WO2023198188A1 - 使用th-302单药或联用parp抑制剂治疗癌症的方法 - Google Patents

使用th-302单药或联用parp抑制剂治疗癌症的方法 Download PDF

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WO2023198188A1
WO2023198188A1 PCT/CN2023/088379 CN2023088379W WO2023198188A1 WO 2023198188 A1 WO2023198188 A1 WO 2023198188A1 CN 2023088379 W CN2023088379 W CN 2023088379W WO 2023198188 A1 WO2023198188 A1 WO 2023198188A1
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cancer
drug
tumor
group
mutations
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PCT/CN2023/088379
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English (en)
French (fr)
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齐天阳
孟繁英
段建新
刘星
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深圳艾欣达伟医药科技有限公司
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods of treating cancer, in particular methods of treating cancer patients who are sensitive to PARP inhibitors (PARPi).
  • PARPi PARP inhibitors
  • the first human clinical trial of the PARPi drug Olaparib confirmed for the first time that PARPi can inhibit the growth of tumor cells carrying BRCA1/2 mutations, which is mainly based on the synthetic lethality theory (Ashworth, A., & Lord, CJ ( 2018). Synthetic lethal therapies for cancer: what's next after PARP inhibitors?. Nature r eviews. Clinical oncology, 15(9), 564–576. https://doi.org/10.1038/s41571-018-0055-6) : PARP inhibitors can inhibit the DNA single-strand damage repair function of PARP, resulting in a large number of single-stranded DNA damage in cells that cannot be repaired in time.
  • Unrepaired single-stranded DNA damage can trigger replication fork collapse and result in double-stranded DNA damage.
  • Double-stranded DNA damage with strong cytotoxicity can be mediated simultaneously in normal cells by proteins such as BRCA1 and BRCA2.
  • the source recombination repair (HR) pathway is repaired, but in BRCA1/2-deficient tumor cells, double-stranded DNA damage cannot be repaired, leading to the eventual death of the tumor cells.
  • HR The source recombination repair
  • PARPi was originally developed for radiotherapy and chemotherapy sensitization, and there are also preclinical studies supporting the development of PARPi as a single drug for the treatment of BRCA1/2 gene-deficient cancers. Therefore, the initial target population for testing the PARPi-BRCA hypothesis was selected as BRCA1/2 germline mutation (gBRCA1/2) carriers.
  • niraparib and rucaparib FDA and EMA approved niraparib maintenance regimen regardless of BRCA1/2 status
  • rucaparib Talazoparib has also been registered by the FDA and EMA as an optional treatment option for patients with BRCA1/2 mutation-related ovarian cancer who have previously received two lines of chemotherapy
  • talazoparib has also been approved by the FDA for the treatment of BRCA Mutated/HER-2-negative metastatic breast cancer (Mateo, J., Lord, CJ, Serra, V., Tutt, A., J., Castroviejo-Bermejo, M., Cruz, C., Oakni n, A., Kaye, SB, & de Bono, JS (2019). A decade of clinical development of PA RP inhibitors in perspective. Annals of oncology: official journal of the European Society for Medical Oncology, 30(9),1437–1447. https://doi.org/10.1093/annonc/mdz192).
  • TH-302 (Evofosfamide, CAS No. 918633-87-1) is a 2-nitroimidazole-induced hypoxia-activated prodrug (HAP) brominated isophosphamide. Under hypoxic conditions, the inactive TH-302 prodrug can release highly toxic Br-IPM.
  • HAP hypoxia-activated prodrug
  • TH-302 has a broad spectrum of biological activities in vivo and in vitro, as well as specific hypoxia selective activation activity and induction of H2AX phosphorylation and DNA cross-linking activities, leading to cell cycle arrest. Therefore, this compound has been studied by many pharmaceutical companies and scientific research institutes. Development of anticancer drugs.
  • TH-302 has broad-spectrum activity against various tumors and has excellent hypoxia-selective activity enhancement effect. Studies have shown that the in vitro cytotoxicity of TH-302 in 32 human cancer cell lines under hypoxic conditions was significantly stronger than that under normoxic conditions, indicating that the compound has selective cytotoxicity to cancer cells in a hypoxic environment.
  • POR one-electron reductase
  • Cytochrome P450 oxidoreductase reduces TH-302, a prodrug, to obtain intermediate free radical anions, which are then unstable and decomposed into the cytotoxic cytotoxin Br-IPM.
  • the key step in this step is the single-electron reduction process. Research has confirmed that the presence of oxygen will reverse the single-electron reduction process. That is to say, the presence of oxygen will hinder the single-electron reduction process. Therefore, only in an oxygen-deficient environment, TH-302 can It can be reduced to produce Br-IPM with stronger cytotoxicity.
  • DNA repair mutant cell lines based on Chinese hamster ovary cells including cell lines lacking base excision, nucleotide excision, non-homologous end joining repair or homologous end joining repair cell lines (the cell lines lack homologous end joining repair) source-dependent repair cell lines) to detect the in vitro cytotoxicity of TH-302.
  • the study found that cell lines lacking homologous end joining to repair defects alone or together with nucleotide excision were significantly more sensitive to TH-302 hypoxia. However, cell lines repaired by base excision, nucleotide excision or non-homologous end joining alone have no effect on TH-302 sensitivity.
  • TH-302 is particularly sensitive to BRCA mutations
  • TH-302 drugs may have particularly significant therapeutic effects on certain cancer patients.
  • the inventor's experimental results further prove that TH-302 is more effective in treating cancer than PARP inhibitors, even for patients with BRCA pathogenic mutations who have excellent effects on PARP inhibitors.
  • this application provides the following cancer treatment methods.
  • Treatment method which uses a drug containing a hypoxia-activated compound of formula (1) alone or in combination with a PARP inhibitor to treat cancer and tumor patients:
  • R is each independently selected from H, -CH 3 , -CH 2 CH 3 , -CF 3 , and X is each independently selected from leaving functional groups such as Cl, Br, MsO, and TsO.
  • the medicines described herein refer to medicines or preparations, and the medicines prepared contain the hypoxia-activated compound of formula (1) or a salt or solvate thereof as an active ingredient in a specific dosage range, and/or the medicines prepared are specific Dosage form and specific administration method.
  • the prepared medicines, medicines and preparations may also contain pharmaceutically acceptable auxiliary materials or excipients.
  • the drug can be in any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, and small injection needles. , freeze-dried powder for injection or large infusion.
  • the pharmaceutically acceptable excipients or excipients in the medicine may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, and binders. , fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • TH-302 With TH-302 or its similar compounds
  • Relevant preparations include oral preparations, freeze-dried preparations and concentrated injections, and the relevant prescriptions, preparation methods, clinical compatibility, and administration methods are described in detail and disclosed by Threshold's relevant patents: WO2010048330A1, WO2012142520A2, and WO2008083101A1.
  • Threshold's relevant patents WO2010048330A1, WO2012142520A2, and WO2008083101A1.
  • the present invention will The full text of the above application text is introduced.
  • TH-302 or similar compounds It is a DNA alkylating agent anti-cancer drug with a wide range of cancer treatment potential.
  • Threshold and other pharmaceutical companies such as WO2016011195A2, WO2004087075A1 , WO2007002931A1, WO2008151253A2, WO2009018163A1, WO2009033165A2, WO2010048330A2, WO2012142520A1, WO2008083101A2, WO2020007106A1, WO2020118 251A1, WO2014169035A1, WO2013116385A1, WO2019173799A2, WO2016081547A1, WO2014062856A1, WO2015069489A1, WO2012006032A2, WO2018026606A2, WO2010 048330A2, WO2015171647A1, WO2013096687A1, WO2013126539A2, WO2013096684A2, WO2010 048330A2, WO2015171647A1,
  • Cancer refers to leukemias, lymphomas, carcinomas, and other malignancies (including solid tumors) with potentially unrestrained growth that can expand locally by invasion and systemically by metastasis.
  • treatable cancers include, but are not limited to, adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nervous tissue, pancreas, prostate, Cancers of the parathyroid gland, skin, stomach and thyroid.
  • cancers include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysepithelial carcinoma and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, multiple glioblastoma, pilocytic tumors, intestinal ganglioneuroma, proliferative corneal neurotumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid tumor, malignant melanoma , malignant hypercalcemia, Marfanoid tumor, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, ovarian tumors, Pheochromocytoma, polycythemia ver
  • PARP is an enzyme, its full name is poly(ADP-ribose Polymerase, PARP).
  • PARP is a DNA single-strand repair enzyme that plays a key role in the DNA repair pathway.
  • PARP is activated when a single strand of DNA is damaged and broken. As a molecular sensor of DNA damage, it has the function of identifying and binding to the location of DNA breaks, thereby activating and catalyzing the polyADP ribosylation of the receptor protein and participating in the single strand of DNA. repair process.
  • PARP inhibitors By inhibiting the work of PARP enzymes, PARP inhibitors prevent these PARP enzymes, which are equivalent to repairmen, from working properly. Single-strand damage to DNA cannot be repaired, and cells will die.
  • PARP inhibitors are used to prevent PARP from doing its job, the DNA of cancer cells cannot be repaired. In this way, PARP inhibitors only kill cancer cells but not normal cells.
  • Synthetic Lethality simply refers to when two different genes (BRCA) or proteins (PRAP) lose their function at the same time. Will cause cell death, but if only one of these two genes/proteins loses function, it will not cause cell death.
  • PARP inhibitors are compounds that inhibit PARP enzyme, that is, all substances that can inhibit PARP enzyme activity are PARP inhibitors.
  • the PARP inhibitor here essentially refers to drugs containing the active ingredient of a PARP inhibitor.
  • Talazoparib is indicated for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer.
  • the commercially available dosage form of talazoparib tosylate capsule is 0.25 mg/1 mg, 1 mg taken orally once a day. In case of adverse reactions, treatment interruption or dose reduction should be considered:
  • the oral dose is reduced to 0.75 mg (three 0.25 mg capsules), once a day;
  • the oral dose is reduced to 0.5 mg (two 0.25 mg capsules), once a day;
  • the oral dose was reduced to 0.25 mg (one 0.25 mg capsule), once a day.
  • Niraparib is indicated for the maintenance treatment of adult patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved complete or partial response to platinum-containing chemotherapy.
  • the commercially available dosage form of niraparib tosylate capsule is 100 mg. Take 300 mg orally once a day until disease progression or intolerable adverse reactions occur. In the case of adverse reactions, consider treatment interruption or dose reduction:
  • the dosage is first reduced from 3 capsules per day (300mg) to 2 capsules per day (200mg);
  • the dose can be reduced a second time from 2 capsules per day (200mg) to 1 capsule per day (100mg);
  • Rucaparib is for women with advanced ovarian cancer whose tumors carry a specific gene mutation (a harmful BRCA) and have been treated with two or more chemotherapy drugs.
  • the commercially available dosage forms are tablets: 200mg, 250mg and 300mg, in three strengths.
  • the recommended dose is 600 mg taken orally twice daily with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider interrupting treatment or reducing the dose.
  • Olaparib is indicated for treatment-na ⁇ ve adult patients with germline or somatic BRCA mutations (gBRCAm or sBRCAm) in advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who achieve complete or partial response to platinum-based chemotherapy. Maintenance therapy after platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after achieving complete or partial response to platinum-containing chemotherapy.
  • the commercially available dosage forms are tablets: 150mg and 100mg, in two specifications. The recommended dose is 300 mg (2 150 mg tablets) twice daily, equivalent to a total daily dose of 600 mg. 100 mg tablets for use during dose reduction:
  • treatment interruption or dose reduction may be considered;
  • the recommended dose is reduced to 250 mg (one 150 mg tablet, one 100 mg tablet), taken twice daily (equivalent to a total daily dose of 500 mg);
  • the recommended dose is reduced to 200 mg (two 100 mg tablets) taken twice daily (equivalent to a total daily dose of 400 mg).
  • Fluzoparib is used for the treatment of patients with platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer with germline BRCA mutations (gBRCAm) who have received second-line or above chemotherapy.
  • Commercially available dosage form capsule 50mg specification.
  • TH-302 (concentrate for administration solution) used in clinical trials is a sterile liquid formulation of TH-302.
  • TH-302 was formulated with 70% absolute ethanol, 25% dimethylacetamide and 5% polysorbate 80. It is supplied by the sponsor in 10 mL glass vials with rubber stoppers and flip-off closures.
  • TH-302 drug product is a clear, colorless to pale yellow solution that contains essentially no visible particles.
  • each single-use vial contains a nominal fill volume of 6.5 mL of TH-302 drug product (equivalent to 100 mg/mL) and is clearly labeled with the The batch number, route of administration, required storage conditions, name of the sponsor, and appropriate warning labeling required by applicable regulations are disclosed. It needs to be diluted according to the pharmacy manual before administration.
  • TH-302 Dilute to a total volume of 500 mL (1000 mL for total doses ⁇ 1000 mg) with commercially available 5% aqueous glucose solution prior to administration to obtain the desired final concentration.
  • Each dose of TH-302 is prepared with a 5% aqueous dextrose solution without di(2-ethylhexyl) phthalate (DEHP-free) and administered intravenously using a DEHP-free intravenous infusion administration device.
  • DEHP-free di(2-ethylhexyl) phthalate
  • a solution (20 mL) of TH-302 (100 mg) and sucrose (1 g) was added to a lyophilized vial and lyophilized to produce a lyophilized unit dosage form of TH-302 with a drug loading of less than 5 mg/cm 3 .
  • the follow-up dosing regimen for the phase I clinical trial of TH-302 in human patients uses a freeze-dried preparation.
  • the TH-302 freeze-dried preparation for injection is prepared in a 100 mL glass vial with a drug loading of 100 mg/100 ml. The dosage is maintained at 2-8°C. Store under controlled conditions.
  • Monotherapy refers to the use of only one anticancer drug in a course of treatment.
  • Combination therapy refers to the simultaneous or sequential use of two or more anti-cancer drugs in one course of treatment.
  • combination therapy requires exploring different dosages and administration cycles based on the characteristics of the disease and the types of combined drugs. Only based on the above conditions, the explored combination drug treatment plan can achieve better therapeutic effects than single drug treatment.
  • damaged DNA repair enzymes are selected from:
  • Homologous recombination DNA repair enzyme (homologous recombination repair) is damaged
  • Nucleotide excision repair enzyme (nucleotide excision repair) is damaged
  • Base excision repair enzyme (base excision repair) is damaged
  • Fanconi s anemia involves damage to one or more of the pathway repair enzymes.
  • any one or more of homologous recombination DNA repair enzymes, nucleotide excision repair enzymes, and base excision repair enzymes are damaged, and more preferably, a single homologous recombination DNA repair enzyme is damaged. Or both homologous recombination DNA repair enzymes are damaged and nucleotide excision repair enzymes are damaged.
  • the patient's tumor or cancer tissue was detected to have any of the genes corresponding to BRCA1 and BRCA2. It means one pathogenic gene mutation or two pathogenic gene mutations; or the patient is detected to have any one pathogenic gene mutation or two pathogenic gene mutations in the genes corresponding to BRCA1 and BRCA2.
  • Olaparib partner detection kit BRACAnalysisCDx developed by the American company Myriad, this genetic test is used to detect BRCA gene mutations in blood samples of ovarian cancer patients;
  • BRCA1/2 gene mutation detection kit (combined probe-anchored polymerization sequencing method), developed by BGI Biotechnology (Wuhan) Co., Ltd., is used to detect the BRCA1/2 gene in patients with clinically diagnosed ovarian cancer and breast cancer. Qualitative detection of germline variants in subregions and adjacent intronic regions;
  • the human BRCA1 gene and BRCA2 gene mutation detection kit (reversible end termination sequencing method), developed by Xiamen Aide Biomedical Technology Co., Ltd., can be used for relevant medication guidance of the PARP inhibitor Lynparza Tablets.
  • BRCA1 and BRCA2 mutations include germline mutations (gBRCAm) and systemic mutations (sBRCAm).
  • hypoxia-activating compound of formula (1) is selected from compounds with the following structures:
  • TH-302 is preferred.
  • the cancer or tumor is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, colon cancer, rectal cancer, etc.
  • the TMB (tumor gene mutation burden) level of the BRCA pathogenic gene mutation is medium.
  • TMB Tumor mutation load (burden), that is, tumor gene mutation load
  • burden Tumor mutation load
  • TMB Tumor mutation load
  • Mb represents every million bases
  • CheckMate-032 This is a phase II clinical trial that included 401 patients with advanced lung cancer who failed first-line treatment and received PD-1 inhibitors alone or in combination with ipilimumab.
  • TMB Tumor mutation load
  • the effective rates of the three groups are 62%, 20%, and 23% respectively.
  • the effective rate of the people with high TMB is higher 3 times; and the median overall survival of the three groups were: 22.0 months, 3.6 months, 3.4 months - 22.0 months and 3.4 months, a 6-fold difference!
  • cancer or tumor patients are sensitive or resistant to PARP inhibitors.
  • Susceptibility and resistance are qualitative judgments that evaluate whether a patient is resistant to a drug. They are commonly used in drug susceptibility testing of microbial pathogens and antibacterial (bacteria and fungi) drugs.
  • Sensitivity and resistance are two different results shown in clinical drug susceptibility testing.
  • the so-called sensitivity means that during the drug sensitivity test, it is found that the pathogen is very sensitive to this drug, that is, this drug can kill all pathogens; and drug resistance means that during the experiment, it is found that this drug cannot kill the pathogen, that is, This drug is ineffective.
  • this result is obtained clinically, it is very meaningful for treatment, and more sensitive drug treatment can be selected to kill the pathogen.
  • there is also a result in the results that is moderately sensitive which means moderately sensitive. It is easy to develop resistance but it may be useful, but the efficacy will not be very good and not as effective as sensitive treatments.
  • chemotherapy compared to surgery and radiotherapy, chemotherapy here is broad and refers to the use of drugs to treat cancer
  • a series of chemotherapy drugs are usually used sequentially: when the first drug is administered for a period of After a period of time, when there is no therapeutic effect on the patient or the therapeutic effect is very weak, it is considered that the patient with the cancer has developed resistance or resistance to the drug.
  • other drugs second-line drugs
  • the corresponding second-line drugs may also be used.
  • third-line drugs need to be used. Sensitivity and resistance are diagnosed and judged by medical professionals or clinicians.
  • the specific meaning of cancer and tumor patients being sensitive to PARP inhibitors is that if the patient is diagnosed with a BRCA pathogenic mutation and has an effect after taking a PARP inhibitor, or it is judged that the PARP inhibitor will be effective after a doctor's diagnosis and treatment, In this case, TH-302 alone or combined with PARP inhibitor TH-302 will have a better therapeutic effect.
  • TH-302 administration of TH-302 according to the present invention will replace PAPR inhibitors, and TH-302 can be substituted for all indications of PAPR inhibitors: the indications of PAPR inhibitors approved on the market include platinum-sensitive recurrent epithelial ovary Cancer, fallopian tube cancer or primary peritoneal cancer; advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer carrying germline or somatic BRCA mutations. The corresponding TH-302 may be effective for these indications with excellent efficacy. for PAPR inhibitors.
  • the invention also provides a treatment method, which includes the following steps:
  • R is each independently selected from H, -CH 3 , -CH 2 CH 3 , -CF 3 , and X is each independently selected from leaving functional groups such as Cl, Br, MsO, and TsO.
  • the above-mentioned drugs should also add pharmaceutically acceptable auxiliary materials or excipients according to the specificity of the drug, drug, and preparation.
  • the drug can be in any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, and small injection needles. , freeze-dried powder for injection or large infusion.
  • pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, viscosifiers, Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • the above drugs can be used alone or in combination with PARPi drugs for treatment.
  • Preparation unit packaging including an independent packaging container containing a pharmaceutical preparation, an outer packaging component for accommodating the independent packaging container, and pharmaceutical instructions, characterized in that the pharmaceutical preparation contains a hypoxia-activated compound of formula (I), and the pharmaceutical preparation
  • the instructions state that the drug is used in combination with PARP inhibitors to treat cancer and tumor patients:
  • R is each independently selected from H, -CH 3 , -CH 2 CH 3 , -CF 3 , and X is each independently selected from leaving functional groups such as Cl, Br, MsO, and TsO.
  • Preparation unit packaging is a concept in the process of drug production and sales. It refers to the process of production, storage, transportation and sales.
  • Drugs pharmaceuticalals
  • labels or printed labels are affixed or printed on the outer wall of the drug inner packaging container.
  • the final product has Labels and independent packaging containers with medicines inside are placed in the outer packaging component (usually a paper packaging box, directly seen by consumers), and the drug instructions (Label) that record the most critical information about the medicine are also It is packed into the outer packaging assembly together with the independent packaging container.
  • Label Usually legal drug instructions (Label) have the following legal contents:
  • drug instructions must record the drug name, ingredients (active ingredients, excipients), properties, specifications, indications, usage and dosage, contraindications, warnings and precautions, adverse reactions, drug interactions, and use by pregnant and lactating women.
  • children's medication elderly medication, drug abuse and drug dependence, drug overdose, clinical pharmacology (pharmacodynamics, pharmacokinetics, pharmacogenetics), pharmacology and toxicology (pharmacological effects, toxicology research), clinical trials, Storage, packaging, validity period, implementation standards, approval number, drug marketing authorization holder (name, registered address), production company (company name, production address), etc.
  • the drug instructions in the packaging of the final sold preparation unit are the key content for the use of the drug: without the drug instructions, the drug will not be usable. Therefore, the drug instructions are indispensable for the final function of the drug and are also an important part of the drug development and manufacturing process. Inevitable link, in fact, it is impossible for drug R&D and manufacturing-related entities (drug R&D manufacturers, drug sales agencies, medical institutions) to directly produce specific single drugs/combination indications without going through research activities such as R&D and clinical trials. Drugs are even less likely to be sold, distributed and administered to patients. Therefore, the content of drug instructions is very important and is a key and indispensable link in the drug manufacturing process (the final administered drug must have drug instructions).
  • Drugs used in combination with PARP inhibitors to treat cancer and tumor patients belong to the Indications and Usage of the drug (United States) and Indications (China).
  • hypoxia-activated compound of formula (I) in the preparation of preparation unit packaging, the pharmaceutical use is achieved by the following operations:
  • the pharmaceutical preparation contains a hypoxia-activated compound of formula (I), and the pharmaceutical instructions record that the pharmaceutical is used in combination with a PARP inhibitor to treat cancer and tumor patients:
  • R is each independently selected from H, -CH 3 , -CH 2 CH 3 , -CF 3 , and X is each independently selected from Cl, Br, MsO, T sO and other leaving functional groups.
  • the patient's DNA repair enzyme is damaged
  • the patient's tumor or cancer tissue is detected to have a pathogenic gene mutation or two pathogenic gene mutations in the genes corresponding to BRCA1 and BRCA2; or the patient is detected to have a pathogenic gene mutation corresponding to BRCA1 or BRCA2. Mutations in any one or two disease-causing genes in the gene,
  • BRCA1 and BRCA2 mutations include germline mutations (gBRCAm) and systemic mutations (sBRCAm) BRCA1 and BRCA2 mutations,
  • hypoxia-activating compound of formula (I) is selected from compounds with the following structures:
  • the PARP inhibitor is selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, and Pamiparib,
  • the cancer or tumor is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, colon cancer, and rectal cancer,
  • the cancer or tumor patient is sensitive or resistant to PARP inhibitors.
  • Figure 1 is the growth curve of tumor volume in each group of mice in the in vivo efficacy experiment of TH-302 and Olaparib in the Olaparib-sensitive OV5304 PDX model;
  • Figure 2 is the in vivo efficacy experiment of TH-302 and Olaparib in the Olaparib-sensitive OV5304 PDX model; the body weight percentage change curve of each group of mice;
  • Figure 3 is the growth curve of tumor volume in each group of mice using TH-302 and Olaparib in the Capan-1 CDX model of pancreatic cancer;
  • Figure 4 is a graph showing the percentage change in body weight of mice in each group using TH-302 and Olaparib in the Capan-1 CDX model of pancreatic cancer.
  • a patient and “individual” are used interchangeably and refer to a mammal in need of cancer treatment. Typically, the patients are humans. Typically, a patient is a human being diagnosed with cancer. In certain embodiments, a "patient” or “individual” may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, used for screening, characterizing, and evaluating drugs and therapies. Or rats.
  • Prodrug refers to a compound that is metabolized or otherwise converted to a compound (or drug) that is biologically active or more active with respect to at least one property after administration or administration.
  • a prodrug is chemically modified relative to the drug in a manner that renders it less or inactive relative to the drug, but the chemical modification is such that the corresponding drug is produced by metabolism or other biological processes upon administration of the prodrug.
  • Prodrugs may have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavor relative to the active drug. Prodrugs can be synthesized using reactants other than the corresponding drug.
  • Treating means administering, using or administering to a patient a therapeutically effective amount of a drug relevant to the present invention.
  • administer or “administer” a drug to a patient.
  • “Use” means direct administration or administration (which may be administered or administered to the patient by a medical professional or may be self-administered or administered) and/or indirect administration or administration, which may be a prescribed drug. the behavior of. For example, a physician who instructs a patient to self-administer or administer a drug and/or provides a prescription for a drug to the patient is administering or administering the drug to the patient.
  • a "therapeutically effective amount" of a drug is one that, when administered or administered to a patient with cancer, will have the desired therapeutic effect (e.g., alleviation, amelioration, alleviation, or elimination of the clinical manifestations of one or more cancers in the patient) the amount of drug.
  • the therapeutic effect does not necessarily occur by administering or administering one dose, and may occur only after administering or administering a series of doses.
  • a therapeutically effective amount may be administered or administered in one or more times.
  • Treatment of a condition or patient means taking steps to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical results include (but are not limited to) alleviation or improvement of one or more cancer symptoms; reduction in disease severity; delay or slowing of disease progression; improvement, remission, or stabilization of disease status; or other beneficial results.
  • treatment of cancer can result in partial response or stabilization of the disease.
  • Tumor cells refers to tumor cells of any appropriate species (eg, mammal, eg, murine, canine, feline, equine, or human).
  • Subcutaneous vaccination using BALB/c nude female mice Model OV5304 tumor mass was used to establish a subcutaneous transplantation tumor model of human ovarian cancer.
  • the trial is divided into glucose injection control group, test drug Olaparib 50mg/kg single drug group, test drug TH-302 20mg/kg, 40mg/kg and 80mg/kg single drug group and Olaparib 50mg/kg and TH-302 40mg/kg Combination drug group.
  • the glucose injection control group, the test drug TH-302 20mg/kg, 40mg/kg and 80mg/kg single drug group, and the TH-302 40mg/kg in the Olaparib 50mg/kg and TH-302 40mg/kg combined drug group It is administered by tail vein injection once a week for three consecutive weeks.
  • the test drug Olaparib 50mg/kg single drug group and the Olaparib 50mg/kg and TH-302 40mg/kg combination group were administered orally by gavage once a day for 30 consecutive days.
  • the specific dosage regimen and TGI are shown in Table 1.
  • test drug efficacy experiments show that in BRCA1 pathogenic mutations, In the ovarian cancer OV5304 model, the test drug Olaparib (50mg/kg) monotherapy group had a significant tumor inhibitory effect on the 30th day after the first administration, with a relative tumor inhibition rate TGI (%) of 96.16%, compared with the control group There is a statistically significant difference (p ⁇ 0.001).
  • the test drug TH-30 20mg/kg treatment group, TH-302 40mg/kg and TH-302 80mg/kg monotherapy groups also showed significant tumor inhibition on the 30th day after the first administration, with a relative tumor inhibition rate TGI (%) were 82.81%, 97.98% and 100% respectively.
  • the p values were p ⁇ 0.01, p ⁇ 0.001 and ⁇ 0.001 respectively, and TH-302 single drug had a statistically significant effect in this model. showed dose dependence.
  • Statistical analysis results of mouse TGI in each group showed that the TH-302 80 mg/kg group had a significant difference in the inhibitory effect on tumor proliferation compared with Olaparib 50 mg/kg.
  • the anti-tumor effect of the test drug TH-302 40mg/kg and Olaparib 50mg/kg combined treatment group was significantly better than that of the Oplaparib 50mg/kg monotherapy group and TH-302 40mg/kg monotherapy group, and it was statistically significant. This shows that the anti-tumor effects of TH-302 and Olaparib are synergistic.
  • TH-302 alone or in combination with Olaparib showed significantly better tumor clearance and anti-tumor proliferation abilities than the Olaparib alone group;
  • test drugs TH-302 and Olaparib did not show any obvious weight loss in the single-drug or combined-drug treatment groups.
  • the mice were well tolerated during the treatment. Preliminary indications are that the two drugs are effective at certain dosages. At a certain level, combined use has a certain degree of safety.
  • mice were subcutaneously inoculated with human pancreatic cancer Capan-1 cells to establish a subcutaneous transplantation model of human pancreatic cancer.
  • the trial is divided into test drug Olaparib 100mg/kg single drug group (Group 2), TH-302 50mg/kg single drug group (Group 3, QD), TH-302 100mg/kg single drug group (Group 4, QW), TH -302 50mg/kg single drug group (Group 5, QW), TH-302 25mg/kg single drug group (Group 6, QW), TH-302 25mg/kg and Olaparib 100mg/kg combined administration group (Group 7) And 10% absolute ethanol + 10% polyoxyethylene (35) castor oil + 80% glucose injection D5W (pH7.4) vehicle control group (Group 1), a total of 7 groups, 6 mice in each group. The vehicle control group and each test drug of TH-302 were administered by tail vein injection.
  • the TH-302 50mg/kg single drug group (Group 3, QD) was administered once a day for 3 consecutive days, followed by a 4-day break, and then rested for two weeks; then administered every day for 3 consecutive days.
  • TH-302 100mg/kg (Group 4, QW), 50mg/kg (Group 5, QW), 25mg/kg (Group 6, QW) single drug group and TH-302 25mg/kg and Olaparib 100mg/kg combined administration TH-302 in Group 7 was administered once a week for a total of three weeks.
  • the test drug Olaparib in each group was administered orally by gavage once a day for a total of 30 days.
  • the specific administration routes, dosages and regimens in the Capan-1 animal model of human pancreatic cancer are shown in Table 2.
  • Table 2 Administration routes, dosages and regimens in the Capan-1 animal model of human pancreatic cancer Note: The dosage volume is 10 ⁇ L/g.
  • the tumor growth of each treatment group and control group was recorded on different days of the test, as shown in Table 3.
  • the corresponding growth curve of tumor volume of mice in each group is shown in Figure 3.
  • the efficacy was evaluated based on the relative tumor proliferation rate and relative tumor inhibition rate.
  • the efficacy analysis of each group is shown in Table 4.
  • the results of the mouse weight change rate on day 43 are shown in Table 5.
  • the weight of each treatment group changes with time.
  • the change curve is shown in Figure 4.
  • Table 3 Changes in tumor volume of mice in each group with treatment time in the Capan-1 model of human pancreatic cancer (mm 3 )
  • Table 5 Body weight changes in each group in the Capan-1 subcutaneous model of human pancreatic cancer (day 43 after vaccination)
  • mice in the vehicle control group were 1301.38mm 3 on Day 43 after tumor cell inoculation.
  • the average tumor volume of the test drug Olaparib 100mg/kg (Group 2) treatment group on Day 43 after tumor cell inoculation was 846.86mm 3 , and the relative tumor inhibition rate TGI (%) was 37.43%.
  • TGI tumor inhibition rate
  • the relative tumor inhibition rate TGI (%) was 89.17%.
  • the relative tumor inhibition rate TGI (%) was 90.89%.
  • the relative tumor inhibition rate TGI (%) was 80.18%, and the complete tumor inhibition rate was 33.3%.
  • the relative tumor inhibition rate TGI (%) was -21.59%.
  • TH-302 100mg/kg (Group 4, QW), 50mg/kg (Group 5, QW) and 25mg/kg (Group 6, QW) monotherapy groups showed dose-dependent anti-tumor effects of the drug.
  • the TH-302 100mg/kg (Group 4, QW) and 50mg/kg (Group 5, QW) monotherapy groups were statistically significant compared with the TH-302 25mg/kg monotherapy group (Group 6, QW). sexual differences (p ⁇ 0.001).
  • the anti-tumor effect of the combined treatment group of Olaparib 100mg/kg and TH-302 25mg/kg (Group 7) is better than that of Olaparib 100mg/kg (Group 2) and TH-302 25mg/kg single drug group (Group 6), statistically There are significant differences (p ⁇ 0.05 and p ⁇ 0.001), and the specific dose combination of Olaparib and TH-302 can show a synergistic effect in tumor suppression.
  • Test drugs Olaparib 100mg/kg (Group 2), TH-302 25mg/kg (Group 6), TH-302 50mg/kg (Group 3, QD), TH-302 50mg/kg (Group 5, QW), TH- The body weight of mice in the combined administration group (Group 7) and vehicle control group (Group 1) of 302 100mg/kg (Group 4, QW), Olaparib 100mg/kg and TH-302 25mg/kg was well tolerated.
  • TH-302 single-drug treatment regimen is resistant to Olaparib (the statistical average TGI in six experimental mice is 37.43%, and the general judgment standard of technicians is about 60%. This result shows a certain degree of resistance. showed excellent anti-tumor effects in pancreatic cancer models (Group 3, Group 4, Group 5); while low-dose TH-302 monotherapy had no anti-tumor effect (Group 6).
  • the PARP inhibitor selected in the embodiments of this application is Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib, etc. It is also a PARP inhibitor, and its mechanism of action is similar to that of Olaparib. They both block the enzymes involved in repairing damaged DNA. Therefore, it can be inferred that Rucaparib, Niraparib, and Talazopar PARPi such as Talazoparib, Fluzoparib, and Pamiparib have similar tumor inhibitory effects to Olaparib in the above experiments.
  • TH-302 is a hypoxia-activated DNA alkylating agent, a compound of the general formula of claim 1:

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Abstract

本发明提供TH-302及其类似物单药或联用PARP抑制剂治疗癌症的方法，特别是TH-302单药治疗对PARP抑制剂敏感的癌症患者、TH-302联用PARP抑制剂治疗癌症患者。

Description

使用TH-302单药或联用PARP抑制剂治疗癌症的方法 技术领域
本发明涉及癌症的治疗方法，特别是PARP抑制剂(PARPi)敏感的癌症患者的治疗方法。
背景技术
PARPi药物奥拉帕利Olaparib的第一个人体临床试验，首次证实了PARPi可抑制携带BRCA1/2突变的肿瘤细胞的生长，这主要基于合成致死性理论(Ashworth,A.,& Lord,C.J.(2018).Synthetic lethal therapies for cancer:what's next after PARP inhibitors？.Nature r eviews.Clinical oncology,15(9),564–576.https://doi.org/10.1038/s41571-018-0055-6)：PARP抑制剂可以抑制PARP的DNA单链损伤修复功能，导致细胞内大量单链DNA损伤不能及时修复。未被修复的单链DNA损伤会引发复制叉崩解并由此产生双链DNA损伤，具有较强细胞毒性的双链DNA损伤在正常细胞内可通过BRCA1及BRCA2等蛋白共同参与介导的同源重组修复(HR)途径进行修复，而在BRCA1/2缺陷的肿瘤细胞内，双链DNA损伤无法修复，导致肿瘤细胞的最终死亡。PARPi最初开发用于放射治疗和化疗增敏，也有临床前研究支持PARPi可以作为治疗BRCA1/2基因缺陷癌症的单一药物进行开发。由此，PARPi-BRCA假说验证的初始目标人群选定为BRCA1/2胚系突变(gBRCA1/2)携带者。PARPi在卵巢癌中的最初研究入组人群均是既往已接受过铂类化疗，且研究发现铂类敏感与PARPi响应有直接关联(铂类化疗药是DNA损伤剂，会导致DNA交联，部分可由HR通路修复；因此DNA修复缺陷型肿瘤预期会对铂类化疗敏感)。另外两个PAR Pi已在卵巢癌中获批：尼拉帕利Niraparib和芦卡帕利Rucaparib：FDA和EMA批准了尼拉帕利的维持治疗方案(不管BRCA1/2状态如何)；芦卡帕利也被FDA和EMA登记为BRCA1/2突变相关卵巢癌患者，既往接受过两线化疗方案之后的可选治疗方案；而他拉唑帕利现也得到了FDA的获批，用于治疗BRCA突变/HER-2阴性转移性乳腺癌(Mateo,J.,Lord,C.J.,Serra,V.,Tutt,A.,J.,Castroviejo-Bermejo,M.,Cruz,C.,Oakni n,A.,Kaye,S.B.,& de Bono,J.S.(2019).A decade of clinical development of PA RP inhibitors in perspective.Annals of oncology:official journal of the European Socie ty for Medical Oncology,30(9),1437–1447.https://doi.org/10.1093/annonc/mdz192)。
发明内容
TH-302(Evofosfamide，埃夫索胺，cas号918633-87-1)是一种2-硝基咪唑引发的乏氧激活前药(HAP)溴代异磷酰胺。在乏氧情况下，无活性TH-302前药可释放高毒性的Br-IPM。TH-302具有广谱的体内外生物活性以及特异的乏氧选择性激活活性以及诱导H2AX磷酸化、DNA交联活性，从而导致细胞周期停滞，因而该化合物被多家制药公司以及科研院所进行抗癌药物的开发。
Meng F Y(孟繁英)等人发表的研究文章指出：TH-302对于各种肿瘤具有广谱活性，并且具有优异的缺氧选择性的活性增强效应。研究表明，缺氧条件下32个人癌细胞系中TH-302的体外细胞毒性均明显强于常氧条件下的，显示该化合物对于缺氧环境下的癌细胞具有选择性的细胞毒性。使用单电子还原酶(POR)过表达的人源细胞证实了TH-302在乏氧条件下单电子还原酶依赖性的活性增强原理，如下反应式1：
细胞色素P450氧化还原酶将TH-302这个前药进行还原，得到中间体自由基负离子，然后自由基负离子不稳定而被分解为具有细胞毒性的细胞毒素Br-IPM发挥作用。该步骤的关键步骤是单电子还原过程，研究证实氧气的存在会使得单电子还原过程逆转，也就是说，氧气的存在会阻碍单电子还原过程，所以只有乏氧的环境下，TH-302才可还原产生具有更强细胞毒性的Br-IPM。进一步使用基于中国仓鼠卵巢细胞的DNA修复突变细胞系，包括缺乏碱基切除、核苷酸切除，非同源末端连接修复的细胞系或同源末端连接修复的细胞系(该细胞系为缺乏同源依赖性修复的细胞系)检测TH-302的体外细胞毒性。研究发现缺乏同源末端连接修复单独缺损或与核苷酸切除共同修复缺损的细胞系，对TH-302缺氧敏感性明显增强。但是单独缺损碱基切除、核苷酸切除或非同源末端连接修复的细胞系对TH-302敏感性无影响。与该发现一致的是，在缺乏BRCA1，BRCA2和FANCA DNA双链修复的细胞体外实验中中也观察到对TH-302的敏感性增强；并且在临床试验中也观察到TH-302对于BRCA基因突变的患者具有更好的治疗效果(Meng F,Evans J W,Bhupathi D,et al.Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302.[J].Molecular Cancer Therapeutics,2012,11(3):740；Conroy,M.,Borad,M.J.,& Bryce,A.H.(2017).Hypoxia-Activated Alkylating Agents in BRCA1-Mutant Ovarian Serous Carcinoma.Cureus,9(7),e1517.https://doi.org/10.7759/cureus.1517；WO2012135757A2，Methods for treating cancer；WO2015013448A1，Treatment of pancreatic cancer with a combination of a hypoxia-acti vated prodrug and a taxane；WO2020007106A1，埃夫索胺的抗癌医药用途)。
这些关于TH-302的作用机理研究，特别是揭示的TH-302对于BRCA突变的特别敏感性事实启发TH-302药物可能对某些癌症患者具有特别显著的治疗效果。发明人的实验结果进一步证明了TH-302治疗癌症的效果强于PARP抑制剂，即使是对于PARP抑制剂具有优异效果的BRCA致病突变的患者，为此本申请提供以下的癌症治疗方法。
治疗方法，其使用含有式(1)的乏氧激活化合物的药物单药或联用PARP抑制剂治疗癌症、肿瘤患者：
其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
关于本文所述药物是指药品或制剂，所制得的药品包含特定剂量范围的有效成分式(1)的乏氧激活化合物或其盐或溶剂合物，和/或所制得的药物为特定剂型、特定给药方式施用。
所制得的药品、药物、制剂还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂 型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
与TH-302或其类似化合物相关的制剂包括口服制剂、冻干制剂和浓缩注射液，并且相关处方、制备方法和临床配伍、施用方法被Threshold公司的相关专利：WO2010048330A1、WO2012142520A2、WO2008083101A1所详细说明并公开，在此本发明将上述申请文本的全文引入。
TH-302或其类似化合物是一个的DNA烷化剂类抗癌药，具有广泛的癌症治疗潜力，这些相关的癌症适应症实验、临床试验被公开在相关的Threshold公司及其他制药公司的专利申请文本中(比如WO2016011195A2、WO2004087075A1、WO2007002931A1、WO2008151253A2、WO2009018163A1、WO2009033165A2、WO2010048330A2、WO2012142520A1、WO2008083101A2、WO2020007106A1、WO2020118251A1、WO2014169035A1、WO2013116385A1、WO2019173799A2、WO2016081547A1、WO2014062856A1、WO2015069489A1、WO2012006032A2、WO2018026606A2、WO2010048330A2、WO2015171647A1、WO2013096687A1、WO2013126539A2、WO2013096684A2、WO2012009288A2、WO2012145684A2、WO2016014390A2、WO2019055786A2、WO2012135757A2、WO2015013448A2、WO2016011328A2、WO2013177633A2、WO2016011195A2、WO2015051921A2)以及FDA登记的临床试验中(NCT02402062、NCT02020226、NCT02076230、NCT01381822、NCT02093962、NCT01440088、NCT02255110、NCT02342379、NCT01864538、NCT01149915、NCT02433639、NCT00743379、NCT01485042、NCT01721941、NCT02047500、NCT00742963、NCT01497444、NCT00495144、NCT01746979、NCT01144455、NCT01403610、NCT01522872、NCT01833546、NCT02598687、NCT03098160、NCT02496832、NCT02712567)，在此本发明将上述相关申请文本以及临床试验信息全部引入。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。
在此列举TH-302或其类似化合物能治疗的癌症的实例包括(但不限于)肾上腺、骨、脑、***、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、***、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、 嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及***型二者的鳞状细胞癌、增生、***瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤。
PARP是一种酶，全称叫聚腺苷酸二磷酸核糖基聚合酶(Poly ADP-ribose Polymerase，PARP)。PARP是一种DNA单链修复酶，在DNA修复通路中起关键作用。DNA单链损伤断裂时会激活PARP，它作为DNA损伤的一种分子感受器，具有识别、结合到DNA断裂位置的功能，进而激活、催化受体蛋白的聚ADP核糖基化作用，参与DNA单链的修复过程。
PARP抑制剂通过抑制PARP酶的工作，让这些相当于修理工的PARP酶没法正常工作，DNA的单链损伤得不到修复，细胞就会死亡。
因为细胞并不是只有PARP这一个修理工，所以即使PARP出问题，细胞的DNA损伤被带到下一个工序中，还有另一个修理工例如双链修复在等待，仍然可以把DNA修复。BRCA基因负责产生的蛋白正是这另一个修理工的重要成员。正常细胞拥有这套双保险机制，即使PARP抑制剂破坏了其中一重保险，另一重仍然可以工作，所以细胞不会死亡。
但是在具有BRCA基因突变的卵巢癌或乳腺癌细胞，BRCA这个修理工已经不能正常工作。当然，由于PARP班组还在继续工作，所以癌细胞还不会死。
如果用PARP抑制剂让PARP也干不了活，癌细胞的DNA就无法修复了。这样，PARP抑制剂就实现了只杀死癌细胞而不杀正常细胞的作用。
PARP抑制剂+BRCA基因突变加起来就是我们所说的“合成致死(Synthetic Lethality)”，合成致死简单来讲指的是，当两种不同的基因(BRCA)或蛋白(PRAP)同时失去功能时会导致细胞死亡，而这两种基因/蛋白中如果只有一种失去功能则不会导致细胞死亡。
PARP抑制剂就是对PARP酶有抑制作用的化合物，即所有能抑制PARP酶活性的物质均是PARP抑制剂。
选自已经上市销售的5个药物即奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib以及他拉唑帕利Talazoparib、氟唑帕利Fluzoparib以及进入临床三期的药物即帕米帕利Pamiparib，显然此处的PARP抑制剂实质是指含有PARP抑制剂活性成分的药物。

他拉唑帕利Talazoparib，适用于有害或疑似有害种系BRCA突变(gBRCAm)HER2阴性局部晚期或转移性乳腺癌的成人。市售剂型为0.25mg/1mg的他拉唑帕利甲苯磺酸盐胶囊，口服一次1毫克，每天1次，在不良反应的情况下考虑治疗中断或剂量减少：
首次出现不良反应，口服剂量减少到0.75mg(三个0.25mg胶囊)，每天1次；
第二次出现不良反应，口服剂量减少到0.5mg(两个0.25mg胶囊)，每天1次；
第三次出现不良反应，口服剂量减少到0.25mg(一个0.25mg胶囊)，每天1次。
尼拉帕利Niraparib，用于铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。市售剂型为100mg的尼拉帕利甲苯磺酸盐胶囊，每天一次口服300mg,直至出现疾病进展或不可耐受的不良反应，在不良反应的情况下考虑治疗中断或剂量减少：
剂量下调首先从每天3粒胶囊(300mg)减少至每天2粒胶囊(200mg)；
如果需要进一步下调剂量，可第二次下调剂量，从每天2粒胶囊(200mg)减少至每天1粒胶囊(100mg)；
如果暂停给药和下调剂量无法控制不良反应，建议停药。
芦卡帕利Rucaparib，用于肿瘤携带一种特定基因突变(有害的BRCA)，且已使用两种或多种化疗药物治疗过的晚期卵巢癌女性。市售剂型为片剂：200mg，250mg和300mg，三种规格。推荐剂量为600毫克，每日口服两次，含或不含食物。继续治疗直至疾病进展或不可接受的毒性。对于不良反应，考虑中断治疗或减少剂量。
奥拉帕利Olaparib，用于携带胚系或体细胞BRCA突变的(gBRCAm或sBRCAm)晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌初治成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗；铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。市售剂型为片剂：150mg和100mg，两种规格。推荐剂量为300mg(2片150mg片剂)，每日2次，相当于每日总剂量为600mg。100mg片剂用于剂量减少时使用：
为处理不良事件，比如恶心、呕吐、腹泻、贫血等，可考虑中断治疗或减量；
如果需要减量，推荐剂量减至250mg(1片150mg片剂，1片100mg片剂)，每日服用2次(相当于每日总剂量为500mg)；
如果需要进一步减量，则推荐剂量减至200mg(2片100mg片剂)，每日服用2次(相当于每日总剂量为400mg)。
氟唑帕利Fluzoparib，用于既往经过二线及以上化疗的伴有胚系BRCA突变(gBRCAm)的铂敏感复发性卵巢癌、输卵管癌或原发性腹膜癌患者的治疗。市售剂型胶囊剂：50mg规格。
其他在研的进入临床的PARPi候选药物参见网页链接https://www.selleckchem.com/PARP.html及相关学术综述文献。
TH-302或其类似化合物治疗癌症的推荐剂量可以参考Threshold公司及其他制药公司的专利申请文本中(比如WO2016011195A2、WO2004087075A1、WO2007002931A1、WO2008151253A2、WO2009018163A1、WO2009033165A2、WO2010048330A2、WO2012142520A1、WO2008083101A2、WO2020007106A1、WO2020118251A1、WO2014169035A1、WO2013116385A1、WO2019173799A2、WO2016081547A1、WO2014062856A1、WO2015069489A1、WO2012006032A2、WO2018026606A2、WO2010048330A2、WO2015171647A1、WO2013096687A1、WO2013126539A2、WO2013096684A2、 WO2012009288A2、WO2012145684A2、WO2016014390A2、WO2019055786A2、WO2012135757A2、WO2015013448A2、WO2016011328A2、WO2013177633A2、WO2016011195A2、WO2015051921A2)以及FDA登记的临床试验中(NCT02402062、NCT02020226、NCT02076230、NCT01381822、NCT02093962、NCT01440088、NCT02255110、NCT02342379、NCT01864538、NCT01149915、NCT02433639、NCT00743379、NCT01485042、NCT01721941、NCT02047500、NCT00742963、NCT01497444、NCT00495144、NCT01746979、NCT01144455、NCT01403610、NCT01522872、NCT01833546、NCT02598687、NCT03098160、NCT02496832、NCT02712567)中的剂量：
120mg/m2至460mg/m2的日剂量来静脉注射给药；
480mg/m2至大约670mg/m2或者例如575mg/m2的周剂量来静脉注射给药。
用于临床试验的TH-302(用于施用溶液的浓缩物)是TH-302的无菌液体制剂。用70％无水乙醇、25％二甲基乙酰胺和5％聚山梨酯80配制TH-302。它由发起人提供，在具有橡胶塞和flip-off封口的10mL玻璃小瓶中。TH-302药物产品是澄清的、无色至淡黄色的溶液，基本上不含可见颗粒。对于标称总量为650mg的TH-302，每个单次使用的小瓶含有标称填充体积为6.5mL的TH-302药物产品(相当于100mg/mL)，并且被清楚地贴上标签，其公开了批号、施用途径、所需的储存条件、发起人的名称和适用的规定所要求的适宜的预警标记。在施用前需要按照药房手册进行稀释。
在施用前用可商购获得的5％葡萄糖水溶液稀释至总体积为500mL(对于≥1000mg的总剂量为1000mL)施用，以获得所需的终浓度。用不含邻苯二甲酸二(2-乙基己基)酯(无DEHP)的5％葡萄糖水溶液制备每剂TH-302，并使用不含DEHP的静脉输液施用装置静脉滴注。
当然也可以使用Threshold公司开发的冻干制剂：
将TH-302(100mg)和蔗糖(1g)的溶液(20mL)加入冻干小瓶中并冻干以产生TH-302的冻干单位剂型，载药量不到5mg/cm3。为了人类施用的目的，将单位剂型溶解在的5％葡萄糖注射液中，并向患者施用适量的该溶液；
后续人类患者TH-302的I期临床试验给药方案使用冻干制剂,在100mL玻璃小瓶中制备注射用TH-302冻干制剂，载药量为100mg/100ml，在2-8℃°的受控条件下储存，使用时注射到冻干制剂瓶中250mL的5％葡萄糖注射液，并通过输注泵在30分钟内静脉滴注。
单药，即单药治疗。联用，即联合用药治疗。单药治疗是指在一个疗程中仅使用一种抗癌药物。联合治疗是指在一个疗程中同时或先后使用两种或两种以上的抗癌药物。
一般而言，联合治疗需要根据病情特点、联用药物种类探索不同的给药剂量、给药周期，只有根据上述情况，探索得到的联合用药治疗方案才可能取得较单一用药治疗好的治疗效果。
单药和联用治疗方案的药物给药剂量、给药周期均需要在参考上述TH-302及其类似化合物和PARPi的剂量、给药方案通过临床试验探索得到。
进一步的，所述患者的DNA修复酶受损。
根据相关研究文献，DNA修复酶受损选自：
同源重组DNA修复酶(homologous recombination repair)受损、
核苷酸切除修复酶(nucleotide excision repair)受损、
非同源末端连接酶受损(nonhomologous end joining)、
碱基切除修复酶(base excision repair)受损、
错配修复酶(mismatch repair)受损、
范康尼贫血(Fanconi’s anemia)途径修复酶受损中的一种或更多种。
优选为同源重组DNA修复酶受损、核苷酸切除修复酶受损、碱基切除修复酶受损中的任意一种或更多种，更优选为单独的同源重组DNA修复酶受损或同时具有同源重组DNA修复酶受损与核苷酸切除修复酶受损。
进一步，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任 意一个致病基因突变或两个致病基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变。
BRCA1、BRCA2对应的基因中的任意一个基因突变或两个基因突变可以通过市售的(伴随)诊断试剂盒检测得到：
奥拉帕利Olaparib伴侣检测试剂盒BRACAnalysisCDx，由美国Myriad公司公司开发，该基因检测用于发现卵巢癌患者血样中BRCA基因突变；
BRCA1/2基因突变检测试剂盒(联合探针锚定聚合测序法)，由华大生物科技(武汉)有限公司开发，用于对临床确诊为卵巢癌及乳腺癌患者的BRCA1/2基因外显子区以及邻近内含子区的胚系变异进行定性检测；
人类BRCA1基因和BRCA2基因突变检测试剂盒(可逆末端终止测序法)，由厦门艾德生物医药科技股份有限公司开发，可用于PARP抑制剂奥拉帕利片的相关用药指导。
BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
式(1)的乏氧激活化合物选自以下结构的化合物：
即TH-302，以及特别的，优选TH-302。
进一步，所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、***癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌等。
所述的BRCA致病基因突变的TMB(肿瘤基因突变负荷)水平为中。
由于不同瘤种之间TMB(Tumor mutation load(burden)即肿瘤基因突变负荷)高低不同：一般认为：TMB超过20个突变/Mb(Mb代表的就是每百万个碱基)，就是高；低于10个突变/Mb，就是低，处于中间的就是中。2017年世界肺癌大会上，施贵宝公司公布过一项名为CheckMate-032的临床试验结果。这是一项纳入了401名一线治疗失败的晚期肺癌患者的II期临床试验，接受PD-1抑制剂单独或联合伊匹木治疗。按照TMB高低划分成TMB高、TMB中、TMB低三类病人，那么在接受联合治疗的人群中，三组的有效率分别为62％、20％、23％，TMB高的人群有效率高3倍；而三组的中位总生存期，分别为：22.0个月、3.6个月、3.4个月——22.0个月与3.4个月，相差6倍！该试验证明，对于不同的癌症治疗药物，不同的TMB水平对于药物的疗效有很大的影响。
其中，所述癌症、肿瘤患者对PARP抑制剂是敏感的或耐药的。
敏感和耐药是评价患者对于一种药物是否具有抗性的定性判断，常见于微生物病原体与抗菌(细菌和真菌)药的药敏实验中。
敏感和耐药都是临床在进行药敏试验时，表现出来的两种不同的结果。所谓敏感就是在做药敏试验的时候，发现病原体对这种药物很敏感，也就是这种药能全部杀死病原体；而耐药就是在实验的时候发现这种药不能杀死病原体，也就是这种药物是没有效果的。另外临床得到这个结果的时候，对治疗就很有意义的，就可以选择比较敏感的药物治疗来杀死病原体。同时结果里面还有一个结果是中敏，就是中度敏感的意思，很容易产生耐药但也有可能有用，但疗效不会很好，不如敏感的治疗有效果。
在癌症治疗的化疗(相对于手术和放疗，这里的化疗是广义的，指使用药物治疗癌症)方案中，根据临床治疗指南，通常是次第使用一系列化疗药物：当首次施用的药物在施用一段时间后已经对于患者没有治疗效果或治疗效果很弱时，就认为该癌种患者已经对这种药物产生耐药或抵抗，此时需要使用其他药物(二线药物)，对应的可能二线药物也会在 施用一段时间后出现耐药或抵抗，此时需要使用三线药物。敏感和耐药是有医学专业人员或临床医师进行诊断、判断。
显然，癌症、肿瘤患者对PARP抑制剂是敏感的具体意思是如果该患者经诊断为具有BRCA致病突变，在施用PARP抑制剂后有效果或通过医生的诊疗后判断PARP抑制剂将有效果，此种情况单用TH-302或PARP抑制剂联用TH-302将有更好的治疗效果。
也就是说，根据本发明施用TH-302将替代PAPR抑制剂，PAPR抑制剂的适应症TH-302均可以进行替代：市面上批准的PAPR抑制剂其适应症包括铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌；携带胚系或体细胞BRCA突变晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌，对应的TH-302将可能对这些适应症有效，且疗效优于PAPR抑制剂。
本发明还提供了一种治疗方法，包括以下步骤：
检测癌症、肿瘤患者的BRCA1、BRCA2基因突变情况；
如该患者具有BRCA1、BRCA2基因突变，则使用含有式(1)的乏氧激活化合物的药物单药或联用PARP抑制剂进行治疗：
其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
上述药物除含有式(1)的乏氧激活化合物外，还应根据药品、药物、制剂的特定，添加药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
在使用时，可以单用上述药物或联合PARPi药物进行治疗。
制剂单位包装，包括盛装有药物制剂的独立包装容器、用于容纳独立包装容器的外包装组件以及药品说明书，其特征在于，所述药物制剂含有式(I)的乏氧激活化合物，所述药品说明书记载药品用于联合PARP抑制剂治疗癌症、肿瘤患者：
其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
制剂单位包装是药品生产销售过程中的一个概念，指生产储运销售过程中，药品(药剂)被装载到独立的药品内包装容器中并在药品内包装容器外壁粘贴标签或印刷标签，最终具有标签、内转载有药剂的独立包装容器被放置到外包装组件(通常是一个纸质的包装盒，被消费者直接看到)中，而记载有药品最关键信息的药品说明书(Label)则也和独立包装容器一并被装进外包装组件中。
通常法定的药品说明书(Label)有以下法定的内容：
对美国而言，药品说明书label必须记载
Boxed Warning黑框警告(部分具有药物严重副作用的药物)
1.Indications and Usage适应症与用途
2.Dosage and Administration用量与用法
3.Dosage Forms and Strengths剂型与规格
4.Contraindications禁忌证
5.Warnings and Precautions注意事项
6.Adverse Reactions不良反应
7.Drug Interactions药物相互作用
8.Use in Specific Populations特殊人群用药
9.Drug Abuse and Dependence药物滥用和依赖性(部分药品无)
10.Overdosage用药过量
11.Description性状(含化学名称，分子式，分子量，结构式，理化性质)
12.Clinical Pharmacology临床药理学
13.Nonclinical Toxicology非临床毒理学
14.Clinical Studies临床研究
15.References参考(部分药品无)
16.How Supplied/Storage and Handling包装与贮藏
17.Patient Counseling Information患者咨询信息
对中国而言，药品说明书必须记载药品名称、成份(活性成份、辅料)、性状、规格、适应症、用法用量、禁忌、警告和注意事项、不良反应、药物相互作用、孕妇及哺乳期妇女用药、儿童用药、老年用药、药物滥用和药物依赖、药物过量、临床药理学(药效动力学、药代动力学、遗传药理学)、药理毒理(药理作用、毒理研究)、临床试验、贮藏、包装、有效期、执行标准、批准文号、药品上市许可持有人(名称、注册地址)、生产企业(企业名称、生产地址)等。
可以说，最终销售的制剂单位包装中的药品说明书是药品能使用的关键内容：没有药品说明书，药品将无法使用，因此药品说明书是药品最终发挥作用所不可缺少的，也是药品研发制造过程中的必然环节，实际上，无法在不经过研发、临床试验等研究活动的基础上而药品研发制造相关主体(药品研发厂商、药品销售机构、医疗机构)能直接生产特定单药/联用适应症的药品，更不可能进行销售分发和患者施用，因此药品说明书的内容是十分重要的，是药品制造过程中的一个关键而不可缺少的环节(最终施用的药品必然具有药品说明书)。
药品用于联合PARP抑制剂治疗癌症、肿瘤患者属于药物的Indications and Usage适应症与用途(美国)、适应症(中国)。
当然，上述药品的制剂单位包装，也可以体现为制药用途形式：
式(I)的乏氧激活化合物在制备制剂单位包装中的制药用途，该制药用途通过以下操作来实现：
将药物制剂盛装到独立包装容器中；
将内转载有药剂的独立包装容器被放置到外包装组件中；
将药品说明书放置到外包装组件中，
其特征在于，所述药物制剂含有式(I)的乏氧激活化合物，所述药品说明书记载药品用于联合PARP抑制剂治疗癌症、肿瘤患者：
其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、T sO等离去官能团。
优选的，所述患者的DNA修复酶受损，
优选的，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变，
优选的，BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变，
优选的，式(I)的乏氧激活化合物选自以下结构的化合物：
优选的，PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib，
优选的，所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、***癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌，
优选的，所述癌症、肿瘤患者对PARP抑制剂是敏感的或耐药的。
附图说明
图1是TH-302、Olaparib在Olaparib敏感型的OV5304 PDX模型的体内药效实验各组小鼠肿瘤体积的生长曲线；
图2是TH-302、Olaparib在Olaparib敏感型的OV5304 PDX模型的体内药效实验各组小鼠体重百分比变化曲线；
图3是TH-302、Olaparib在胰腺癌Capan-1 CDX模型中各组小鼠肿瘤体积的生长曲线图；
图4是TH-302、Olaparib在胰腺癌Capan-1 CDX模型中各组小鼠体重变化百分比曲线图。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味。前药可使用除相应药物以外的反应物来合成。
“治疗”或“治疗患者”是指向患者投与、使用或施用本发明相关的治疗有效量的药物。
向患者“投与”或“施用”“使用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用，其可是开处药物的行为。举例而言，指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用、使用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
以下提供本发明的具体实验。
一、TH-302在Olaparib敏感型的OV5304 PDX模型中的药效及安全性评价(E4354-B2136实验)
为了评价TH-302在Olaparib敏感模型中的体内药效，我们选用带有BRCA致病突变，并对Olaparib敏感的卵巢癌OV5304 PDX模型，该模型带有一个BRCA1的致病突变位点p.F580Kfs。
利用BALB/c nude雌性小鼠皮下接种模型OV5304瘤块，建立人卵巢癌皮下移植肿瘤模型。试验分为葡萄糖注射液对照组、测试药Olaparib 50mg/kg单药组、测试药TH-302 20mg/kg、40mg/kg和80mg/kg单药组及Olaparib 50mg/kg和TH-302 40mg/kg联用药组。其中，葡萄糖注射液对照组、测试药TH-302 20mg/kg、40mg/kg和80mg/kg单药组及Olaparib 50mg/kg和TH-302 40mg/kg联用药组中的TH-302 40mg/kg是尾静脉注射给药，每周给药一次，连续给药三周。测试药Olaparib 50mg/kg单药组和Olaparib 50mg/kg和TH-302 40mg/kg联用药组中的Olaparib 50mg/kg组是口服灌胃给药，每天给药一次，连续给药30天。具体给药方案和TGI如表1所示。
表1.在卵巢癌OV5304模型中各组药效分析数据


注：
1.数据以“平均值±标准误差”表示，即
2.T/C％＝TRTV/CRTV×100％或T/C％＝TTV/CTV×100％(TRTV：治疗组平均RTV；CRTV：溶媒对照组
平均RTV；RTV＝Vt/V0，V0为分组时该动物的瘤体积，Vt为治疗后该动物的瘤体积，下同)；
3.TGI％＝(1-T/C)×100％(T和C分别为治疗组和对照组在某一特定时间点的平均相对肿瘤体积(RTV))。
对应的肿瘤体积随和小鼠体重百分比随时间变化的曲线图如图1、2所示。
药效方面：药效实验结果表明，在BRCA1致病突变的卵巢癌OV5304模型中，测试药Olaparib(50mg/kg)单药治疗组在首次给药后的第30天有显著的抑瘤作用，相对肿瘤抑制率TGI(％)为96.16％，相较对照组统计学上有显著性差异(p<0.001)。测试药TH-30220mg/kg治疗组、TH-302 40mg/kg和TH-302 80mg/kg单药治疗组在首次给药后的第30天也表现出显著的抑瘤作用，相对肿瘤抑制率TGI(％)分别为82.81％、97.98％和100％，相较对照组统计学上有显著性差异，p值分别为p<0.01、p<0.001和<0.001，并且TH-302单药在该模型中表现出剂量依赖性。
我们选用TH-302单药的中间剂量组40mg/kg和Olaparib 50mg/mg剂量组进行联用，检测两个单药在该Olaparib敏感模型中是否有协同效应。结果显示，联用组的相对肿瘤抑制率TGI(％)为100％，相较对照组统计学上有显著性差异(p<0.001)。
我们发现很难从相对肿瘤抑制率TGI的结果上区分Olaparib单药和TH-302各单药给药组以及联用药组的药效差异，但是我们的研究发现TH-302单药及联用药在肿瘤的清除能力上明显优于Olaparib单药治疗组。研究结果表明，Olaparib单药组的6只小鼠中，没有肿瘤被完全清除；TH-302 40mg/kg和80mg/kg单药组中，分别有1只和6只小鼠的肿瘤被完全清除，清除率分别为16.7％和100％。完全清除的结果也出现在TH-302 40mg/kg和Olaparib 50mg/kg联用治疗组中。结果显示，TH-302 40mg/kg只有1只小鼠的肿瘤被完全清除，而Olaparib单药组没有小鼠的肿瘤被完全清除，但是在相同剂量的联用药治疗组中，6只小鼠的肿瘤均被完全清除，清除率达到100％。各组小鼠TGI的统计学分析结果显示，TH-302 80mg/kg组相较Olaparib 50mg/kg对肿瘤增殖的抑制作用具有显著差异。同时，测试药TH-302 40mg/kg和Olaparib 50mg/kg联用治疗组抑瘤效果明显优于Oplaparib 50mg/kg单药治疗组和TH-30240mg/kg单药治疗组，且具有统计学意义，说明TH-302和Olaparib的抑瘤作用具有协同作用。
上述结果均表明：
1、TH-302在Olaparib敏感的卵巢癌OV5304 PDX模型中，无论TH-302单药还是与Olaparib联用药组均显示出明显优于Olaparib单药组的肿瘤清除能力和抗肿瘤增殖的能力；
2、进一步对比可知，TH-302单药治疗BRCA突变癌症模型的治疗疗效优于单药PAPR抑制剂Olaparib的疗效；
3、在实验中，观察到TH-302与PAPR抑制剂Olaparib联用的疗效优于各自单药治疗的效果。
总之，在疗效方面，即使实验模型为Olaparib敏感模型中，TH-302单用疗效明显优于PARP抑制剂Olaparib，且与Olaparib联用疗效更佳。
另在安全性方面，测试药TH-302和Olaparib各单药组及联用药治疗组小鼠没有出现任何明显的体重下降的现象，治疗期间耐受良好，初步显示两个药物在一定给药剂量水平下，联用具有一定的安全性。
二、TH-302在Olaparib耐药的胰腺癌Capan-1 CDX模型中的药效及安全性评价
方案：BALB/c裸小鼠皮下接种人源胰腺癌Capan-1细胞，建立人源胰腺癌皮下移植模型。
试验分为测试药Olaparib 100mg/kg单药组(Group 2)、TH-302 50mg/kg单药组(Group 3，QD)、TH-302 100mg/kg单药组(Group 4，QW)、TH-302 50mg/kg单药组(Group 5，QW)、TH-302 25mg/kg单药组(Group 6，QW)、TH-302 25mg/kg和Olaparib 100mg/kg联合给药组(Group 7)以及10％无水乙醇+10％聚氧乙烯(35)蓖麻油+80％葡萄糖注射液D5W(pH7.4)溶媒对照组(Group 1)，共7组，每组6只小鼠。溶媒对照组、TH-302各测试药均为尾静脉注射给药。其中TH-302 50mg/kg单药组(Group 3，QD)每天给药一次，连续给药3天，休息4天，再休息两周；再每天给药，连续给药3天。TH-302 100mg/kg(Group 4，QW)、50mg/kg(Group 5，QW)、25mg/kg(Group 6，QW)单药组以及TH-302 25mg/kg和Olaparib 100mg/kg联合给药组(Group 7)中的TH-302，均为每周给药一次，共给药三周。各组中测试药Olaparib均为口服灌胃给药，每天给药一次，共给药30天。具体人源胰腺癌Capan-1动物模型中的给药途径、剂量及方案如表2所示。
表2：人源胰腺癌Capan-1动物模型中的给药途径、剂量及方案

注：给药体积为10μL/g。
在试验不同天数记录各治疗组和对照组肿瘤生长情况，如表3所示，相应地各组小鼠肿瘤体积的生长曲线如图3所示。根据相对肿瘤增殖率和相对肿瘤抑制率对疗效进行评价，各组药效分析如表4所示。记录治疗组和对照组给药后体重变化，研究人源胰腺癌Capan-1皮下模型中各组的安全性，第43天小鼠体重变化率结果如表5所示，各治疗组体重随时间变化曲线图如图4所示。
表3：人胰腺癌Capan-1模型中各组小鼠肿瘤体积随治疗时间的变化(mm3)
表4：在人源胰腺癌Capan-1皮下模型中各组药效分析表
表5：在人源胰腺癌Capan-1皮下模型中各组体重变化情况(接种后的第43天)
上述数据表明：
溶媒对照组小鼠在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为1301.38mm3。测试药Olaparib 100mg/kg(Group 2)治疗组在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为846.86mm3，相对肿瘤抑制率TGI(％)为37.43％，相较对照组统计学上没有显著性差异(p>0.05)。
测试药TH-302 50mg/kg治疗组(Group 3，QD)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为146.99mm3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为89.17％。测试药TH-302 100mg/kg治疗组(Group 4，QW)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为124.68mm3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为90.89％。测试药TH-302 50mg/kg治疗组(Group 5，QW)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为263.45mm3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为80.18％，肿瘤完全抑制率为33.3％。测试药TH-302 25mg/kg治疗组(Group 6，QW)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为1521.33mm3，相较对照组统计学上没有显著性差异(p>0.05)，相对肿瘤抑制率TGI(％)为-21.59％。Olaparib 100mg/kg和TH-302 25mg/kg的联合治疗组(Group 7)，在肿瘤细胞接种后的第43天(Day 43)平均肿瘤体积为378.56mm3，相较对照组统计学上有显著性差异(p<0.001)，相对肿瘤抑制率TGI(％)为74.36％。
TH-302 100mg/kg(Group 4，QW)、50mg/kg(Group 5，QW)和25mg/kg(Group 6，QW)单药治疗组表现出药物抑瘤作用的剂量依赖性。TH-302 100mg/kg(Group 4，QW)、50mg/kg(Group 5，QW)单药治疗组相较TH-302 25mg/kg单药治疗组(Group 6，QW)统计学上均有显著性差异(p均<0.001)。
Olaparib 100mg/kg与TH-302 25mg/kg的联合治疗组(Group 7)抗肿瘤作用优于Olaparib 100mg/kg(Group 2)以及TH-302 25mg/kg单药组(Group 6)，统计学上有显著性差异(p<0.05以及p<0.001)，Olaparib与TH-302联用的特定剂量组合可以显示出抑瘤效果的协同作用。
测试药Olaparib 100mg/kg(Group 2)、TH-302 25mg/kg(Group 6)、TH-302 50mg/kg(Group 3，QD)、TH-302 50mg/kg(Group 5，QW)、TH-302 100mg/kg(Group 4，QW)、Olaparib 100mg/kg和TH-302 25mg/kg联合给药组(Group 7)、溶媒对照组(Group 1)小鼠体重均没有明显下降，耐受良好。
上述研究结果表明：
1、一定剂量的TH-302单药治疗方案在Olaparib耐药(TGI在六只实验小鼠中统计平均值为37.43％，技术人员一般的判断基准为60％左右，该结果显示一定程度的耐药)的胰腺癌模型中显示出优异的抗肿瘤效果(Group 3、Group 4、Group 5)；而低剂量的TH-302单药治疗方案无抗肿瘤疗效(Group 6)。
2、进一步的，使用低剂量TH-302与Olaparib联用能对Olaparib耐药的胰腺癌模型显示抗肿瘤效果(Group 7)；
也就是说，对于Olaparib耐受的患者，或者只能接受TH-302低剂量治疗的患者(在这种低剂量的治疗方案中，肿瘤生长被抑制的效果较差或不能有效抑制)，通过TH-302与Olaparib的联用能够达到肿瘤治疗效果，联用方案将为他们提供一种新的治疗选择。
总而言之，TH-302与Olaparib联用方案，将扩展两种药物的使用场景，使这两种药物各自均没有明显疗效的单药剂量给药方案患者，通过联用方案得到治疗效果而获益，且没有明显降低安全性。
虽然本申请实施例中选用的PARP抑制剂为奥拉帕利Olaparib，但芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib等同样属于PARP抑制剂，作用机理与奥拉帕利Olaparib类似，均是阻断参与修复受损DNA酶发挥作用，因此，可以推定，芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib等PARPi具有与上述实验中的奥拉帕利Olaparib类似的肿瘤抑制疗效。
TH-302为乏氧活化的DNA烷化剂，权利要求1的通式化合物：
在相关专利申请中已被证明是与TH-302类似的机理，因此这类化合物具有与TH-302类似的效果是完全可以预测的。

Claims (13)

  1. 治疗方法，其使用含有式(I)的乏氧激活化合物的药物单药或联用PARP抑制剂治疗癌症、肿瘤患者：
    其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
  2. 根据权利要求1所述的治疗方法，其中，所述患者的DNA修复酶受损。
  3. 根据权利要求1或2所述的治疗方法，其中，
    所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变；或
    所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变。
  4. 根据权利要求3所述的治疗方法，其中，BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变。
  5. 根据权利要求1或2所述的治疗方法，其中，式(I)的乏氧激活化合物选自以下结构的化合物：
  6. 根据权利要求1或2所述的治疗方法，其中，PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
  7. 根据权利要求1或2所述的治疗方法，其中，所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、***癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌。
  8. 根据权利要求1或2所述的治疗方法，其中，所述癌症、肿瘤患者对PARP抑制剂是敏感的或耐药的。
  9. 根据权利要求1或2所述的治疗方法，其使用以下结构化合物单药治疗对PARP抑制剂敏感或耐药的癌症、肿瘤患者：
  10. 根据权利要求1或2所述的治疗方法，其使用以下结构化合物联用PARP抑制剂治疗对PARP抑制剂敏感或耐药的癌症、肿瘤患者：
  11. 根据权利要求1所述的治疗方法，其中，所述的基因突变的TMB(肿瘤基因突变负荷)水平为中。
  12. 治疗方法，包括以下步骤：
    检测癌症、肿瘤患者的BRCA1、BRCA2基因突变情况；
    如被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变，则使用含有式(I)的乏氧激活化合物的药物单药或联用PARP抑制剂进行治疗：
    其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团。
  13. 制剂单位包装，包括盛装有药物制剂的独立包装容器、用于容纳独立包装容器的外包装组件以及药品说明书，其特征在于，所述药物制剂含有式(I)的乏氧激活化合物，所述药品说明书记载药品用于联合PARP抑制剂治疗癌症、肿瘤患者：
    其中，R各自独立地选自H、-CH3、-CH2CH3、-CF3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团，
    优选的，所述患者的DNA修复酶受损，
    优选的，所述患者的肿瘤或癌组织被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变；或所述患者被检测出具有BRCA1、BRCA2对应的基因中的任意一个致病基因突变或两个致病基因突变，
    优选的，BRCA1、BRCA2突变包括胚系突变(gBRCAm)和体系突变(sBRCAm)的BRCA1、BRCA2突变，
    优选的，式(I)的乏氧激活化合物选自以下结构的化合物：
    优选的，PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib，
    优选的，所述癌症、肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、***癌、非小细胞肺癌、小细胞肺癌、肝癌、结肠癌、直肠癌，
    优选的，所述癌症、肿瘤患者对PARP抑制剂是敏感的或耐药的。
PCT/CN2023/088379 2022-04-15 2023-04-14 使用th-302单药或联用parp抑制剂治疗癌症的方法 WO2023198188A1 (zh)

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