WO2009099651A1 - Use of picoplatin and cetuximab to treat colorectal cancer - Google Patents
Use of picoplatin and cetuximab to treat colorectal cancer Download PDFInfo
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- WO2009099651A1 WO2009099651A1 PCT/US2009/000773 US2009000773W WO2009099651A1 WO 2009099651 A1 WO2009099651 A1 WO 2009099651A1 US 2009000773 W US2009000773 W US 2009000773W WO 2009099651 A1 WO2009099651 A1 WO 2009099651A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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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
- A61K31/33—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
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A61P35/00—Antineoplastic agents
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- 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
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- A—HUMAN NECESSITIES
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Definitions
- Colorectal cancer remains the second most common cause of cancer- related death in the United States and a significant cause of cancer-related death in other countries as well. 1
- the only approved chemotherapeutic drug for treatment of colorectal cancer was 5-fluorouracil (5-FU), and it continues to be the backbone of most first-line chemotherapeutic regimens for patients with advanced disease.
- 5-fluorouracil 5-fluorouracil
- mCRC metastatic colorectal cancer
- Picoplatin is a platinum analogue that has demonstrated synergy with 5- FU in vitro in pre-clinical studies and has undergone extensive Phase 1 and 2 testing in a variety of cancers. 1 ' "22 Like other platinum analogues, picoplatin causes cell death by the formation of covalent cross-links in DNA that interfere with DNA replication and transcription, leading to cell death. Cisplatin, the first platinum analogue, was introduced approximately 20 years ago and is still widely used. The approval of cisplatin was followed by approval of carboplatin, and most recently by that of oxaliplatin.
- Treatment with platinum analogues is limited by their toxicity. While neurotoxicity and nephrotoxicity are the main dose-limiting toxicities (DLT) observed following cisplatin treatment, myelosuppression is most significant following carboplatin treatment. Carboplatin is known to cause cumulative dose-related toxicity that results in slow bone marrow recovery. Peripheral neurotoxicity is well documented in patients treated with oxaliplatin. The unacceptable nephrotoxicity, oto-, and neurotoxicity associated with earlier platinum analogues has not been reported with picoplatin either in animal studies or in clinical trials. 11 ' 19"22
- platinum analogues are also limited by several (intrinsic or acquired) mechanisms of resistance, including impaired cellular uptake, intracellular inactivation by thiols [e.g., reduced glutathione], and enhanced DNA repair and/or increased tolerance to platinum-DNA adducts. 23 Pre-clinical studies indicate that picoplatin can overcome these three mechanisms of resistance. This has been demonstrated in vitro and by using human ovarian xenograft tumor models that exhibit resistance to cisplatin. 13"17 Several human ovarian and colon cell lines with induced resistance to oxaliplatin retain sensitivity to picoplatin.
- Cetuximab is a recombinant human/mouse chimeric epidermal growth factor receptor (EGFR) monoclonal antibody. It was approved by the U.S. Food and Drug Administration in February 2004 to be used in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal cancer in patients who had failed to improve with irinotecan-based or oxaliplatin-based chemotherapy. Cetuximab was also approved for administration as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy. It is marketed by Bristol-Myers Squibb under the brand name of Erbitux ® .
- EGFR epidermal growth factor receptor
- EGFR epidermal growth factor receptor
- a growth-factor-receptor tyrosine kinase and/or its cognate ligands have been identified as a common component of multiple cancer types and appear to promote solid tumour growth.
- EGFR epidermal growth factor receptor
- tyrosine kinase a growth-factor-receptor tyrosine kinase
- its cognate ligands have been identified as a common component of multiple cancer types and appear to promote solid tumour growth.
- Cetuximab has been approved as a first-line therapy used in combination with oxaliplatin and irinotecan-based regimens and as second-line therapies in combination with other drugs or as monotherapies for the treatment metastatic colorectal cancer (mCRC), for example see JJ. Lee et al., Clin Colorectal Cancer. 2007;6 Suppl 2:S42-6; and W. Zhang et al., Ann Med. 2006;38:545-51. About 40% of patients with mCRC have K-ras mutations and their mCRC does not respond to epidermal growth factor receptor (EGFR) inhibitors such as cetuximab and panitumumab.
- EGFR epidermal growth factor receptor
- K-ras testing is now used in routine clinical practice to select the subset of mCRC patients most likely to benefit from treatment with an EGFR inhibitor. Subset selection spares patients who are unlikely to respond to EGFR inhibitors for side effects and the cost of an ineffective drug. Examples of companies that offer K-ras testing to medical oncologists include:
- the present invention is directed to methods of treatment of metastatic colorectal cancer with picoplatin, cetuximab (Erbitux®) and optionally with 5- fluorouracil (5-FU) and leucovorin; to the use of picoplatin in conjunction with cetuximab, and optionally 5 -FU and leucovorin in the treatment of colorectal cancer; and to kits adapted for administration of picoplatin in conjunction with cetuximab, 5-FU and leucovorin.
- the invention provides a method of treatment of colorectal cancer, comprising administering to a patient afflicted with colorectal cancer picoplatin, cetuximab, 5-fluorouracil (5-FU) and leucovorin, wherein 5- FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, the picoplatin is administered with the leucovorin and 5-FU every other time that the fluorouracil and leucovorin are administered, and the cetuximab is administered at least twice at one-week intervals.
- the picoplatin can be administered at a dose of about 60-180 mg/m 2 , preferably at a dose of about 150 mg/m 2 .
- the interval of administration of the 5- FU and the leucovorin can be about two weeks and the interval of administration of the picoplatin can be about four weeks.
- the invention provides a method of treatment of colorectal cancer, comprising administering to a patient afflicted with colorectal cancer effective amounts of a combination of picoplatin, cetuximab, 5-FU and leucovorin, wherein the picoplatin, and the 5-FU and the leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, and the cetuximab is administered at least twice at one-week intervals, wherein an amount of picoplatin administered is less than the maximum tolerated dose of picoplatin.
- the picoplatin can be administered at a dose of about 45-150 mg/m 2 , preferably at a dose of about 135-150 mg/m 2 .
- the interval of administration of the picoplatin, 5-FU and the leucovorin can be about two weeks.
- the invention provides a method for selecting a treatment regimen for metastatic colorectal cancer (mCRC) comprising (a) providing a patient afflicted with mCRC; (b) determining if the patient is a K-ras wild type mCRC patient; and (c) if the patient comprises K-ras wild type mCRC, selecting for said patient a regimen comprising a EGFR inhibitor and picoplatin.
- mCRC metastatic colorectal cancer
- the invention provides a method of treatment of colorectal cancer comprising (a) identifying a patient afflicted with colorectal cancer who has failed FOLFOX-4 and/or FOLPI regimens; and (b) administering about 5-150 mg/m 2 picoplatin to the patient every 21 days in combination with a first dose of 400 mg/m 2 cetuximab followed by a 250 mg/m 2 dose of cetuximab administered every week.
- the invention provides a method of treatment of colorectal cancer comprising (a) identifying a patient afflicted with colorectal cancer who has received irinotecan, FOLFOX, or FOLPI regimens, with or without bevacizumab or cetuximab, wherein the cancer is in remission, and (b) administering about 5-150 mg/m 2 picoplatin to the patient every 21 days in combination with a first dose of 400 mg/m 2 cetuximab followed by a 250 mg/m 2 dose of cetuximab administered every week as an adjuvant therapy to prevent recurrence.
- the invention provides a method for selecting a regimen of treatment for a patient afflicted with a metastatic cancer that comprises EGFR, comprising (a) identifying a patient afflicted with a metastatic cancer, (b) determining if the cancer comprises a wild-type K-ras gene or a mutation-positive K-ras gene and (c) selecting a treatment regimen comprising picoplatin and an EGFR inhibitor if the wild type K-ras gene is present, or selecting a treatment regimen comprising picoplatin without an EGFR inhibitor if the mutation-positive K-ras gene is present.
- the metastatic cancer that comprises EGFR can comprise SCLC, NSCLC, a pancreatic cancer, a colorectal cancer, an epithelial cancer, or a head and neck, ovarian, cervical, bladder, esophageal, gastric, breast, or endometrial cancer.
- the invention provides a method for selecting a regimen of treatment for a patient afflicted with mCRC comprising: (a) identifying a patient afflicted with mCRC, (b) determining if the mCRC comprises a wild type K-ras gene or a mutated K-ras gene and (c) if the m-CRC comprises a K-ras wild type genotype, then administering to the patient an EGFR inhibitors such as cetuximab, erlotinib or panitumumab, in combination with picoplatin and, optionally, 5 -FU and leucovorin, or (d) if the mCRC comprises a K-ras mutation positive genotype, then administering to the patient picoplatin and, optionally, 5-FU and leucovorin.
- the EGFR inhibitor can comprise cetuximab.
- the invention provides a use of picoplatin in conjunction with cetuximab, 5-fluorouracil (5-FU), and leucovorin to treat colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, the picoplatin is administered with the leucovorin and 5-FU every other time that the fluorouracil and leucovorin are administered, and the cetuximab is administered at least twice at one-week intervals.
- the picoplatin can be administered at a dose of about 60-180 mg/m 2 , preferably at a dose of about 150 mg/m 2 .
- the interval of administration of the 5-FU and the leucovorin can be about two weeks and the interval of administration of the picoplatin can be about four weeks.
- the invention provides a use of picoplatin in conjunction with cetuximab, 5-FU and leucovorin, wherein the picoplatin, and the 5-FU and the leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, and the cetuximab is administered at least twice at one-week intervals, wherein an amount of picoplatin administered is less than the maximum tolerated dose of picoplatin.
- the picoplatin can be administered at a dose of about 45-150 mg/m 2 , preferably at a dose of about 135- 150 mg/m 2 .
- the interval of administration of the picoplatin, 5-FU and the leucovorin can be about two weeks.
- a kit is provided, the kit being adapted for the intravenous administration of a FOLPI plus cetuximab regimen to a patient; the kit comprising a first container comprising a solution of picoplatin and a second container comprising a solution of leucovorin; further comprising a coupling adapted to be independently connected to the first container, the second container, and a single intravenous tube, so that the content of the first container and the second container can be simultaneously administered to the patient; the kit further comprising a container comprising a solution of cetuximab (Erbitux®) and a container comprising a solution of 5-FU, adapted for intravenous administration to the patient; optionally further comprising instructions for use.
- a container comprising a solution of picoplatin and a second container comprising a solution of leucovorin
- a coupling adapted to be independently connected to the first container, the second container, and a single intravenous tube, so that the content of the first container and the second container can be simultaneously administered
- the kit can include, in the first container, picoplatin in a dosage form comprising an isotonic solution comprising water, a tonicity adjuster comprising NaCl, and about 0.5 mg/mL dissolved picoplatin.
- the dosage form can also comprise an effective amount of dissolved or dispersed 5- FU and/or leucovorin in accord with the doses disclosed herein.
- the dosage form also does not contain a preservative or bacteriostatic agent.
- An appropriate volume of the dosage form can be administered to achieve a desired therapeutic dose.
- the invention provides a method of treatment of colorectal cancer, comprising administering to a patient afflicted with colorectal cancer picoplatin, cetuximab, 5-fluorouracil (5-FU) and leucovorin, wherein 5- FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, the picoplatin is administered with the leucovorin and 5-FU every other time that the fluorouracil and leucovorin are administered, and the cetuximab is administered at least twice at one-week intervals.
- 5- FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks
- the picoplatin is administered with the leucovorin and 5-FU every other time that the fluorouracil and leucovorin are administered
- the cetuximab is administered at least twice at one-week intervals.
- the picoplatin can be administered at a dose of about 60-180 mg/m 2 , preferably at a dose of about 150 mg/m 2 .
- the interval of administration of the 5- FU and the leucovorin can be about two weeks and the interval of administration of the picoplatin can be about four weeks.
- the invention provides a method of treatment of colorectal cancer, comprising administering to a patient afflicted with colorectal cancer effective amounts of a combination of picoplatin, cetuximab, 5-FU and leucovorin, wherein the picoplatin, and the 5-FU and the leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, and the cetuximab is administered at least twice at one-week intervals, wherein an amount of picoplatin administered is less than the maximum tolerated dose of picoplatin.
- the picoplatin can be administered at a dose of about 45-150 mg/m 2 , preferably at a dose of about 135-150 mg/m 2 .
- the interval of administration of the picoplatin, 5-FU and the leucovorin can be about two weeks.
- the leucovorin and the 5-FU can be administered about every two weeks, the picoplatin is administered with the leucovorin about every 4 weeks, and the cetuximab is administered weekly.
- the picoplatin can be administered at least once at a dosage of about 60-75 mg/m 2 .
- the picoplatin can be administered at least once at a dose of about 150 mg/m 2 .
- a subsequent dose of picoplatin can be administered at about a 15-30 mg/m 2 lower dose than a previous dose.
- the patient has not previously been treated for metastatic disease, hi other embodiments, the patient can have previously been treated with an irinotecan, FOLFOX and/or FOLPI regimen. Or, the patient can have previously been treated with a FOLFOX regimen, and subsequently with a FOLPI regimen and has relapsed within 6 months of completing the FOLPI regimen. Alternatively, the patient can have previously been treated with a first regimen comprising FOLFOX or irinotecan, and subsequently with a second regimen comprising cetuximab alone, irinotecan plus cetuximab, or FOLPI, and has relapsed within 6 months following cessation of the second regimen.
- a first regimen comprising FOLFOX or irinotecan
- a second regimen comprising cetuximab alone, irinotecan plus cetuximab, or FOLPI
- the patient has not previously been treated for metastatic disease, or the patient has not previously had systemic treatment, such as chemotherapy, for localized or metastatic disease.
- the patient may have had surgery to remove or to de-bulk the primary tumor and then be treated with one of the picoplatin, 5 -FU, leucovorin regimens (e.g., FOLPI) of the invention to prevent or delay progression of the cancer, including to prevent or delay the development of metastases.
- the patient may have received earlier chemotherapy at the time of primary tumor treatment, at least 6 months prior to the present picoplatin treatment.
- the picoplatin can be administered with curative intent, rather than merely seeking to arrest the disease with no remission.
- the dosage of the picoplatin can be increased beyond that bringing about disease stasis in order to achieve a cure in the patient.
- the picoplatin can be administered substantially concurrently with the leucovorin followed by administration of the 5-FU at every treatment of the patient, and the cetuximab is administered at one week intervals.
- the picoplatin can be administered at least once at a dosage of about 40-45 mg/m 2 .
- the patient can be previously been treated with an earlier systemic regimen of chemotherapy and the cancer be in remission.
- the patient can have been treated with an earlier FOLPI regimen, with or without bevacizumab or cetuximab.
- the picoplatin can be administered in a dosage form comprising an isotonic solution comprising water, a tonicity adjuster comprising NaCl, and about 0.5 mg/mL dissolved picoplatin, wherein the dosage form does not contain a preservative or bacteriostatic agent.
- the picoplatin, the cetuximab and the leucovorin can be administered substantially concurrently.
- the picoplatin and the leucovorin can be administered simultaneously.
- the term "concurrently" means that the administrations are simultaneous, overlapping or close enough in time so that the two or more agents administered are present in vivo in therapeutically effective amounts.
- the 5 -FU can be administered following the administration of the picoplatin, leucovorin and cetuximab.
- the leucovorin can be administered at an initial dosage of about 200-400 mg/m 2 .
- the 5-FU can be administered at a total dosage per dosing of about 1000-3000 mg/m 2 .
- the picoplatin can be administered at a dosage of about 60-180 mg/m 2 . More specifically, the picoplatin can administered at a dosage of about 120-150 mg/m 2 . For example, the picoplatin can be administered at least once at a dosage of about 150 mg/m 2 . In various embodiments, a subsequent dose of picoplatin can be administered at about a 15-30 mg/m 2 lower dose than a previous dose; for example when the previous dose is about 150 mg/m 2 , the subsequent dose can be about 120-135 mg/m 2 .
- a cumulative dose of greater than about 900 mg/m 2 of picoplatin is delivered to the patient.
- the cetuximab can be administered intravenously at a first dose of about 400 mg/m 2 , then once a week at a dose of about 250 mg/m 2 .
- the leucovorin at a dosage of about 400 mg/m 2 , can be administered as a 2 hour infusion, the administration of the leucovorin being followed by a 5-FU bolus at a dosage of about 400 mg/m 2 ; the 5-FU bolus being followed by 5-FU at a dosage of about 2,400 mg/m 2 administered as a 46 hour continuous infusion; wherein the leucovorin and the 5-FU are administered to the patient every 2 weeks and about 60-150 mg/m 2 of the picoplatin is administered to the patient with the leucovorin every 4 weeks, wherein at least the initial dose of picoplatin is about 150 mg/m 2 , and wherein the cetuximab is administered at an initial dose of about 400 mg/m 2 , then once a week at a dose of about 250 mg/m 2 .
- the picoplatin is administered substantially concurrently with the leucovorin and the picoplatin is administered at every second treatment of the patient with the 5-FU and the leucovorin, e.g., every four weeks.
- the cetuximab is administered in a relatively high dose concurrently with the picoplatin and then weekly thereafter.
- the leucovorin can be administered at a dosage of about 200-500 mg/m 2 , preferably at about 400 mg/m 2 .
- the picoplatin is administered at a dosage of about 60-180 mg/m 2 .
- the cetuximab is administered by infusion at a dose of 400 mg/m 2 over about 20 hrs.
- the 5-FU is administered at a total dosage of about 1000-3000 mg/m 2 .
- a preferred treatment cycle for leucovorin and 5-FU is every two weeks, and picoplatin is administered every 4 weeks, e.g., at a low dose of about 60-75 mg/m 2 , e.g., 60 mg/m 2 , or at a high dose of about 120-180 mg/m , preferably about 120-150 mg/m , e.g. about 150 mg/m .
- the leucovorin at a dosage of 200-500 mg/m 2 , is administered as an about 2 hour infusion concurrently with the picoplatin, when it is given, wherein the picoplatin dosage is 120-180 mg/m 2 , e.g., about 150 mg/m 2 ; the administration of the leucovorin and the picoplatin being followed by a 5-FU dosage of about 400 mg/m 2 as a bolus; the 5-FU dosage being followed by 5-FU at a dosage of 600 mg/m 2 or 2,400 mg/m 2 , preferably administered as a 22 hour or as a 46 hour continuous infusion, respectively, wherein the leucovorin and 5-FU are provided to the patient at intervals of two weeks and the leucovorin, picoplatin, and 5-FU are provided to the patient at alternating intervals of four weeks.
- the picoplatin dosage is 120-180 mg/m 2 , e.g., about 150 mg/m 2
- the administration of the leucovorin and the picoplatin being
- the cetuximab is administered as described above, at an initial dose of 400 mg/m 2 followed by weekly doses of 250 mg/m 2 .
- a low dose of picoplatin of about 45-75 mg/m 2 , e.g., about 60-75 mg/m 2 , e.g., about 60 mg/m 2 , is administered.
- Such 5-FU/leucovorin/picoplatin regimens can be broadly termed FOLPI regimens which, in the present invention, are supplemented by cetuximab infusions.
- the leucovorin at a dosage of 400 mg/m 2 , is administered as a 2 hour infusion; the administration of the leucovorin being followed by a 5-FU bolus at a dosage of 400 mg/m 2 ; the 5-FU bolus dosage being followed by parenteral 5-FU at a dosage of 400 mg/m 2 or 2,400 mg/m 2 , preferably administered as a 22 hour or as a 46 hour continuous infusion, respectively; the administration of the leucovorin and the 5-FU taking place every two weeks; wherein every two weeks picoplatin, at a dosage of up to about 50 mg/m 2 , e.g., at about 40-50 mg/m 2 , e.g., about 45 mg/m 2 , is administered concurrently with the leucovorin, preferably simultaneously.
- Picoplatin dosages of about 45-105 mg/m 2 can also be administered. Cetuximab is given weekly as described hereinabove. It has unexpectedly been found that, in some cases, the combination of low doses of picoplatin administered with leucovorin and 5-FU at every treatment cycle, are as effective as, or more effective than, higher doses, e.g., the MTD, given at the same intervals, in producing a response.
- the MTD for the 2 week and 4 week picoplatin administration schedules are discussed below.
- such doses in the initial treatment are lower or substantially lower than the MTD.
- Such doses can range from about 40-60 mg/m 2 of picoplatin every two weeks, given with leucovorin and cetuximab and followed by 5-FU, as discussed below.
- the patient preferably has not previously had systemic treatment, such as chemotherapy, for metastatic disease.
- the patient may have, however, received earlier adjuvant therapy at the time of primary tumor treatment, at least 6 months prior to the present picoplatin- cetuximab treatment.
- the patient has been treated with an earlier systemic regimen of chemotherapy, such as a FOLFOX regimen and is in remission.
- the present regimen broadly termed FOLPI, with or without cetuximab
- the MCRC patient has been treated with an earlier FOLPI regimen, with or without bevacizumab or cetuximab, and the cancer is in remission, and a present method of FOLPI plus cetuximab, or a combination of picoplatin and cetuximab, can be used as an adjuvant therapy to prevent recurrence of the cancer.
- the patient exhibits EGFR expression in at least some of the cells of the metastatic colorectal cancer.
- Picoplatin can used in combination with 5-fluorouracil (5-FU) and leucovorin in the FOLPI regimen as a first-line treatment in patients with mCRC and cetuximab can also be administered.
- Epidermal growth factor receptor (EDFR) inhibitors such as the monoclonal antibodies cetuximab or panitumumab are used as second- and third- line treatments in patients with mCRC.
- mCRC patients with a tumor genotype that is K-ras mutation positive are unresponsive to cetuximab and other EGFR agonists, hi various embodiments of the present invention, picoplatin and cetuximab, optionally including 5 -FU and leucovorin, can be used in the treatment of patients having K-ras mutation positive mCRC.
- picoplatin and cetuximab optionally including 5 -FU and leucovorin
- a patient who would otherwise receive a particular dose of cetuximab, but whose mCRC cancer cell genotype is found to be K-ras mutation positive can be administered picoplatin in conjunction with 5-FU and leucovorin in various dosing regimens.
- an embodiment of the present invention also comprises a method for selecting a regimen of treatment for a patient afflicted with mCRC comprising: (a) providing a patient afflicted with mCRC, (b) determining if the mCRC comprises a wild type K-ras gene or a mutated K-ras gene and (c) selecting a regimen for said K-ras wild type mCRC patient comprising the combination therapy of the invention described hereinabove, comprising one or more EGFR inhibitors such as cetuximab (such as Erbitux®), erlotinib (such as Tarceva®) or panitumumab (such as Vectibix®), picoplatin, 5-FU and leucovorin.
- cetuximab such as Erbitux®
- erlotinib such as Tarceva®
- panitumumab such as Vectibix®
- an EGFR inhibitor would be omitted from the picoplatin, 5- FU, leucovorin regimen.
- a further embodiment comprises treating said patient with the selected regimen.
- the present method can generally be employed to select a regimen of treatment for a patient afflicted with a cancer, such as SCLC, NSCLC, a pancreatic cancer, a colorectal cancer, an epithelial cancer, or a head and neck, ovarian, cervical, bladder, esophageal, gastric, breast, or endometrial cancer, or the like, that comprises EGFR, by providing a patient afflicted with a tumor, (b) determining if the tumor comprises a wild-type K-ras gene or a mutated K-ras gene and (c) selecting a treatment regimen comprising picoplatin and an EGFR inhibitor if the wild type K-ras gene is present.
- a cancer such as SCLC, NSCLC, a pancreatic cancer, a colorectal cancer
- An embodiment of the invention also provides a method for selecting a regimen of treatment for a patient afflicted with mCRC comprising: (a) identifying a patient afflicted with mCRC, (b) determining if the mCRC comprises a wild type K-ras gene or a mutated K-ras gene and (c) if the m-CRC comprises a K-ras wild type genotype, then administering to the patient an EGFR inhibitors such as cetuximab, erlotinib or panitumumab, in combination with picoplatin and, optionally, 5-FU and leucovorin, or (d) if the mCRC comprises a K-ras mutation positive genotype, then administering to the patient picoplatin and, optionally, 5-FU and leucovorin.
- an EGFR inhibitors such as cetuximab, erlotinib or panitumumab
- the EGFR inhibitor can be cetuximab.
- the patient afflicted with colorectal cancer has failed first line therapy (FOLFOX or irinotecan) and has failed second-line therapy as well (cetuximab alone, irinotecan plus cetuximab or FOLPI).
- FOLFOX first line therapy
- cetuximab alone, irinotecan plus cetuximab or FOLPI cetuximab alone, irinotecan plus cetuximab or FOLPI.
- the present modified FOLPI plus cetuximab regimens can be employed as "third-line therapy.”
- intravenous picoplatin (5-150 mg/m 2 ) every 3 weeks in combination with the cetuximab regimen 400 mg/m 2 i.v. initial loading dose, then 250 mg/m 2 i.v. weekly maintenance doses can be employed as third- line therapy, without further administration of 5-FU and leucovorin.
- the term “concurrently” means that the administrations are simultaneous, overlapping or close enough in time so that the two or more agents administered are present in vivo in therapeutically effective amounts.
- the present method also can comprise administration of an effective amount of a 5-HT 3 receptor antagonist, as an anti-emetic.
- An embodiment of the invention provides a use of picoplatin in conjunction with cetuximab, 5-fluorouracil (5-FU), and leucovorin to treat metastatic colorectal cancer, wherein the 5 -FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, the picoplatin is administered with the leucovorin and 5 -FU every other time that the fluorouracil and leucovorin are administered, and the cetuximab is administered at least twice at one- week intervals.
- the leucovorin and the 5 -FU can be administered about every two weeks, the picoplatin administered with the leucovorin about every 4 weeks, and the cetuximab administered weekly.
- the picoplatin can be administered at least once at a dosage of about 60-75 mg/m 2 .
- Another embodiment of the invention provides a use of picoplatin in conjunction with cetuximab, 5-fluorouracil (5-FU), and leucovorin to treat metastatic colorectal cancer, wherein the picoplatin, 5-FU and leucovorin are administered intravenously at least twice at intervals of about two weeks, and the cetuximab is administered at least twice at one-week intervals, wherein the amount of picoplatin is less than the maximum tolerated dose of picoplatin when administered in said combination.
- Another embodiment of the invention provides a use of picoplatin in conjunction with cetuximab, 5-fluorouracil (5-FU), and leucovorin to treat metastatic colorectal cancer, wherein 5-FU and leucovorin are administered intravenously at intervals of about two weeks, and the picoplatin is administered with the leucovorin and 5-FU every time that the fluorouracil and leucovorin are administered, wherein the picoplatin is administered at a dose of about 45-120 mg/m 2 , and wherein the cetuximab is administered intravenously at a first dose of about 250-500 mg/m 2 , followed by doses of about 200-300 mg/m 2 administered at weekly intervals.
- 5-FU and leucovorin are administered intravenously at intervals of about two weeks
- the picoplatin is administered with the leucovorin and 5-FU every time that the fluorouracil and leucovorin are administered
- the picoplatin is administered at a dose of about 45-120 mg/
- the picoplatin can administered substantially concurrently with the leucovorin followed by administration of the 5-FU at every treatment of the patient, and the cetuximab administered at one week intervals.
- the picoplatin can be administered at least once at a dosage of about 40-45 mg/m 2 .
- the patient has not previously been treated for metastatic disease.
- the patient has previously been treated with a FOLFOX and/or FOLPI regimen.
- the patient can previously have been treated with a FOLFOX regimen and subsequently with a FOLPI regimen and relapsed within 6 months of completing the FOLPI regimen.
- the patient afflicted with colorectal cancer can have been treated with a first regimen comprising FOLFOX or irinotecan, and subsequently with a second regimen, comprising cetuximab alone, irinotecan plus cetuximab or FOLPI, and have relapsed within 6 months following cessation of the second regimen.
- the patient can have previously been treated with an earlier systemic regimen of chemotherapy and the cancer can be in remission.
- the patient can have been treated with an earlier FOLPI regimen, with or without bevacizumab or cetuximab, and the cancer can be in remission.
- the picoplatin can be administered in a dosage form comprising an isotonic solution comprising water, a tonicity adjuster comprising NaCl, and about 0.5 mg/mL dissolved picoplatin, wherein the dosage form does not contain a preservative or bacteriostatic agent.
- the picoplatin, the cetuximab and the leucovorin can be administered substantially concurrently.
- the term “concurrently” means that the administrations are simultaneous, overlapping or close enough in time so that the two or more agents administered are present in vivo in therapeutically effective amounts.
- the picoplatin and the leucovorin can be administered simultaneously.
- the 5-FU can be administered following the administration of the picoplatin, leucovorin and cetuximab.
- the leucovorin can be administered at an initial dosage of about 200-400 mg/m 2 .
- the 5-FU can be administered at a total dosage per dosing of about 1000-3000 mg/m 2 .
- the picoplatin can be administered at a dosage of about 60-180 mg/m 2 . More specifically, the picoplatin can administered at a dosage of about 120-150 mg/m 2 ; for example, the picoplatin can be administered at least once at a dosage of about 150 mg/m 2 .
- a subsequent dose of picoplatin can be administered at about a 15-30 mg/m 2 lower dose than a previous dose; for example when the previous dose is about 150 mg/m 2 , the subsequent dose can be about 120-135 mg/m 2 .
- a cumulative dose of greater than about 900 mg/m 2 of picoplatin can be delivered to the patient.
- the cetuximab can be administered intravenously at a first dose of about 400 mg/m 2 , then once a week at a dose of about 250 mg/m 2 .
- the leucovorin at a dosage of about 400 mg/m 2 , can be administered as a 2 hour infusion, the administration of the leucovorin being followed by a 5-FU bolus at a dosage of about 400 mg/m 2 ; the 5-FU bolus being followed by 5-FU at a dosage of about 2,400 mg/m 2 administered as a 46 hour continuous infusion; wherein the leucovorin and the 5-FU are administered to the patient every 2 weeks and about 60-150 mg/m 2 of the picoplatin is administered to the patient with the leucovorin every 4 weeks, wherein at least the initial dose of picoplatin is about 150 mg/m 2 , and wherein the cetuximab is administered at an initial dose of about 400 mg/m 2 , then once a week at a dose of about 250 mg/m 2 .
- the patient can exhibit EGFR expression in at least some cells of the metastatic colorectal cancer.
- about 5-150 mg/m 2 picoplatin can be administered every 21 days in conjunction with a first dose of 400 mg/m 2 cetuximab followed by a 250 mg/m 2 dose of cetuximab administered every week in treatment of colorectal cancer in a patient afflicted with colorectal cancer who has failed FOLFOX-4 and/or FOLPI regimens.
- about 5-150 mg/m 2 picoplatin can be administered every 21 days in conjunction with a first dose of 400 mg/m 2 cetuximab followed by a 250 mg/m 2 dose of cetuximab administered every week to prevent recurrence of colorectal cancer in a patent afflicted with colorectal cancer who has received irinotecan, FOLFOX, or FOLPI regimens, with or without bevacizumab or cetuximab, wherein the cancer is in remission.
- the use can further comprise administration of a 5-HT 3 receptor antagonist.
- the invention provides a kit adapted for the intravenous administration of a FOLPI plus cetuximab regimen to a patient; the kit comprising a first container comprising a solution of picoplatin and a second container comprising a solution of leucovorin; further comprising a coupling adapted to be independently connected to the first container, the second container, and a single intravenous tube, so that the content of the first container and the second container can be simultaneously administered to the patient; the kit further comprising a container comprising a solution of cetuximab (Erbitux®) and a container comprising a solution of 5-FU, adapted for intravenous administration to the patient; optionally further comprising instructions for use.
- a kit adapted for the intravenous administration of a FOLPI plus cetuximab regimen to a patient
- the kit comprising a first container comprising a solution of picoplatin and a second container comprising a solution of leucovorin; further comprising a coupling adapted to be independently connected
- the first container can comprise a dosage form of picoplatin comprising an isotonic solution comprising water, a tonicity adjuster, and about 0.5 mg/mL dissolved picoplatin, wherein the dosage form does not contain a preservative or bacteriostatic agent.
- Picoplatin (SP-4-3) (cis-aminedichloro(2-methylpyridine)Pt(II)), and useful prodrugs and analogs thereof are disclosed in U.S. Patent Nos. 5,665,771; 6,518,428; 6,413,953; U.S. patent application Ser. No. 11/982,891, filed November 5, 2007; and PCT/GB/01/02060, which are incorporated herein by reference.
- the doses disclosed herein can be providing by oral administration of an effective amount of picoplatin in combination with a pharmaceutically acceptable vehicle, as well as by intravenous infusion.
- ERBITUX ® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR).
- EGFR epidermal growth factor receptor
- ERBITUX ® is composed of the Fv regions of a murine anti-EGFR antibody with human IgGl heavy and kappa light chain constant regions and has an approximate weight of 152 kDa.
- ERBITUX ® is produced in mammalian (murine myeloma) cell culture. See, Goldstein et al. (U.S. Patent No. 7,060,808).
- ERBITUX ® is provided as a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous, cetuximab particulates.
- Each single-use, 50-mL vial contains 100 mg of cetuximab at a concentration of 2 mg/mL and is formulated in a preservative- free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP.
- ERBITUX ® administered in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics.
- the area under the concentration time curve (AUC) increased in greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m 2 as the dose increased from 20 to 200 mg/m 2 , and at doses >200 mg/m 2 , it appeared to plateau.
- the volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2-3 L/m 2 .
- the recommended dose regimen is 400 mg/m 2 initial dose as a 120 min. intravenous infusion followed by 250 mg/m 2 weekly dose infused i.v. over 60 min., continued until disease progression or unacceptable toxicity.
- the in vitro concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 ⁇ g/mL, respectively.
- the mean half-life of cetuximab was approximately 112 hours (range 63-230 hours).
- the pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer. Cetuximab has been evaluated in combination with FOLFOX 4 regimen without undue side effects.
- Phase 1 is a dose escalation study to identify the maximum tolerated dose (MTD) of picoplatin that can be administered either every two weeks or every four weeks, with 5 -FU and leucovorin (LV) administered every two weeks, as initial therapy for subjects with metastatic colorectal cancer who have not been previously treated for metastatic disease.
- Phase 2 is a randomized study. In one arm of the study, picoplatin is administered at 150 mg/m 2 every four weeks, combined with 5-FU and leucovorin that are administered every two weeks.
- a modified FOLFOX 6 regimen is employed wherein the 100 mg/m 2 oxaliplatin dose in FOLFOX 6 has been reduced to 85 mg/m 2 , and is administered every 2 weeks, so that the two agents can be compared in the context of a widely used regimen. It is believed that cancer patients can be more effectively treated with the regimens of the present invention, which employ picoplatin instead of cisplatin, carboplatin or oxaliplatin, because they will experience fewer side effects, such as neuropathy, while preferably receiving higher doses of the platinum (Pt) drug. Phase 3 will be a study comparing the FOLPI regimen with and without weekly Erbitux ® infusions.
- Phase 1 Subjects eligible for the Phase 1 study will have Stage IV colorectal cancer and will have received no systemic therapy for metastatic cancer.
- Subjects are assigned centrally to treatment with picoplatin administered either every two or every four weeks and are assigned a dose of picoplatin to be given dependent on the study results to date. Each patient also receives 5 -FU and leucovorin therapy every two weeks. Cohorts of 3 subjects receive their assigned dose of picoplatin and leucovorin and 5-FU according to the following schedule:
- Day 1 Picoplatin, assigned dosage, as a 2-hour infusion, given either every cycle of 5-FU and leucovorin (q 2 weeks, Schedule A) or with every other cycle of 5-FU and leucovorin (q 4 weeks, Schedule B).
- Leucovorin 400 mg/m 2 in D5W (water-5% dextrose), will be administered as a 2 hour infusion, either alone or, if the patient is to receive picoplatin, at the same time as picoplatin in separate bags using a Y-line.
- Subjects in Phase 1 are centrally assigned to one of two schedules of picoplatin.
- the first cohort of q 2 week (Schedule A) subjects are treated with picoplatin at a dosage of 45 mg/m 2 , every cycle, q 2 weeks.
- Subsequent sequential cohorts of subjects assigned to this schedule receive picoplatin at dose levels increasing by 15 mg/m 2 if treatment is well tolerated and until unacceptable dose-limiting toxicity (DLT) establishes the MTD.
- DLT dose-limiting toxicity
- the MTD is defined as the dose of picoplatin below the dose at which at least one third of at least 6 subjects experience a DLT. Tolerance data from only the first 4 weeks of treatment is used to determine the MTD.
- the cohort size is 3 subjects, and is expanded to 6 subjects if a DLT is observed.
- picoplatin dose escalation may proceed in the next cohort of that schedule of picoplatin. If one DLT is observed, the cohort size at the specified dose and schedule of picoplatin is expanded to 6 subjects. Additional subjects may be entered at any dosage level and schedule below the dose at which 2 of 6 have DLT to obtain additional safety or efficacy data. Phase 2
- the dose of the Phase 2 component of this study is selected based on the dose intensity of picoplatin achieved on each dose and schedule, the number of cycles tolerated and a subjective assessment of the tolerability and safety profile of each dose and schedule and a preliminary assessment of response rate in accord with Phase 1.
- the schedule for Phase 2 is selected as Schedule B, the q 4 week schedule.
- the subjects (approximately 100 with metastatic CRC, at about 25 clinical sites) are randomized to the modified FOLFOX 6 6 or to FOLPI- 150.
- the FOLPI regimen is as follows:
- Picoplatin 150 mg/m 2 is administered with every alternate cycle of 5-FU and leucovorin ( q 4 weeks, Schedule B) as a 2 hour infusion.
- Leucovorin (400 mg/m 2 in D5W) is administered every 2 weeks as a 2-hour infusion, either alone, or given at the same time as the picoplatin in a separate bag using a Y-line.
- the administration of leucovorin ⁇ picoplatin is followed by a 5-FU bolus of 400 mg/m 2 and then by 5-FU, 2400 mg/m 2 in D5W administered as a 46 hour continuous infusion.
- the modified FOLFOX 6 regimen is as follows:
- Oxaliplatin 85 mg/m 2 is administered every 2 weeks.
- Leucovorin 400 mg/m 2 in D5W
- Oxaliplatin is given at the same time as the leucovorin in a separate bag using a Y-line.
- the administration of leucovorin + oxaliplatin is followed by a 5-FU bolus of 400 mg/m 2 and then by 5-FU, 2400 mg/m 2 in D5W administered as a 46 hour continuous infusion.
- Neuropathy assessment is performed at baseline and after every two cycles of therapy (approximately every month) by an independent neurologist. The subject and the neurologist are not informed whether the platinum infused is oxaliplatin or picoplatin. This assessment by the neurologist is used to determine the incidence of Grade 2 or greater peripheral neuropathy. In Phase 2, for the purpose of determining toxicity for dose reduction or study drug discontinuation, the treating physician performs a neurological assessment using the NCI CTCAE. These CTCAE criteria are used to determine the need to dose reduce prior to each cycle. The assessment of the neurologist is used for determination of the safety endpoint, the incidence of neuropathy, and is performed independently every other cycle using the protocol-specified neuropathy scale, but is not be used for dose modification.
- Treatment cycles (5-FU and leucovorin ⁇ picoplatin or oxaliplatin depending on schedule) are repeated every 2 weeks, but may be delayed up to 2 weeks while awaiting recovery of clinical or laboratory abnormalities. Data from all cycles of treatment and cumulative toxicity are assessed for safety analysis.
- Tumor evaluations will be done at baseline and after every 4th treatment of 5-FU/leucovorin (every 8 weeks, unless doses have been delayed) on study.
- the efficacy endpoint will include objective response rate according to RECIST criteria. 26 Duration of response, time to progression, progression- free survival, and overall survival are also evaluated.
- a Picoplatin over 2 hours 150 mg/m 2 ; oxaliplatin: 85 mg/m 2 , over 2 hours; LV: 400 mg/m 2 over 2 hours (concurrent with picoplatin when given or oxaliplatin) followed by 5-FU: 400 mg/m 2 bolus and then 2400 mg/m 2 over 46 hours. All subjects continue cycles every two weeks until progression or discontinuation of study drug due to toxicity.
- Picoplatin was generally tolerated in combination with other myelosuppressive chemotherapeutic agents in previous Phase 1 studies at doses of 120-150 mg/m 2 administered every 3 weeks, i.e., doses equivalent to 80-100 mg/m 2 every 2 weeks or 160-200 mg/m 2 administered every 4 weeks. None of these studies, however, studied picoplatin in combination with 5-FU and leucovorin. 5-FU/leucovorin is not generally myelotoxic and thus the doses of picoplatin selected as the initial starting doses in the dose escalation portions of the current study, i.e., 45 mg/m 2 every two weeks and 60 mg/m 2 every four weeks, were well below the expected MTDs of picoplatin administered on these schedules. Administration of Picoplatin
- Picoplatin is supplied as a ready- to-use formulation.
- the contents of the vials must be transferred to a suitable bag for administration.
- the compatibility of the formulation with typical infusion equipment has been assessed, and results have established compatibility with EVA infusion bags, PVC infusion tubing, and polypropylene syringes when the materials are protected from light. PVC infusion bags are not recommended for administration of picoplatin.
- the compatibility of the formulation with typical administration sets has been assessed, and limits of acceptability have been set as 8 hours in a covered infusion bag.
- the product is highly sensitive to light and should not be exposed to ambient light for more than 1 hour without light protection.
- Picoplatin should be administered by peripheral vein or central line; it must not be given by the intramuscular or subcutaneous route. The starting dose will be calculated based on the body surface area from the height and weight of the patient. If the patient's weight changes by more than 10%, the treating physician must recalculate the body surface area and amend the dose. Picoplatin should be administered over 2 hours. It should be administered concurrently with leucovorin, in separate bags using a Y-line, when the two drugs are to be given on the same day. These two drugs have been tested and shown to be compatible when administered in this manner.
- Subjects also received anti-emetic therapy consisting of a 5-HT 3 receptor antagonist plus dexamethasone 30 minutes prior to a dose of picoplatin. Subjects may also receive anti-emetic therapy for several days following treatment, which may include oral lorazepam, prochlorperazine, or equivalent for up to 7 days, as clinically indicated for breakthrough nausea and/or vomiting.
- Guidance for Administration may include oral lorazepam, prochlorperazine, or equivalent for up to 7 days, as clinically indicated for breakthrough nausea and/or vomiting.
- ANC absolute neutrophil count
- Dose reduction is also required for any treatment events involving any treatment-related Grade 3 toxicity, any Grade 4 toxicity, or any renal toxicity or neurotoxicities as described below.
- the dose reduction should be 15 mg/m 2 ; for subjects receiving picoplatin every 4 weeks the dose reduction should be 30 mg/m 2 .
- Serum creatinine must be measured before every dose of picoplatin.
- the dose of picoplatin (but not 5-FU or leucovorin) must be modified according to the following table in Phase 1 :
- the dose of picoplatin should be modified according to the CTCAE grade of toxicity and its duration as follows:
- Dose Modification of 5-FU The first time the dose of picoplatin is reduced, the bolus dose of 5-FU should be omitted. The second time the dose of picoplatin is reduced, the infusional dose should be reduced by 600 mg/m 2 . Once decreased, the reduced dose of 5-FU should be continued; i.e., the dose of 5-FU should not be subsequently increased. If the platelet count or ANC count is Grade 1 or 2 at day 15 in a cycle with picoplatin, and the subject receives the alternate i.e., even numbered cycle that does not include picoplatin, the dose of 5-FU should not be reduced at this cycle. At the next treatment cycle, the doses of picoplatin and 5-FU should be reduced by one level. Dose modifications for Grade 3 or 4 non-hematological events must be made. Continue treatment only once toxicity has resolved to ⁇ Grade 3.
- the preferred dosage range is about 45-120 mg/m 2 , e.g., doses of 45 tol05 mg/m 2 , e.g., 45 mg/m 2 .
- the preferred dose can be higher, e.g., about 120-210 mg/m 2 , e.g., 120-180 mg/m 2 , e.g., 150 mg/m 2 .
- a lower dose can also be administered, e.g., at 45-90 mg/m 2 , e.g., 60 mg/m 2 .
- Useful agents for administration with picoplatin and methods of treatment are also disclosed in include the platinum and non-platinum anticancer drugs disclosed in U.S. Patent application Serial Nos. 10/276,503, filed September 4, 2003; 11/982,841, filed November 5, 2007; 11/935,979, filed November 6, 2007; 11/982,839, filed November 5, 2007; in U.S. Pat. Nos. 7,060,808 and 4,673,668; in PCT WO/98/45331 and WO/96/40210.
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CA2715353A CA2715353A1 (en) | 2008-02-08 | 2009-02-06 | Use of picoplatin and cetuximab to treat colorectal cancer |
AU2009210656A AU2009210656A1 (en) | 2008-02-08 | 2009-02-06 | Use of picoplatin and cetuximab to treat colorectal cancer |
EP09708387A EP2249827A4 (en) | 2008-02-08 | 2009-02-06 | Use of picoplatin and cetuximab to treat colorectal cancer |
US12/866,706 US20110052581A1 (en) | 2008-02-08 | 2009-02-06 | Use of picoplatin and cetuximab to treat colorectal cancer |
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PCT/US2009/000770 WO2009099649A1 (en) | 2008-02-08 | 2009-02-06 | Use of picoplatin and bevacizumab to treat colorectal cancer |
PCT/US2009/000773 WO2009099651A1 (en) | 2008-02-08 | 2009-02-06 | Use of picoplatin and cetuximab to treat colorectal cancer |
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US8168661B2 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
US8173686B2 (en) | 2006-11-06 | 2012-05-08 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
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US10867706B2 (en) | 2010-07-20 | 2020-12-15 | Applied Invention, Llc | Multi-scale complex systems transdisciplinary analysis of response to therapy |
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US20180193479A1 (en) * | 2010-10-08 | 2018-07-12 | City Of Hope | Meditopes and meditope-binding antibodies and uses thereof |
US11246942B2 (en) * | 2010-10-08 | 2022-02-15 | City Of Hope | Meditopes and meditope-binding antibodies and uses thereof |
US20150030535A1 (en) * | 2010-10-08 | 2015-01-29 | City Of Hope | Meditopes and meditope-binding antibodies and uses thereof |
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WO2013162368A1 (en) * | 2012-04-26 | 2013-10-31 | Stichting Vu-Vumc | Biomarkers |
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AU2009210656A1 (en) | 2009-08-13 |
WO2009099634A3 (en) | 2010-01-21 |
AU2009210734A1 (en) | 2009-08-13 |
US20110053879A1 (en) | 2011-03-03 |
US20110052581A1 (en) | 2011-03-03 |
EP2249644A2 (en) | 2010-11-17 |
JP2011511074A (en) | 2011-04-07 |
EP2244714A1 (en) | 2010-11-03 |
JP2011511072A (en) | 2011-04-07 |
CN101998851A (en) | 2011-03-30 |
EP2249644A4 (en) | 2012-05-30 |
WO2009099649A1 (en) | 2009-08-13 |
CN102006875A (en) | 2011-04-06 |
CN102014624A (en) | 2011-04-13 |
US20110052580A1 (en) | 2011-03-03 |
JP2011511071A (en) | 2011-04-07 |
CA2715329A1 (en) | 2009-08-13 |
WO2009099634A2 (en) | 2009-08-13 |
EP2249827A1 (en) | 2010-11-17 |
EP2249827A4 (en) | 2012-05-30 |
CA2715348A1 (en) | 2009-08-13 |
AU2009210654A1 (en) | 2009-08-13 |
EP2244714A4 (en) | 2012-06-06 |
CA2715353A1 (en) | 2009-08-13 |
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