claim 146, wherein the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
148. The method of any one of claims 138-147, wherein if an amount of 64Cu within neoplastic tissue is determined to be elevated compared to an amount of 64Cu within non-neoplastic tissue, additional administrations are performed of the first therapeutically effective amount of copper salt, the therapeutically effective amount of disulfiram, the second therapeutically effective amount of copper salt, or combinations thereof.
149. The method of claim 148, wherein if an amount of 64Cu within neoplastic tissue is determined to be elevated compared to an amount of 64Cu within non-neoplastic tissue, a dosage is increased of the additional administrations of the first therapeutically effective amount of copper salt, the therapeutically effective amount of disulfiram, the second therapeutically effective amount of copper salt, or combinations thereof.
150. The method of claim 138, wherein the patient is administered at least one additional chemotherapeutic agent.
151. The method of claim 150, wherein if an amount of 64Cu within tumor tissues is determined not to be elevated compared to an amount of 64Cu within non-neoplastic tissue, the patient will be administered a different at least one additional
chemotherapeutic agent.
152. The method of any one of claims 138-151, wherein the copper-avid cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple- negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
153. The method of claim 152, wherein the cancer is prostate cancer.
154. The method of claim 153, wherein the cancer is metastatic prostate cancer.
155. The method of claim 153, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
156. The method of claim 153, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
157. The method of any one of claims 154-156, wherein the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
158. The method of any one of claims 153-157, wherein the prostate cancer is
CRPC after treatment with chemotherapy.
159. The method of any one of claims 153-157, wherein the prostate cancer is chemotherapy-naive mCRPC.
160. The method of any one of claims 153-159, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).
161. The method of any one of claims 153-160, wherein the prostate cancer is progressing on other treatments.
162. The method of claim 161, wherein the prostate cancer is progressing on androgen deprivation treatment.
163. A method of identifying a cancer that will be responsive to split-route treatment with copper and disulfiram, the method comprising: performing 64Cu PET imaging on the patient; and
determining that the cancer is copper-avid and thus will be responsive,
wherein the split-route treatment regimen comprises:
administering to a patient with cancer a first therapeutically effective amount of copper salt by intravenous administration; and
administering to the patient a therapeutically effective amount of disulfiram by oral administration; wherein
the administration of the first therapeutically effective amount of copper salt by intravenous administration is performed prior to the administration of disulfiram for at least a first treatment cycle.
164. The method of claim 163, wherein the copper avidity of the cancer is determined by comparing an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging to an amount of 64Cu present in non-neoplastic tissue determined by 64CuPET imaging; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue compared to 64Cu present in non-neoplastic tissue.
165. The method of claim 163, wherein the copper avidity of the cancer is determined by comparing a baseline amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging prior to the administration of the first therapeutically effective amount of copper salt to an amount of 64Cu present in neoplastic tissue determined by 64CuPET imaging after the administration of the first therapeutically effective amount of copper salt; wherein the cancer is copper-avid if there is increased 64Cu in neoplastic tissue after administration of the first therapeutically effective amount of copper salt compared to Cu present in neoplastic tissue at baseline prior to administration of the first therapeutically effective amount of copper salt.
166. The method of claim 163, wherein the copper avidity of the cancer is determined by examining tissue obtained from a tumor biopsy, wherein the tissue is imaged and the amount of copper present in the tumor biopsy is assessed; wherein the cancer is copper avid if there is increased 64Cu in the tumor compared to a predetermined threshold.
167. The method of any one of claims 163-166, further comprising the step of determining cemloplasmin levels in the patient prior to the administration of the first therapeutically effective amount of copper salt, for at least one cycle.
168. The method of claim 167, further comprising the step of determining cemloplasmin levels after the administration of the first therapeutically effective amount of copper salt, for at least one cycle; and wherein increased cemloplasmin levels prior to or following administration of the first therapeutically effective amount of copper indicates that a cancer will be responsive to treatment with disulfiram and copper.
169. The method of claim 167 or claim 168, wherein the cemloplasmin levels are used to determine a dose of the first therapeutically effective amount of copper salt.
170. The method of any one of claims 163-169, wherein the first therapeutically effective amount of copper salt is an amount of copper chloride (CuCh).
171. The method of any one of claims 163-170, wherein the treatment regimen further comprises the step of administering to the patient a second therapeutically effective amount of copper salt by oral administration.
172. The method of claim 171, wherein the second therapeutically effective amount of copper salt is an amount of copper gluconate or copper glycinate.
173. The method of any one of claims 163-172, wherein the cancer is selected from the group consisting of prostate cancer, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, glioma, medulloblastoma, atypical teratoid or rhabdoid tumors, ependymoma, pituitary adenoma, melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, esophageal cancer, breast cancer, triple-negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, pancreatic cancer, rectal cancer, head and neck cancer, gastric cancer, bladder cancer, kidney cancer, colon cancer, ovarian cancer, uterine cancer, mesothelioma, acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma.
174. The method of any one of claims 173, wherein the cancer is prostate cancer.
175. The method of claim 174, wherein the cancer is metastatic prostate cancer.
176. The method of claim 175, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of liver metastases, peritoneal metastases, and combinations thereof.
177. The method of claim 175, wherein the metastatic prostate cancer comprises metastases selected from the group consisting of lymph node metastases, bone metastases, lung metastases, and combinations thereof.
178. The method of any one of claims 175-177, wherein the metastatic prostate cancer is castration resistant prostate cancer (CRPC).
179. The method of any one of claims 174-178, wherein the prostate cancer is CRPC after treatment with chemotherapy.
180. The method of any one of claims 174-178, wherein the prostate cancer is chemotherapy-naive mCRPC.
181. The method of any one of claims 174-180, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).
182. The method of any one of claims 174-181, wherein the prostate cancer is progressing on other treatments.
183. The method of claim 182, wherein the prostate cancer is progressing on androgen deprivation treatment.
184. A method of treating prostate cancer, comprising: administering to a patient a first therapeutically effective amount of CuCh by intravenous administration;
administering to a patient a therapeutically effective amount of disulfiram by oral administration; and
administering to a patient a second therapeutically effective amount of copper gluconate by oral administration;
wherein the administration of the first therapeutically effective amount of CuCh by intravenous administration is performed prior to the administration of disulfiram;
wherein the DSF is administered at a dose of 80 mg, TID;
wherein the second therapeutically effective amount of copper gluconate is administered at a dose of 1.5 mg, TID; and
wherein the second therapeutically effective amount of copper gluconate is administered not within one hour of administration of DSF.
PCT/US2017/061362 2017-11-13 2017-11-13 Disulfiram and copper salt dosing regimen WO2019094053A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111803477A (en) * 2020-08-11 2020-10-23 上海交通大学 Application of abstinence sulfur in preparation of anti-head and neck cancer and anti-fibrosis drugs
US11033516B1 (en) 2020-09-18 2021-06-15 Spring Discovery, Inc. Combination therapies with disulfiram
CN113444114A (en) * 2021-04-16 2021-09-28 吴超君 Application of copper dibenzyl dithiocarbamate medicament to treatment of triple negative breast cancer
CN115350169A (en) * 2021-05-17 2022-11-18 复旦大学 Application of thiram in preparation of medicine for treating gastric cancer
CN115572768A (en) * 2022-11-04 2023-01-06 山东第一医科大学附属省立医院(山东省立医院) Prognosis evaluation and combined treatment aiming at diffuse large B cell lymphoma

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050096304A1 (en) * 1998-09-08 2005-05-05 David White Method of treating cancer using dithiocarbamate derivatives
US20130090591A1 (en) * 2010-03-01 2013-04-11 The Regents Of The University Of California Localization of agents at a target site with a composition and an energy source
US20140037715A1 (en) * 2010-12-09 2014-02-06 University Of Wolverhampton Disulfiram formulation and uses thereof
WO2015120254A1 (en) * 2014-02-06 2015-08-13 Texas Tech University System Disulfiram compositions and treatments for brain tumors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050096304A1 (en) * 1998-09-08 2005-05-05 David White Method of treating cancer using dithiocarbamate derivatives
US20130090591A1 (en) * 2010-03-01 2013-04-11 The Regents Of The University Of California Localization of agents at a target site with a composition and an energy source
US20140037715A1 (en) * 2010-12-09 2014-02-06 University Of Wolverhampton Disulfiram formulation and uses thereof
WO2015120254A1 (en) * 2014-02-06 2015-08-13 Texas Tech University System Disulfiram compositions and treatments for brain tumors

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111803477A (en) * 2020-08-11 2020-10-23 上海交通大学 Application of abstinence sulfur in preparation of anti-head and neck cancer and anti-fibrosis drugs
US11033516B1 (en) 2020-09-18 2021-06-15 Spring Discovery, Inc. Combination therapies with disulfiram
US11065214B1 (en) 2020-09-18 2021-07-20 Spring Discovery, Inc. Combination therapies with disulfiram
US11612575B2 (en) 2020-09-18 2023-03-28 Spring Discovery, Inc. Combination therapies with disulfiram
CN113444114A (en) * 2021-04-16 2021-09-28 吴超君 Application of copper dibenzyl dithiocarbamate medicament to treatment of triple negative breast cancer
CN115350169A (en) * 2021-05-17 2022-11-18 复旦大学 Application of thiram in preparation of medicine for treating gastric cancer
CN115572768A (en) * 2022-11-04 2023-01-06 山东第一医科大学附属省立医院(山东省立医院) Prognosis evaluation and combined treatment aiming at diffuse large B cell lymphoma
CN115572768B (en) * 2022-11-04 2023-12-19 山东第一医科大学附属省立医院(山东省立医院) Prognosis evaluation and combined treatment for diffuse large B cell lymphoma

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