HK1155088A - Use of picoplatin and cetuximab to treat colorectal cancer - Google Patents

Description

Use of picoplatin and cetuximab to treat colorectal cancer

Cross Reference to Related Applications

Priority of U.S. No.61/027,387 filed on 8/2/2008, U.S. No.61/027,382 filed on 8/2/2008, and U.S. No.61/027,360 filed on 8/2/2008, the disclosures of which are hereby incorporated by reference in their entireties. Priority is also claimed in U.S. No.60/857,066 (filed on 6/2006), 60/857,725 (filed on 8/2006), 60/877,495 (filed on 28/2006), 60/889,191 (filed on 9/2/2007), 60/931,589 (filed on 24/5/2007), and 60/983,852 (filed on 30/10/2007), and U.S. No.11/982,841, filed on 5/11/2007, the disclosures of which are hereby incorporated by reference in their entireties.

Technical Field

Colorectal cancer remains the second most common cause of cancer-related death in the United states, and is also a significant cause of cancer-related death in other countries¹. For decades, the only chemotherapeutic drugs approved for the treatment of colorectal cancer were 5-fluorouracil (5-FU), which remains the primary drug of the first-line chemotherapeutic regimen in most patients with advanced disease. However, great progress has been made in the treatment of metastatic colorectal cancer (mCRC) over the past decade, including the approval of several new therapeutic agents including irinotecan (irinotecan), oxaliplatin (oxaliplatin), capecitabine (capecitabine), and recently cetuximab (cetuximab) and bevacizumab (bevacizumab)^2，3. Importantly, new chemotherapeutic regimens have been designed using these drugs, which result in improved response rates and an increasing progression time and median survival in patients with advanced disease^2，3. Response rates for 5-FU/leucovorin, irinotecan, oxaliplatin as monotherapy were low (23%, 18% and 12%, respectively), short survival without progression (4.0, 4.3 and 4.0 months median, respectively), and short survival median of approximately (12, 12 and 14.5 months, respectively)⁴. With the introduction of a 5-FU based combination chemotherapy regimen "FOLFOX regimen" using irinotecan and oxaliplatin, the response rate was significantly improved, reportedly as high as 64% (FOLFOX7), with progression times from 8.9 to 12.3 months in some reports, with median survival now approaching about 20 months^2-4。

Unfortunately, however, these newer combination chemotherapy regimens have increased toxicity. Irinotecan-containing regimens have been associated with severe diarrhea and other gastrointestinal toxicities, while those containing oxaliplatin have been associated with neurotoxicity^2-10. There are two types of neurotoxicity observed: first, cumulative and often dose-limiting sensory loss with paresthesia that can interfere with function, and second, cold sensitivity that limits patient discomfort from receiving FOLFOX regimen^7-10。

Picoplatin (pic)opatin) is a platinum analog that has been shown to act synergistically with 5-FU in vitro in preclinical studies and has been extensively tested in stages 1 and 2 in a variety of cancers^11-22. Like other platinum analogs, picoplatin causes cell death by forming covalent crosslinks in DNA that interfere with DNA replication and transcription leading to cell death. Cisplatin (the first platinum analog) was introduced about 20 years ago and is still widely used at present. Cisplatin approval was followed by approval of Carboplatin (Carboplatin), and oxaliplatin was recently approved.

Treatment with platinum analogs is limited by their toxicity. While neurotoxicity and nephrotoxicity are the major Dose Limiting Toxicities (DLT) observed after cisplatin treatment, myelosuppression is the most significant toxicity after carboplatin treatment. Carboplatin is known to cause cumulative dose-related toxicity that results in slow bone marrow recovery. There is a large body of literature demonstrating peripheral neurotoxicity in patients treated with oxaliplatin. Unacceptable nephrotoxicity, ototoxicity and neurotoxicity associated with early platinum analogs have not been reported in animal experiments or clinical trials of picoplatin^11，19-22。

The efficacy of platinum analogs is also limited by several (intrinsic or acquired) resistance mechanisms, including impaired cellular uptake, thiols [ e.g., reduced glutathione]Resulting intracellular inactivation, and enhanced DNA repair and/or increased tolerance to platinum-DNA adducts²³. Preclinical studies have shown that picoplatin can overcome these three resistance mechanisms. This has been demonstrated in vitro by using a human ovarian cancer xenograft tumor model that exhibits cisplatin resistance^13-17. Several human ovarian and colon cell lines with induced resistance to oxaliplatin retain sensitivity to picoplatin^16-18。

In phase 1 studies, tolerable side effects and indications of activity were found in patients with ovarian, non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC), colorectal, head and neck, renal cell carcinoma, thymus, pancreatic, gastric, leiomyosarcoma, liver, mesothelioma, and prostate cancer^24，25. In the phase 2 study, indications of efficacy were found in patients with ovarian cancer, NSCLC, SCLC, mesothelioma, prostate cancer, and breast cancer.

Cetuximab (cetuximab) is a recombinant human/murine chimeric Epidermal Growth Factor Receptor (EGFR) monoclonal antibody. FDA in usa in 2004 has approved in february, it is used in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal cancer in patients who failed to improve irinotecan-based or oxaliplatin-based chemotherapy. Cetuximab has also been demonstrated to be administered as a single drug in the treatment of patients with metastatic colorectal cancer that express EGFR (said patients are resistant to irinotecan-based chemotherapy). To be provided withIs marketed by Bristol-Myers Squibb.

EGFR is known to be expressed in a wide range of cancer cell lines, and it has been reported that "elevated levels of Epidermal Growth Factor Receptor (EGFR), growth factor receptor tyrosine kinase and/or their cognate ligands have been identified as a common component of a variety of cancer types and shown to promote growth of solid tumors". See, for example, Nicholson RI, Gee JM, Harper ME, "EGFR and Cancer Prognosis," Eur.J.cancer, (Sept.2001), 37suppl.4, S9-15.

Cetuximab has been demonstrated to be used as a first-line therapy for the treatment of metastatic Colorectal cancer (mCRC) in combination with oxaliplatin-and irinotecan-based regimens, as well as in a second-line therapy or as a monotherapy in combination with other drugs, see, e.g., j.j.lee et al, Clin colorcancer. 2007; 6Suppl 2: s42-6 and w.zhang et al, Ann med.2006; 38: 545-51.

About 40% of patients with mCRC have K-ras mutations, whose mCRC does not respond to Epidermal Growth Factor Receptor (EGFR) inhibitors such as cetuximab and panitumumab. Many cetuximab-treatment studies in mCRC demonstrated a low response rate or even 0, short progression-free survival and short overall survival in K-ras mutated positive mCRC. Since K-ras wild-type CRC patients treated with EGFR inhibitors have significantly higher objective response rates, improved progression-free survival, and improved overall survival, the K-ras test is currently used in routine clinical practice to select a subset of mCRC patients most likely to benefit from treatment with EGFR inhibitors. Given the side effects and cost of ineffective drugs, subset selection excludes patients who are unlikely to respond to EGFR inhibitors. Examples of companies that provide K-ras tests to medical oncologists include:

for example, see: m.brink et al, cartinogenesis.2003; 24: 703-10 parts of; li [ vre ], et al, J Clin Oncol.2008; 26: 374-9; de Roock et al, Ann oncol.2007, nov.12; F.Di Fiore et al, Br J cancer.2007; 96: 1166-9; li [ vo ] re et al, Cancer Res.2006; 66: 3992-5; c.s.karapetis et al, nejm.2008; 359 (N17): 1757-; amado et al, 2008American Society of Clinical Oncology scientific cancers Symposium, Abstract 278.

Disclosure of Invention

The invention relates to a method for preparing picoplatin and cetuximabAnd optionally 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer; to the use of picoplatin in combination with cetuximab and optionally 5-FU and leucovorin for the treatment of colorectal cancer; and kits suitable for the combined administration of picoplatin with cetuximab, 5-fluorouracil and leucovorin.

In various embodiments, the present invention provides methods of treating colorectal cancer comprising administering to a patient having colorectal cancer picoplatin, cetuximab, 5-fluorouracil (5-FU) and leucovorin, 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 at the time of administration of the fluorouracil and leucovorin, and the cetuximab is administered at least twice at one week intervals. For example, it may be at about 60-180mg/m²The dosage of (a) to (b),preferably about 150mg/m²The dose of picoplatin is administered. For example, the interval between administration of 5-FU and leucovorin may be about two weeks, and the interval between administration of picoplatin may be about four weeks.

In various embodiments, the present invention provides methods of treating colorectal cancer comprising administering to a patient having colorectal cancer an effective amount of a combination of picoplatin, cetuximab, 5-FU and leucovorin, wherein the picoplatin and the 5-FU and leucovorin are administered intravenously at least two times at intervals of about 2-6 weeks and the cetuximab at least two times at intervals of one week, wherein the amount of picoplatin administered is below the maximum tolerated dose of picoplatin. For example, it may be at about 45-150mg/m²Preferably about 135-150mg/m²The dose of picoplatin is administered. For example, the interval between the administration of picoplatin, 5-FU, and leucovorin may be about two weeks.

In various embodiments, the present invention provides methods of selecting a treatment regimen for metastatic colorectal cancer (mCRC), comprising (a) providing a patient suffering from mCRC; (b) determining whether the patient is a K-ras wild-type mCRC patient; and (c) selecting a regimen comprising an EGFR inhibitor and picoplatin for the patient if the patient comprises K-ras wild-type mCRC.

In various embodiments, the present invention provides methods of treating colorectal cancer, comprising (a) identifying a patient having colorectal cancer who has failed the FOLFOX-4 and/or FOLPI regimen; and (b) administering to the patient about 5-150mg/m every 21 days²Picoplatin in combination with a first weekly dose of 400mg/m²And a subsequent dose of 250mg/m²Cetuximab of (1).

In various embodiments, the present invention provides methods of treating colorectal cancer comprising (a) identifying a patient having colorectal cancer who has received an irinotecan, FOLFOX, or FOLPI regimen with or without bevacizumab or cetuximab, wherein the cancer is in remission, and (b) administering about 5-150mg/m to the patient every 21 days²Picoplatin and in combination with a first weekly administration dose of 400mg/m²Cetuximab andthe later dose is 250mg/m²Cetuximab as an adjunct therapy to prevent relapse.

In various embodiments, the present invention provides a method of selecting a treatment regimen for a patient having a metastatic cancer that comprises EGFR, comprising (a) identifying a patient having a metastatic cancer, (b) determining whether the cancer comprises a wild-type K-ras gene or a mutation-positive K-ras gene, and (c) selecting a regimen comprising picoplatin and an EGFR inhibitor if the wild-type K-ras gene is present, or selecting a regimen comprising picoplatin but no EGFR inhibitor if the mutation-positive K-ras gene is present. For example, a metastatic cancer comprising EGFR may include SCLC, NSCLC, pancreatic cancer, colorectal cancer, epithelial cancer, or head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, gastric cancer, breast cancer, or endometrial cancer.

In various embodiments, the present invention provides methods of selecting a treatment regimen for a patient with mCRC comprising: (a) identifying a patient having mCRC, (b) determining whether mCRC comprises a wild-type K-ras gene or a mutated K-ras gene, and (c) administering to the patient an EGFR inhibitor, such as cetuximab, erlotinib, or panitumumab, in combination with picoplatin and optionally 5-FU and leucovorin, if m-CRC comprises a K-ras wild-type genotype, or (d) administering to the patient picoplatin and optionally 5-FU and leucovorin, if m-CRC comprises a K-ras mutation-positive genotype. For example, the EGFR inhibitor may include cetuximab.

In various embodiments, the present invention provides the use of picoplatin in combination with cetuximab, 5-fluorouracil (5-FU) and leucovorin in the treatment of colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, picoplatin is administered with the leucovorin and 5-FU every other time at the time of administration of the fluorouracil and leucovorin, and cetuximab is administered at least twice at intervals of 1 week. For example, it may be at about 60-180mg/m²Preferably about 150mg/m²The dose of picoplatin is administered. For example, the interval between administration of 5-FU and leucovorin may be about two weeks, pyridineThe interval between platinum administrations may be about four weeks.

In various embodiments, the present invention provides the use of picoplatin in combination with cetuximab, 5-FU and leucovorin, wherein the picoplatin is administered intravenously at least twice at intervals of about 2-6 weeks with the 5-FU and leucovorin, 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. For example, it may be at about 45-150mg/m²Preferably about 135-150mg/m²The dose of picoplatin is administered. For example, the interval between the administration of picoplatin, 5-FU, and leucovorin may be about two weeks.

In various embodiments of the present invention, a kit is provided that is suitable for intravenous administration of a FOLPI + cetuximab regimen to a patient; the kit comprises a first container containing a picoplatin solution and a second container containing a formyltetrahydrofolate solution; further comprising a coupling device adapted to be independently connected to the first container, the second container and a single intravenous administration tube, such that the contents of the first container and the second container can be administered to the patient simultaneously; the kit further comprises a composition comprising cetuximab suitable for intravenous administration to the patientContainers for solutions and compositions containing

A container of 5-FU solution; instructions for use are also optionally included.

In one embodiment, the kit may include picoplatin in a first container in a dosage form comprising an isotonic solution comprising water, an osmotic pressure regulator (tonicity adjust), and about 0.5mg/ml dissolved picoplatin, wherein the osmotic pressure regulator comprises NaCl. The dosage form may further comprise an effective amount of dissolved or dispersed 5-FU and/or leucovorin, according to the dosage disclosed herein. And the dosage form does not contain preservatives or bacteriostats. An appropriate volume of the dosage form may be administered to achieve the desired therapeutic dose.

Detailed Description

In various embodiments, the present invention provides methods of treating colorectal cancer comprising administering picoplatin, cetuximab, 5-fluorouracil (5-FU) and leucovorin to a patient having 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 at the time of administration of the fluorouracil and leucovorin, and the cetuximab is administered at least twice at intervals of 1 week. For example, it may be at about 60-180mg/m²Preferably about 150mg/m²The dose of picoplatin is administered. For example, the interval between administration of 5-FU and leucovorin may be about two weeks, and the interval between administration of picoplatin may be about four weeks.

In various embodiments, the present invention provides methods of treating colorectal cancer comprising administering to a patient having colorectal cancer an effective amount of a combination of picoplatin, cetuximab, 5-FU and leucovorin, wherein the picoplatin and the 5-FU and leucovorin are administered intravenously at least two times at intervals of about 2-6 weeks and the cetuximab at least two times at intervals of one week, wherein the amount of picoplatin administered is below the maximum tolerated dose of picoplatin. For example, it may be at about 45-150mg/m²Preferably about 135-150mg/m²The dose of picoplatin is administered. For example, the interval between the administration of picoplatin, 5-FU, and leucovorin may be about two weeks.

For example, leucovorin and 5-FU may be administered about every two weeks, picoplatin with leucovorin about every 4 weeks, and cetuximab weekly. For example, it may be at about 60-75mg/m²The dose of picoplatin is administered at least once. Alternatively, it may be at about 150mg/m²The dose of picoplatin is administered at least once. In some embodiments, it may be about 15-30mg/m lower than the previous dose²The subsequent picoplatin dose is administered.

In various embodiments of the methods of the invention, the patient has not previously been treated for metastatic disease. In other embodiments, the patient has previously received an irinotecan, FOLFOX and/or FOLPI regimen. Alternatively, the patient may have been previously treated with the FOLFOX regimen, followed by treatment with the FOLPI regimen, and relapsed within 6 months of completion of the FOLPI regimen. Alternatively, the patient may have been previously treated with a first regimen comprising FOLFOX or irinotecan, followed by treatment with a second regimen comprising cetuximab only, irinotecan + cetuximab, or FOLPI, and relapse within 6 months after cessation of the second regimen.

In various embodiments of the methods of the invention, the patient has not previously been treated for metastatic disease, or the patient has not previously been treated for systemic treatment for localized or metastatic disease, such as chemotherapy. For example, the patient may have undergone surgery to remove or ablate a primary tumor and then be treated with one of the picoplatin, 5-fluorouracil, and leucovorin regimens of the invention (e.g., FOLPI) to prevent or delay the progression of the cancer, including preventing or delaying the occurrence of metastases. The patient may have received earlier chemotherapy at the time of primary tumor treatment (at least 6 months prior to picoplatin treatment of the invention).

In various embodiments, picoplatin can be administered for curative purposes, not just to inhibit unrelieved disease. The dose of picoplatin can be increased beyond the amount that causes the disease to cease in order to achieve a cure for the patient.

For example, leucovorin and picoplatin may be administered substantially simultaneously each time a patient is treated, followed by 5-FU, and cetuximab administered at one week intervals. For example, it may be at about 40-45mg/m²The dose of picoplatin is administered at least once.

In various embodiments, the patient may have previously been treated with an earlier systemic chemotherapy regimen and the cancer is in remission. For example, the patient may receive a too early FOLPI regimen treatment with or without bevacizumab or cetuximab.

In various embodiments of the methods of the present invention, picoplatin can be administered in a dosage form comprising an isotonic solution comprising water, an osmotic pressure regulator (comprising NaCl), and about 0.5mg/ml dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostats.

In various embodiments, picoplatin, cetuximab, and leucovorin may be administered substantially simultaneously. For example, picoplatin and leucovorin may be administered concurrently. As used herein, the term "simultaneous" means synchronized (simultaneousy), overlapping, or sufficiently close in time that two or more administered agents are present in the body in therapeutically effective amounts.

In various embodiments, 5-FU may be administered after the administration of picoplatin, leucovorin, and cetuximab.

In various embodiments, at about 200-400mg/m²Administering leucovorin for the first dose. And, at about 1000-²The total dose of 5-FU is administered.

In various embodiments, it may be present in the range of about 60 to 180mg/m²The dose of picoplatin is administered. More specifically, at about 120-²The dose of picoplatin is administered. For example, it may be about 150mg/m²The dose of picoplatin is administered at least once.

In various embodiments, it may be about 15-30mg/m lower than the previous dose²Administering a subsequent dose of picoplatin; for example, the current dose is about 150mg/m²Then the subsequent dose may be about 120-135mg/m²。

In various embodiments of the methods of the invention, a cumulative dose of greater than about 900mg/m can be delivered to a patient²Picoplatin of (1).

In various embodiments, it may be at about 400mg/m²Is administered intravenously at a first dose of cetuximab and then once a week at about 250mg/m²The dosage of (a).

In a number of embodiments, the first and second electrodes are,the dose may be administered as a 2 hour infusion at about 400mg/m²Leucovorin; after administration of leucovorin, the bolus dose is about 400mg/m²5-FU of (1); the bolus of 5-FU was followed by a 46 hour continuous infusion at a dose of about 2,400mg/m²5-FU of (1); wherein the leucovorin and 5-FU are administered to the patient every two weeks and about 60-150mg/m is administered to the patient with the leucovorin every four weeks²Wherein at least the initial dose of picoplatin is about 150mg/m²Wherein at about 400mg/m²Is administered with cetuximab once a week at about 250mg/m²The dose of (a) is administered with cetuximab.

One embodiment of the methods of the invention provides a method of treating colorectal cancer, comprising:

(a) identifying a patient having colorectal cancer who has failed the FOLFOX-4 and/or FOLPI regimen; and

(b) administering to the patient about 5-150mg/m every 21 days²Picoplatin in combination with a first weekly administration dose of 400mg/m²And a subsequent dose of 250mg/m²Cetuximab of (1).

One embodiment of the methods of the invention provides a method of treating colorectal cancer, comprising:

(a) identifying a patient having colorectal cancer who has received an irinotecan, FOLFOX, or FOLPI regimen with or without bevacizumab or cetuximab, wherein the cancer is in remission, and

(b) administering to the patient about 5-150mg/m every 21 days²Picoplatin in combination with a first weekly administration dose of 400mg/m²And a subsequent dose of 250mg/m²Cetuximab as an adjunct therapy to prevent relapse.

In another embodiment of the invention, the picoplatin is administered substantially concurrently with the leucovorin and every second time the patient is treated with 5-FU and leucovorin (e.g., every four weeks). Co-administration with picoplatinA relatively high dose of cetuximab, after which cetuximab is administered weekly. May be at about 200-500mg/m²Is administered as leucovorin, preferably about 400mg/m². At a rate of about 60-180mg/m²The dose of picoplatin is administered. The infusion dose is 400mg/m at a rate of about 5mL/min over about 20 hours²Followed by 250mg/m weekly²The maintenance dose of (4), intravenous infusion for about 60 minutes. At about 1000-3000mg/m²The total dose of 5-FU is administered. A preferred treatment cycle for leucovorin and 5-FU is administration of picoplatin every two weeks, every four weeks, e.g., about 60-75mg/m²Low dosage of (e.g. 60 mg/m)²Or about 120-180mg/m²Preferably about 120-150mg/m²E.g. about 150mg/m²。

Thus, in one embodiment of the invention, a dose of 200-500mg/m is administered concurrently with picoplatin (when administered) in the form of a 2 hour infusion²Wherein the dose of picoplatin is 120-180mg/m²E.g. about 150mg/m²(ii) a Administration of leucovorin and picoplatin is followed by a bolus dose of about 400mg/m²5-FU of (1); the administration of 5-FU is followed by a dose of 600mg/m²Or 2,400mg/m²Preferably in the form of a 22 hour or 46 hour continuous infusion, respectively, wherein the leucovorin and 5-FU are provided to the patient at two week intervals and the leucovorin, picoplatin and 5-FU are provided to the patient at four week alternating intervals. Cetuximab was administered as described above, at a first dose of 400mg/m²Then 250mg/m per week²The dosage of (a). In another embodiment, about 45-75mg/m is administered²Low dose of picoplatin, e.g., about 60-75mg/m²E.g. about 60mg/m². This 5-FU/leucovorin/picoplatin regimen may be broadly referred to as a FOLPI regimen, which is supplemented with cetuximab infusion in the present invention.

In another embodiment of the invention, the dose administered is 400mg/m as a 2 hour infusion²Leucovorin; after administration of leucovorin, a bolus dose of 400mg/m²5-FU of (1); after a bolus of 5-FUThe parenteral administration dose is 400mg/m²Or 2,400mg/m²Preferably in 22 hours or 46 hours, respectively; administration of leucovorin and 5-FU is performed every two weeks; wherein the simultaneous, preferably simultaneous, administration of the dose of leucovorin and leucovorin is up to about 50mg/m every two weeks²E.g. about 40-50mg/m²E.g. about 45mg/m²Picoplatin of (1). Also, about 45-105mg/m may be administered²The picoplatin dose of (c). Cetuximab was administered weekly as previously described.

It has been unexpectedly found that in some instances, the administration of low doses of picoplatin in combination with leucovorin and 5-FU at each treatment cycle is as effective or more effective in producing a response than higher doses (e.g., MTD) given at the same interval. The MTD for the 2-week and 4-week picoplatin administration schedule (see Table 1) is discussed below. Preferably, such dose is below or significantly below the MTD in the initial treatment. Such dosage may range from about 40 to 60mg/m biweekly²The picoplatin of (a), administered with leucovorin and cetuximab followed by 5-FU, as described below.

It has surprisingly been found that patients can tolerate total cumulative doses in excess of about 900mg/m²No secondary or higher neuropathy was observed.

In one embodiment of the method of the invention, it is preferred that the patient has not previously received systemic treatment, such as chemotherapy, for metastatic disease. However, at least six months prior to the picoplatin-cetuximab treatment of the present invention, the patient may have received earlier adjuvant therapy at the time of primary tumor treatment.

In another embodiment of the invention, the patient has received an earlier systemic regimen of chemotherapy, such as the FOLFOX regimen, and is in remission. In this case, the regimen of the invention (broadly referred to as FOLPI) may be administered to prolong remission or disease-free survival, with or without the combined use of cetuximab. Alternatively, MCRC patients received an earlier FOLPI regimen (with or without bevacizumab or cetuximab) and the cancer is in remission, the FOLPI plus cetuximab or picoplatin in combination with cetuximab methods of the invention may be used as adjuvant therapy to prevent cancer recurrence.

Preferably, the patient exhibits EGFR expression in at least some cells of metastatic colorectal cancer.

As a first line treatment for patients with mCRC, picoplatin may be used in combination with 5-fluorouracil (5-FU) and leucovorin in a FOLPI regimen, and cetuximab may also be administered. Epidermal growth factor receptor (EDFR) inhibitors such as the monoclonal antibody cetuximab or panitumumab (panitumumab) are used as second and third line therapies in patients with mCRC. As discussed above, mCRC patients with K-ras mutation positive tumor genotypes did not respond to cetuximab and other EGFR antagonists. In various embodiments of the invention, picoplatin and cetuximab, optionally including 5-FU and formyltetrahydrofolate, may be used for treatment of mCRC patients positive for K-ras mutations. For example, a patient (unless he receives a specific dose of cetuximab, but finds that his mCRC cancer cell genotype is positive for K-ras mutations) may be administered picoplatin in combination with 5-FU and leucovorin in a variety of dosing regimens.

Accordingly, one embodiment of the present invention also includes a method of selecting a treatment regimen for a patient having mCRC comprising: (a) providing a patient having mCRC, (b) determining whether 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 a combination therapy of the invention as described above, including one or more EGFR inhibitors such as cetuximab (e.g., cetuximab)) Erlotinib (e.g. erlotinib) and pharmaceutically acceptable salts thereof) Or panitumumab (e.g. Abromumab)) Picoplatin, 5-FU and leucovorin. If the patient is determined to contain a K-ras mutation-positive mRC, the EGFR inhibitor should be omitted from the picoplatin, 5-FU, leucovorin regimen. Another embodiment comprises treating the patient with the selected regimen.

The methods of the invention may be used generally to select a treatment regimen for a patient suffering from a cancer, wherein the cancer comprises EGFR, such as SCLC, NSCLC, pancreatic cancer, colorectal cancer, epithelial cancer, or head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, gastric cancer, breast cancer, or endometrial cancer, and the like, by: (a) providing a patient having a tumor; (b) determining whether 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.

One embodiment of the present invention also provides a method of selecting a treatment regimen for a patient with mCRC comprising: (a) identifying a patient suffering from mCRC, (b) determining whether mCRC comprises a wild-type K-ras gene or a mutated K-ras gene, and (c) administering an EGFR inhibitor such as cetuximab, erlotinib, or panitumumab to the patient in combination with picoplatin and optionally 5-FU and leucovorin if m-CRC comprises a wild-type K-ras genotype, or (d) administering picoplatin and optionally 5-FU and leucovorin to the patient if mCRC comprises a K-ras mutation-positive genotype. For example, the EGFR inhibitor may be cetuximab.

In another embodiment of the invention, first line therapy (FOLFOX or irinotecan) fails and second line therapy also fails in patients with colorectal cancer (cetuximab alone, irinotecan plus cetuximab, or FOLPI). In this case, the modified FOLPI plus cetuximab regimen of the present invention can be used as a "three-line therapy".

Alternatively, every three weeks of intravenous administration of picoplatin (5-150 mg/m) is employed²) Combination cetuximab protocol (400 mg/m)²initial loading dose, then 250mg/m²Weekly maintenance dose of i.v.) can be used as a three-line therapy, wherein no additional 5-FU and leucovorin is administered.

As used herein, the term "simultaneously" means synchronized, overlapping, or sufficiently close in time that two or more administered agents are present in the body in therapeutically effective amounts.

The methods of the invention may further comprise administering an effective amount of a 5-HT3 receptor antagonist as an antiemetic agent.

One embodiment of the present invention provides the use of picoplatin in combination with cetuximab, 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks, picoplatin is administered with the leucovorin and 5-FU every other time when the fluorouracil and leucovorin are administered, and cetuximab is administered at least twice at one week intervals.

For example, in various embodiments, leucovorin and 5-FU may be administered about every two weeks, picoplatin may be administered with leucovorin about every four weeks, and cetuximab may be administered weekly. For example, it may be at about 60-75mg/m²The dose of picoplatin is administered at least once.

Another embodiment of the present invention provides the use of picoplatin in combination with cetuximab, 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer, wherein the picoplatin is administered at least twice at intervals of about 2 weeks by intravenous administration of the picoplatin, 5-FU and leucovorin at least twice at one week intervals, wherein the amount of picoplatin, when administered in the combination, is below the maximum tolerated dose of picoplatin.

Another embodiment of the present invention provides the use of picoplatin in combination with cetuximab, 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at least twice at intervals of about 2 weeks, each time the fluorouracil and leucovorin are administered together with the leucovorin and 5-FUAdministering picoplatin at about 45-120mg/m²Wherein the picoplatin is administered at a dose of about 250-500mg/m²The first dose of (a) is intravenously administered with cetuximab followed by administration at intervals of about 200-300mg/m²Cetuximab at the dose.

For example, leucovorin and picoplatin may be administered substantially simultaneously each time a patient is treated, followed by 5-FU, and cetuximab administered at one week intervals. For example, it may be at about 40-45mg/m²The dose of picoplatin is administered at least once.

In various embodiments of the use of the invention, the patient has not previously been treated for metastatic disease. In various other embodiments, the patient was previously treated with a FOLFOX and/or FOLPI regimen. For example, the patient may have been previously treated with the FOLFOX regimen, followed by the FOLPI regimen, and relapsed within 6 months of completion of the FOLPI regimen. Alternatively, the patient with colorectal cancer may have been previously treated with a first regimen comprising FOLFOX or irinotecan, followed by a second regimen comprising cetuximab only, irinotecan + cetuximab, or FOLPI, and relapsed within 6 months after discontinuing the second regimen.

In other embodiments of the use of the invention, the patient may have previously been treated with an earlier systemic chemotherapy regimen and the cancer is in remission. For example, the patient may receive an earlier FOLPI regimen treatment with or without bevacizumab or cetuximab and the cancer is in remission.

In various embodiments, picoplatin can be administered in a dosage form comprising an isotonic solution comprising water, an osmotic pressure regulator (comprising NaCl), and about 0.5mg/ml dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostats.

In various embodiments, picoplatin, cetuximab, and leucovorin may be administered substantially simultaneously. As used herein, the term "simultaneously" means simultaneously, overlapping, or sufficiently close in time that two or more administered agents are present in the body in therapeutically effective amounts. In various embodiments, picoplatin and leucovorin may be administered simultaneously. In various embodiments, 5-FU may be administered after the administration of picoplatin, leucovorin, and cetuximab.

In various embodiments of the use of the present invention, it may be at about 200-400mg/m²Administering leucovorin for the first dose. In other embodiments, about 1000-3000mg/m per administration may be used²The total dose of 5-FU is administered. In various embodiments, it may be present in the range of about 60 to 180mg/m²The dose of picoplatin is administered. More specifically, it may be at about 120-²Administering picoplatin; for example, it may be at about 150mg/m²At least one dose of picoplatin. In various embodiments, it may be about 15-30mg/m lower than the previous dose²Administering a subsequent dose of picoplatin; for example, the current dose is about 150mg/m²Then the subsequent dose may be about 120-135mg/m². In various embodiments, a cumulative dose of greater than about 900mg/m can be delivered to a patient²Picoplatin of (1).

In various embodiments, it may be at about 400mg/m²The first dose of (a) is intravenously administered cetuximab, followed by a weekly administration of about 250mg/m²The dosage of (a).

In various embodiments of the use of the present invention, a dose of about 400mg/m may be administered as a 2 hour infusion²The leucovorin is administered in a bolus dose of about 400mg/m²5-FU of (1); the bolus of 5-FU was followed by a 46 hour continuous infusion at a dose of about 2,400mg/m²5-FU of (1); wherein the leucovorin and 5-FU are administered to the patient every two weeks and about 60-150mg/m is administered to the patient with the leucovorin every four weeks²At least a first dose of picoplatin of about 150mg/m²And wherein at about 400mg/m²Is administered cetuximab, then about 250mg/m once a week²The dosage of (a).

In various embodiments, the patient may exhibit EGFR expression in at least some cells of metastatic colorectal cancer.

In various embodiments, in treating colorectal cancer in a patient having colorectal cancer who has failed the FOLFOX-4 and/or FOLPI regimen, about 5-150mg/m is administered every 21 days²Picoplatin and in combination with a first weekly administration dose of 400mg/m²And a subsequent dose of 250mg/m²Cetuximab of (1).

In various embodiments, about 5-150mg/m may be administered every 21 days²Picoplatin and in combination with a first weekly administration dose of 400mg/m²And a subsequent dose of 250mg/m²To prevent recurrence of colorectal cancer in a patient having colorectal cancer who received an irinotecan, FOLFOX, or FOLPI regimen with or without bevacizumab or cetuximab, wherein the cancer is in remission.

In various embodiments, the use may further comprise administering 5-HT₃A receptor antagonist.

In various embodiments, the present invention provides a kit adapted for intravenous administration of a FOLPI + cetuximab regimen to a patient; the kit comprises a first container containing a picoplatin solution and a second container containing a formyltetrahydrofolate solution; further comprising a coupling device adapted to be independently connected to the first container, the second container and a single intravenous administration tube, such that the contents of the first and second containers can be administered to the patient simultaneously; the kit further comprises a composition comprising cetuximab suitable for intravenous administration to the patientA container for the solution and a container containing the 5-FU solution; instructions for use are also optionally included. For example, the first container may contain a picoplatin dosage form comprising water, an osmotic pressure regulator, and an isotonic solution of approximately 0.5mg/ml dissolved picoplatinThe dosage form of (1) does not contain a preservative or a bacteriostatic agent.

Picoplatin (SP-4-3) (cis-aminodichloro (2-methylpyridine) platinum (II)), and useful prodrugs and analogs thereof, have been disclosed in U.S. patent nos.5,665,771; 6,518,428, respectively; 6,413,953, respectively; U.S. patent application Ser. No.11/982,891, filed on 5.11.2007; and PCT/GB/01/02060, which is incorporated herein by reference. The dosages disclosed herein can be provided by administering an effective amount of picoplatin in combination with a pharmaceutically acceptable carrier, both orally and by intravenous infusion.

(cetuximab) is a recombinant human/murine chimeric monoclonal antibody that specifically binds to the extracellular domain of human Epidermal Growth Factor Receptor (EGFR).Consisting of the Fv region of a murine anti-EGFR antibody, and the constant regions of the heavy and kappa light chains of human IgG1, weighing approximately 152 kDa. Production in mammalian (murine myeloma) cell cultureSee Goldstein et al (U.S. Pat. No.7,060,808).

Is provided in the form of a sterile, clear, colorless liquid having a pH of 7.0 to 7.4It may contain small amounts of easily found, white, amorphous particles of cetuximab. Each single use 50-mL vial contained 100mg cetuximab at a concentration of 2mg/mL, formulated in a preservative-free solution containing 8.48mg/mL sodium chloride, 1.88mg/mL sodium phosphate dibasic heptahydrate, 0.42mg/mL sodium phosphate monobasic monohydrate, and USP water for injection.

Administered in combination with concomitant chemotherapy or radiotherapyExhibit non-linear pharmacokinetics. The area under the concentration time curve (AUC) increased more than in a dose-proportional manner, with dose increasing from 20 to 200mg/m²When the clearance rate of the cetuximab is reduced from 0.08 to 0.02L/h/m²At a dosage of > 200mg/m²And displaying to the platform area. The volume of distribution of cetuximab showed to be close to 2-3L/m, independent of the dose²The vessel volume of (a).

The recommended dosage regimen is 400mg/m for 120 minutes intravenous infusion²Initial dose followed by intravenous infusion of 250mg/m for 60 minutes per week²Until disease progression or unacceptable toxicity. Over the third weekly infusion, the in vitro concentration of cetuximab reached a steady state level with mean peak and trough concentrations throughout the study ranging from 168 to 235 and from 41 to 85 μ g/mL, respectively. Cetuximab has a mean half-life of about 112 hours (in the range of 63-230 hours). In SCCHN patients, the pharmacokinetics of cetuximab are similar to that in colorectal cancer patients. Cetuximab in combination with the FOLFOX 4 regimen has been evaluated without undue side effects 27.

The use of picoplatin for the treatment of metastatic colorectal cancer will be performed in 3 parts. Phase 1 is a dose escalation study to determine the Maximum Tolerated Dose (MTD) of picoplatin that can be administered every two weeks or every four weeks, with the combined administration of 5-FU and Leucovorin (LV) administered every two weeks, for use as initial treatment for patients with metastatic colorectal cancer who have not previously been treated for metastatic disease. Phase 2 is a randomized study. In one branch of the study, at 150mg/m²Picoplatin is administered every four weeks in combination with 5-FU and leucovorin administered every two weeks. In the other branch, a modified FOLFOX 6 regimen was applied, wherein 100mg/m in FOLFOX 6 was used²Has been reduced to 85mg/m²And administered every two weeks so that the two agents can be compared in the context of a widely used regimen. It is believed that the regimen of the present invention using picoplatin in place of cisplatin, carboplatin, or oxaliplatin is more effective in the treatmentCancer patients, as they will present fewer side effects such as neuropathy, and preferably receive higher doses of platinum (Pt) drugs. Phase 3 will be a comparison of with and without weeklyStudy of the FOLPI protocol for infusion.

Subjects who met the phase 1 study criteria had stage IV colorectal cancer and did not receive systemic treatment for metastatic cancer. Adjuvant chemotherapy (without oxaliplatin or irinotecan) based previously on a 5-FU based therapeutic regimen is acceptable if there has been a treatment-free interval of at least 6 months.

Stage 1

Subjects were pooled for treatment with picoplatin every two or four weeks and the dose of picoplatin to be administered was prescribed based on the results of the study to date. Each patient also received 5-FU and leucovorin treatment every two weeks. Groups of 3 patients received their prescribed doses of picoplatin and leucovorin with 5-FU according to the following schedule:

day 1: the indicated dose of picoplatin was administered as an infusion over 2 hours per 5-FU and formyltetrahydrofolate cycle (q2 weeks, schedule A) or every other 5-FU and formyltetrahydrofolate cycle (q4 weeks, schedule B). Administered alone as an infusion for 2 hours at 400mg/m in D5W (water-5% glucose)²Or if the patient is to receive picoplatin, then the picoplatin in a separate infusion bag is administered simultaneously via a Y-tube (Y-line). Folic acid folinate (+ -picoplatin) is followed by a bolus injection of 400mg/m²Followed by a 46 hour continuous infusion of 2,400mg/m in D5W²5-FU of (1).

The subjects in phase 1 were assigned collectively to one of two picoplatin plans. The first group q2 week (plan A) of subjects used a dose of 45mg/m²Picoplatin treatment (per cycle, q2 weeks). If the treatment is well tolerated, subjects assigned to subsequent order groups in the planned regimen are accepted at 15mg/m²In increments ofDose levels of picoplatin until unacceptable Dose Limiting Toxicity (DLT) occurs to determine MTD.

The MTD was defined as the picoplatin dose below the dose that caused at least 1/3 to develop DLT in 6 subjects. Only tolerance data from the first 4 weeks of treatment was used to determine MTD. Thus, only data from the first two doses of picoplatin in subjects at week q2 (a plan) and only data from the first dose of picoplatin in subjects at week q4 (B plan) were considered. The dosage is 60mg/m²The first group of q4 weeks (B plan) subjects were treated with picoplatin (q4 weeks every other cycle). If the treatment is well tolerated, subjects assigned to subsequent order groups in the program are accepted at 30mg/m²Increasing dose levels of picoplatin until unacceptable Dose Limiting Toxicity (DLT) occurs to determine MTD. Depending on the mode and severity of toxicity observed, additional intermediate dose levels for either of the two picoplatin administration schedules can be studied.

In each plan, the size of the group was 3 objects, and the DLT was observed to expand to 6 objects. For each group of each program, one patient was treated first; if no DLT is observed for the next 4 weeks (2 drug cycles), the remaining two subjects are treated. Adjuvant chemotherapy (without oxaliplatin or irinotecan) previously based on a 5-FU based treatment regimen was acceptable.

Stage 1

Subjects were pooled for treatment with picoplatin every two or four weeks and the dose of picoplatin to be administered was prescribed based on the results of the study to date. Each patient also received 5-FU and leucovorin treatment every two weeks. Groups of 3 patients received their prescribed doses of picoplatin and leucovorin with 5-FU according to the following schedule:

day 1: the indicated dose of picoplatin was administered as an infusion over 2 hours per 5-FU and formyltetrahydrofolate cycle (q2 weeks, schedule A) or every other 5-FU and formyltetrahydrofolate cycle (q4 weeks, schedule B). Administered alone as an infusion over 2 hours at D5W (water-5% dextrose)Glucose) 400mg/m²Or if the patient is to receive picoplatin, then the picoplatin in a separate infusion bag is administered simultaneously via a Y-tube (Y-line). Folic acid folinate (+ -picoplatin) is followed by a bolus injection of 400mg/m²Followed by a 46 hour continuous infusion of 2,400mg/m in D5W²5-FU of (1).

The subjects in phase 1 were assigned collectively to one of two picoplatin plans. The first group q2 week (plan A) of subjects used a dose of 45mg/m²Picoplatin treatment (per cycle, q2 weeks). If the treatment is well tolerated, subjects assigned to subsequent order groups in the planned regimen are accepted at 15mg/m²Increasing dose levels of picoplatin until unacceptable Dose Limiting Toxicity (DLT) occurs to determine MTD.

The MTD was defined as the picoplatin dose below the dose that caused at least 1/3 to develop DLT in 6 subjects. Only tolerance data from the first 4 weeks of treatment was used to determine MTD. Thus, only data from the first two doses of picoplatin in subjects at week q2 (a plan) and only data from the first dose of picoplatin in subjects at week q4 (B plan) were considered. The dosage is 60mg/m²The first group of q4 weeks (B plan) subjects were treated with picoplatin (q4 weeks every other cycle). If the treatment is well tolerated, subjects assigned to subsequent order groups in the program are accepted at 30mg/m²Increasing dose levels of picoplatin until unacceptable Dose Limiting Toxicity (DLT) occurs to determine MTD. Depending on the mode and severity of toxicity observed, additional intermediate dose levels for either of the two picoplatin administration schedules can be studied.

In each plan, the size of the group was 3 objects, and the DLT was observed to expand to 6 objects. For each group of each program, one patient was treated first; if no DLT is observed for the next 4 weeks (2 drug cycles), the remaining two subjects are treated. If DLT is observed in the first patient in the group, whether additional subjects are included in the group is case specific. All subjects in the q2 week (plan a) group will complete 2 cycles (one cycle 2 days treatment regimen + an additional 12 days follow-up period) before increasing the dose in the next group of subjects. All subjects in the q4 week (plan B) group will complete 1 cycle of 2-day treatment regimen (5-FU/leucovorin should be included) and an additional 26-day follow-up period before increasing the dose for the next group of B-plan subjects.

If no DLT is observed in 3 subjects in the group, then an increase in picoplatin dose can be made in the next group of the picoplatin program. If one instance of DLT is observed, the assigned picoplatin dose and planned group size is expanded to 6 subjects. Additional subjects can be included to obtain additional safety or efficacy data at any dose level and schedule below 2 of 6 doses with DLT.

Stage 2

The dose for phase 2 portion of the study was selected based on the picoplatin dose strength achieved for each dose and schedule in phase 1, the number of cycles tolerated for each dose and schedule, objective assessments of the tolerability and safety characteristics for each dose and schedule, and preliminary assessments of the response rates. The phase 2 plan is selected as the B plan, i.e., the q4 week plan. Subjects (about 100 subjects with metastatic CRC, about 25 clinical points) were randomly assigned to modified FOLFOX 6⁶Or FOLPI-150. The FOLPI protocol was as follows:

150mg/m per alternate cycle of 5-FU and leucovorin (q4 weeks, schedule B) administered as an infusion for 2 hours²Picoplatin. Folic acid folinate alone (400mg/m in D5W) was administered as an infusion for 2 hours every two weeks²) Or picoplatin in separate pouches applied simultaneously through a Y-tube. After administration of leucovorin + -picoplatin, a bolus of 400mg/m²5-FU followed by a 46 hour continuous infusion of 2,400mg/m in D5W²5-FU. The modified FOLFOX 6 protocol was as follows:

administered at 85mg/m in the form of infusion for 2 hours every two weeks²Oxaliplatin. Folic acid folinate (400mg/m in D5W) was administered as an infusion for 2 hours every two weeks²). Simultaneous administration of oxaliplatin via Y-formTubes administer leucovorin in separate bags. After administration of leucovorin + oxaliplatin, a bolus of 400mg/m²5-FU followed by a 46 hour continuous infusion of 2,400mg/m in D5W²5-FU。

Neuropathy assessments were performed by an independent neurologist at baseline and after every two treatment cycles (about monthly). Neither the subject nor the neurologist know whether the infused platinum is oxaliplatin or picoplatin. This assessment by the neurologist is used to determine the incidence of grade 2 or higher peripheral neuropathy. In phase 2, the treating physician performed neurological assessments with NCI CTCAE for the purpose of determining dose-reduced toxicity or study drug discontinuation. These CTCAE criteria were used to determine the need for reduced dose prior to each cycle. The neurologist's assessment is used to determine safety endpoints, incidence of neuropathy, and is performed independently every other cycle with a program prescribed level of neuropathy (neuropathy scale), but not for dose adjustment. Hematology and serum chemistry laboratory studies were obtained prior to each treatment cycle for all subjects. Treatment cycles (5-FU and leucovorin ± picoplatin or oxaliplatin, depending on the schedule) were repeated every two weeks, but by the time of abnormal recovery in the clinic or laboratory, up to 2 weeks may be delayed and data from all treatment cycles and cumulative toxicity evaluated for safety analysis.

In the study, tumor assessments were performed at baseline and after every fourth 5-FU/formyltetrahydrofolate (every 8 weeks, unless dosing was delayed) treatment. According to RECIST criteria, the efficacy end point will include the objective response rate²⁶. Response time, time to progression, progression free survival and overall survival were also assessed.

Study treatment is summarized in table 1 below:

TABLE 1

Stage 2

^aPicoplatin: 150mg/m²2 hours; oxaliplatin: 85mg/m²2 hours; LV: 400mg/m²2 hours (administered concurrently with picoplatin (when given) or oxaliplatin), then 5-FU: 400mg/m²Bolus injection, then 2400mg/m²For 46 hours. All subjects continued to perform the cycle every two weeks until progression or cessation of study drug due to toxicity.

Selection of picoplatin dosage

In the previous phase 1 study, 120-150mg/m was administered every three weeks²The dosage of (i.e., the dosage is equivalent to administration of 80-100mg/m every two weeks²Or 160 mg/m once every four weeks²) In addition, picoplatin is generally tolerated in combination with other myelosuppressive chemotherapeutic agents. However, none of these studies investigated picoplatin in combination with 5-FU and leucovorin. 5-FU/formyl tetrahydrofolic acid is not normally myelosuppressive and therefore the picoplatin dose selected as the initial dose (i.e., 45mg/m biweekly) in the dose escalation portion of the study²And 60mg/m every four weeks²) Significantly below the expected MTD for picoplatin administration in these programs.

Administration of picoplatin

When preparing picoplatin for administration, the investigational personnel must employ standard cytotoxic procedures. Picoplatin is provided in ready-to-use formulations. The contents of the vial must be transferred to a suitable bag for application. Compatibility of the formulation with typical infusion sets has been evaluated and as a result it has been determined that the material has compatibility with EVA infusion bags, PVC infusion tubing and polypropylene syringes when shielded from light. The use of PVC infusion bags for administering picoplatin is not recommended.

Compatibility of the formulation with typical applicators has been evaluated with a limit of acceptability of 8 hours in closed infusion bags. The product is highly sensitive to light and should not be exposed to ambient light for more than 1 hour without light protection. The bag must be protected from light during preparation and application.

No preservatives or bacteriostats are present in the picoplatin formulations. Thus, picoplatin must be transferred under sterile conditions. The solution must be used up or discarded within 8 hours of being introduced into the infusion bag. As with all platinum composites, contact with aluminum should be avoided.

Picoplatin should be administered via the peripheral or central vein (Central line); administration by intramuscular or subcutaneous routes is not possible. The initial dose is calculated based on the body surface area derived 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 change the dosage.

Picoplatin should be administered over 2 hours. When picoplatin and leucovorin are administered on the same day, the two drugs should be administered simultaneously in separate bags using a Y-tube. Both drugs have been tested and when administered in this manner appear to be compatible.

The subjects also received 5-HT 30 minutes prior to picoplatin administration₃Antiemetic therapy consisting of a receptor antagonist plus dexamethasone. Following treatment, the subject may also receive anti-emetic treatment for several days, which may include up to 7 days of oral lorazepam (lorazepam), prochlorperazine (prochlorperazine), or other equivalents that have been clinically shown to inhibit nausea and/or vomiting.

Administration guidance

Detailed instructions for the administration of 5-FU and formyltetrahydrofolate are provided on the product label. Briefly, 400mg/m in D5W was infused with 2 hours IV²Formyl-tetrahydrofolate, if picoplatin is to be administered the same day, is administered simultaneously with the picoplatin in separate bags using a Y-tube,then a bolus of 5-FU 400mg/m²Then 2,400mg/m in D5W as a 46 hour continuous IV infusion²5-FU (recommended).

Dose adjustment

Dose modulation of picoplatin

Dose reduction is forced if any of the following hematological events were observed in the previous cycle: absolute Neutrophil Count (ANC) < 0.5X 10⁹L for at least 5 days; absolute neutrophil count < 1.0X 10⁹L has the heating (higher than 38.5 ℃) with the grade of more than or equal to 2; platelet count < 25X 10⁹L; on day 15, the platelet count was not more than 100X 10⁹a/L and an ANC of 1.5 x 10⁹/L。

Dose reduction is also required for any therapeutic event related to any of the treatment-related grade 3 toxicities, any grade 4 toxicities, or any renal or neurotoxicity described below.

For subjects receiving picoplatin every two weeks, the dose reduction should be 15mg/m²(ii) a For subjects receiving picoplatin every 4 weeks, the dose reduction should be 30mg/m²。

Dose reduction of serum creatinine change events

Serum creatinine must be measured before each administration of picoplatin. For subjects with serum creatinine abnormalities, the dose of picoplatin (as opposed to 5-FU or leucovorin) must be varied during phase 1 according to the following table:

in phase 2, the following dose reductions would be required for serum creatinine elevation:

serum creatinine	Dose variation in stage 2 FOLPI subjects
		Less than or equal to standard ULN	Recommended dosage

Greater than 1.0 to 1.5 times ULN	Reduce by 30mg/m2Picoplatin
		Greater than 1.5 to 2.0 times ULN	Reduce 60mg/m2Picoplatin
Greater than 2.0 times ULN	Discontinuing picoplatin treatment

Dose modulation in neurotoxic events

The dose of picoplatin should be varied according to the CTCAE grade of toxicity and its duration as follows:

if toxicity is not improved or worse in the latter period, up to 3 times 30mg/m can be done²The dose of (a) is reduced.

Dose adjustment of 5-FU

The first reduction in picoplatin dosage should omit the 5-FU bolus. When the picoplatin dose is reduced for the second time, the infusion dose should be reduced by 600mg/m². Once reduced, the reduced dose of 5-FU should be maintained; namely: the dose of 5-FU should not be increased subsequently.

On day 15 of the picoplatin cycle, if the platelet count or ANC count is grade 1 or 2, then the subject receives alternating, even-numbered cycles that do not include picoplatin, during which the dose of 5-FU should not be reduced. In the second treatment cycle, the dose of picoplatin and 5-FU should be reduced by one level. Dose adjustments must be made for grade 3 or 4 non-hematological events. Treatment was continued only when toxicity had subsided to < 3 grade.

Dose adjustment of formyltetrahydrofolic acid

The dose of leucovorin is not adjusted unless drug sensitivity is presumed to arise from a temporal relationship with the time of leucovorin administration.

Results

59 patients were treated in phase 1. In the q2 week schedule, at 105mg/m²At picoplatin dose levels, 1 of 6 patients showed grade 4 thrombocytopenia DLT and 3 of 6 patients showed grade 4 neutropenia. Is now 120mg/m²The q2 week schedule was evaluated. At 180mg/m on a q4 week schedule²In the next 6 patients, DLT was observed in 2 of them. Therefore, the MTD was set to 150m in the q4 week scheduleg/m². Patients received up to 24 cycles and were well tolerated for treatment.

For both plans, the dose delay is mainly due to neutropenia or thrombocytopenia and the increased hematologic toxicity observed at higher doses. Treatment-related grade 3 non-hematologic toxicities included one instance of coronary spasm after FU infusion, one instance of picoplatin infusion allergy, one instance of stomatitis, two instances of diarrhea, one instance of azotemia. Cardiac and stomatitis events are associated with 5-FU components. No grade 2 or higher neuropathy was reported, even with an accumulation of more than about 900mg/m for 4-digit exposure²Patients with picoplatin doses have not been reported, especially for the high incidence of moderate to severe neuropathy observed at comparable oxaliplatin doses, which is an unexpected and unexpected result. This indicates that picoplatin can be safely administered in combination with FU and LV without dose-limiting neuropathy associated with the FOLFOX regimen.

In plan A (picoplatin q2 weeks), the preferred dose range is about 45-120mg/m²E.g. 45 to 105mg/m²In a dosage of, e.g., 45mg/m²。

In plan B (picoplatin q4 weeks), the preferred dose may be higher, such as about 120-210mg/m²E.g. 120-180mg/m²E.g. 150mg/m². Lower doses, e.g., 45-90mg/m, may also be administered²E.g. 60mg/m²。

Of the 44 subjects evaluated by CT scan, 6 of them had confirmed partial response and 1 had complete response (not confirmed) (16%). 26 of the 32 subjects scheduled for week Q2 were evaluated and 2 were observed to have partial responses. Surprisingly, group A1 (45 mg/m)²) The patient of 2/3 showed a partial response. All 18 subjects in the Q4 week schedule were evaluated and 5 observed partial responses (28%).

Reference to the literature

The following references and other publications, patents and patent applications cited herein are hereby incorporated by reference.

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Useful agents and methods of treatment for administration in combination with picoplatin have also been disclosed, including platinum and non-platinum anti-cancer agents, which are disclosed in U.S. patent application 10/276,503 filed 9/4/2003; 11/982,841 filed on 5 th of 11 th of 2007; 11/935,979 filed on 6.11.2007; 11/982,839 filed on 5 th of 11 th of 2007; and in U.S. Pat. Nos. 7,060,808 and 4,673,668 and PCT applications WO/98/45331 and WO/96/40210.

The following patent applications are incorporated herein by reference in their entirety:

US 61/027,387, office docket No.295.114prv, filed on 8.2.2008, 2008

PCT Ser. No. ___________, filing date 2/6 in 2009, office docket No.295.114wo1

US 61/027,382, office docket No.295.115prv, filed on 8.2.2008, 2008

US 61/027,360, firm No.295.116prv, filed on 8.2.2008

PCT Ser. No. __________, filing date 2/6 in 2009, office docket No.295.116wo1

US 11/982,841, office docket No.295.093us1, filed on 5.11.2007

Us ________ filed on 6.2.2009, office docket No. 295.131us1.

Claims (76)

1. A method of treating colorectal cancer, comprising:

administering picoplatin, cetuximab, 5-fluorouracil (5-FU), and leucovorin to a patient suffering from 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 when the fluorouracil and leucovorin are administered, and cetuximab is administered at least twice at intervals of one week.

2. The method of claim 1, wherein the concentration is about 60-180mg/m²Preferably about 150mg/m²The picoplatin is administered at the dosage of (a).

3. The method of claim 1 wherein the administration interval of 5-FU and leucovorin is about two weeks and the administration interval of picoplatin is about four weeks.

4. A method of treating colorectal cancer, comprising:

administering to a patient suffering from colorectal cancer an effective amount of a combination of picoplatin, cetuximab, 5-FU and leucovorin, wherein the picoplatin and the 5-FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks and the cetuximab at least twice at one week intervals, wherein the amount of picoplatin administered is below the maximum tolerated dose of picoplatin.

5. The method of claim 4, wherein the concentration is about 45-150mg/m²Preferably about 135-150mg/m²The dose of picoplatin is administered.

6. The method of claim 4 wherein the interval between the administration of picoplatin, 5-FU, and leucovorin is about two weeks.

7. A method of selecting a metastatic colorectal cancer (mCRC) treatment regimen comprising:

(a) providing a patient suffering from mCRC;

(b) determining whether the patient is a K-ras wild-type mCRC patient; and

(c) selecting a regimen for the patient comprising an EGFR inhibitor and picoplatin if the patient comprises a K-ras wild-type mRC.

8. The method of claim 7, wherein the EGFR inhibitor is cetuximab or panitumumab.

9. The method of claim 7 or 8, wherein the regimen further comprises 5-FU and leucovorin.

10. The method of claim 7 or 8, wherein the patient is further treated with the regimen.

11. The method of any one of claims 1 to 6, wherein the concentration is about 250-500mg/m²Is administered intravenously, followed by administration at weekly intervals of about 200-300mg/m²The dosage of (a).

12. The method of any one of claims 1-7, wherein the patient has not previously been treated for metastatic disease.

13. The method of any one of claims 1-7, wherein the patient has been previously treated with an irinotecan, FOLFOX and/or FOLPI regimen.

14. The method of any one of claims 1-7, wherein the patient has been previously treated with the FOLFOX regimen, and subsequently with the FOLPI regimen, and has relapsed within 6 months of completion of the FOLPI regimen.

15. The method of any one of claims 1-7, wherein the patient has been previously treated with a first regimen comprising FOLFOX or irinotecan, and subsequently treated with a second regimen comprising cetuximab alone, irinotecan plus cetuximab, or FOLPI, and has relapsed within 6 months after discontinuing the second regimen.

16. The method of any one of claims 1-7, wherein the patient has been previously treated with an earlier systemic regimen of chemotherapy and the cancer is in remission.

17. The method of claim 16, wherein the patient has been treated with an earlier FOLPI regimen with or without bevacizumab or cetuximab.

18. The method of any one of claims 1-6 wherein the picoplatin is administered in a dosage form comprising an isotonic solution comprising water, an osmolyte comprising NaCl, and about 0.5mg/ml dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostats.

19. The method of any one of claims 1-6 wherein the cetuximab, the picoplatin when administered, and the formyltetrahydrofolate when administered are administered substantially simultaneously.

20. The method of any one of claims 1-6 wherein the leucovorin and, when administered, picoplatin are administered simultaneously.

21. The method of any one of claims 1-6 wherein the 5-FU when administered is administered after the picoplatin when administered, the leucovorin when administered, and the cetuximab.

22. The method of claim 4 wherein the picoplatin is administered substantially simultaneously with the leucovorin at each treatment of the patient, followed by administration of 5-FU, and cetuximab administered at weekly intervals.

23. The method of any one of claims 1-6, wherein the concentration is about 200-²Administering leucovorin.

24. The method of any one of claims 1-6 wherein each administration is at about 1000-3000mg/m²The total dose of 5-FU is administered.

25. The method of claim 1 or 4, wherein the concentration is about 120-150mg/m²The dose of picoplatin is administered.

26. The method of claim 25, wherein the concentration is about 150mg/m²The dose of picoplatin is administered at least once.

27. The method of any one of claims 1-6, wherein the dose is about 15-30mg/m lower than the previous dose²The subsequent picoplatin dose is administered.

28. The method of claim 1, wherein the concentration is about 60-75mg/m²The dose of picoplatin is administered at least once.

29. The method of claim 4, wherein the concentration is about 40-45mg/m²The dose of picoplatin is administered at least once.

30. The method of any one of claims 1-6, wherein a cumulative dose greater than about 900mg/m is delivered to the patient²Picoplatin of (1).

31. The method of any one of claims 1-6, wherein at about 400mg/m²Is administered intravenously at a first dose of about 250mg/m once a week²The dosage of (a).

32. The method of claim 1, wherein the dose administered by 2 hour infusion is about 400mg/m²Leucovorin; after administration of leucovorin, the bolus dose is about 400mg/m²5-FU of (1); after 5-FU bolus injection, a continuous infusion of about 2,400mg/m for 46 hours was performed²5-FU of (1); wherein the leucovorin and 5-FU are administered to the patient every two weeks and about 60-150mg/m is administered to the patient with the leucovorin every 4 weeks²Wherein at least the initial dose of picoplatin is about 150mg/m²Wherein at about 400mg/m²Is administered with cetuximab once a week at about 250mg/m²The dose of (a) is administered with cetuximab.

33. The method of any one of claims 1-6, further comprising determining that the patient's cancer is free of K-ras mutations prior to administration of cetuximab.

34. A method of treating colorectal cancer, comprising:

(a) identifying a patient having colorectal cancer who has failed a FOLFOX-4 and/or FOLPI treatment regimen; and

(b) administering to said patient about 5-150mg/m every 21 days in combination with weekly administration of cetuximab²Wherein the first dose of cetuximab is 400mg/m²The subsequent dose of cetuximab was 250mg/m²。

35. A method of treating colorectal cancer, comprising:

(a) identifying a patient having colorectal cancer who has received an irinotecan, FOLFOX, or FOLPI treatment regimen, with or without bevacizumab or cetuximab, wherein the cancer is in remission, and

(b) administering to said patient about 5-150mg/m every 21 days in combination with weekly administration of cetuximab²Wherein the first dose of cetuximab is 400mg/m²The subsequent dose of cetuximab was 250mg/m²As an adjuvant therapy to prevent recurrence.

36. The method of any one of claims 1-6, further comprising administering 5-HT₃A receptor antagonist.

37. A method of selecting a treatment regimen for a patient having a metastatic cancer comprising EGFR, comprising:

(a) identifying a patient having metastatic cancer;

(b) determining whether the patient 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 a wild-type K-ras gene is present; or selecting a treatment regimen comprising picoplatin without an EGFR inhibitor if a mutation-positive K-ras gene is present.

38. The method of claim 37, wherein the metastatic cancer that comprises EGFR comprises SCLC, NSCLC, pancreatic cancer, colorectal cancer, epithelial cancer, or head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, gastric cancer, breast cancer, or endometrial cancer.

39. A method of selecting a treatment regimen for a patient with mCRC comprising:

(a) identifying a patient with mCRC;

(b) determining whether the mCRC comprises a wild-type K-ras gene or a mutated K-ras gene; and

(c) administering an EGFR inhibitor such as cetuximab, erlotinib, or panitumumab to the patient in combination with picoplatin and optionally 5-FU and leucovorin if the mCRC comprises a K-ras wild-type genotype, or (d) administering picoplatin and optionally 5-FU and leucovorin to the patient if the mCRC comprises a K-ras mutation-positive genotype.

40. The method of claim 39, wherein the EGFR inhibitor comprises cetuximab.

41. Use of picoplatin in combination with cetuximab, 5-fluorouracil (5-FU) and leucovorin for the treatment of 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 at the time of administration of the fluorouracil and leucovorin, and the cetuximab is administered at least twice at intervals of one week.

42. The use of claim 41, wherein the amount is from about 60 to 180mg/m²Preferably about 150mg/m²The picoplatin is administered at the dosage of (a).

43. The use of claim 41, wherein the administration interval of 5-FU and leucovorin is about two weeks and the administration interval of picoplatin is about four weeks.

44. Use of picoplatin in combination with cetuximab, 5-FU and leucovorin, wherein the picoplatin and the 5-FU and leucovorin are administered intravenously at least twice at intervals of about 2-6 weeks and the cetuximab is administered at least twice at intervals of one week, wherein the amount of picoplatin administered is below the maximum tolerated dose of picoplatin.

45. The use of claim 44, wherein the amount is from about 45 to 150mg/m²Preferably about 135-150mg/m²The dose of picoplatin is administered.

46. The use of claim 44 wherein the interval between the administration of picoplatin, 5-FU, and leucovorin is about two weeks.

47. The use as claimed in any one of claims 41 to 46, wherein the concentration is about 250-500mg/m²Is administered intravenously, followed by about 200 at weekly intervals300mg/m²The dosage of (a).

48. The use of any one of claims 41 to 46, wherein the patient has not previously been treated for metastatic disease.

49. The use of any one of claims 41-46, wherein the patient has been previously treated with a FOLFOX and/or FOLPI regimen.

50. The use of any one of claims 41-46, wherein the patient has been previously treated with a FOLFOX regimen, and subsequently with a FOLPI regimen, and has relapsed within 6 months of completion of the FOLPI regimen.

51. The use of any one of claims 41-46, wherein the patient with colorectal cancer has 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 after cessation of the second regimen.

52. The use of any one of claims 41-46, wherein the patient has been previously treated with an earlier systemic regimen of chemotherapy and the cancer is in remission.

53. The method of claim 52, wherein the patient has been treated with an earlier FOLPI regimen with or without bevacizumab or cetuximab.

54. The use of any one of claims 41-46 wherein the picoplatin is administered in a dosage form comprising an isotonic solution comprising water, an osmolyte comprising NaCl, and about 0.5mg/ml of dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostatic agents.

55. The use of any one of claims 41 to 46 wherein the cetuximab, the picoplatin when administered, and the formyltetrahydrofolate when administered are administered substantially simultaneously.

56. The use of any one of claims 41 to 46 wherein the leucovorin and, when administered, picoplatin are administered simultaneously.

57. The use of any one of claims 41-46, wherein the 5-FU when administered is administered after the picoplatin when administered, the leucovorin when administered, and the cetuximab.

58. The use of claim 41 wherein the picoplatin is administered substantially simultaneously with the leucovorin at each treatment of the patient, followed by administration of 5-FU, and cetuximab administered at weekly intervals.

59. The use of claim 44 wherein the picoplatin is administered substantially simultaneously with the leucovorin at each treatment of the patient, followed by administration of 5-FU, and cetuximab administered at weekly intervals.

60. The use as claimed in any one of claims 41 to 46, wherein the concentration is about 200-400mg/m²Administering leucovorin.

61. The use of any one of claims 41 to 46,wherein each administration is at about 1000-3000mg/m²The total dose of 5-FU is administered.

62. The use as claimed in claim 41 or 44, wherein the concentration is about 120-150mg/m²The dose of picoplatin is administered.

63. The use of any one of claims 41 to 46, wherein at about 150mg/m²The dose of picoplatin is administered at least once.

64. The use of any one of claims 41 to 46, wherein the dose is about 15 to 30mg/m lower than the previous dose²The subsequent picoplatin dose is administered.

65. The use of claim 41, wherein the amount is from about 60 to 75mg/m²The dose of picoplatin is administered at least once.

66. The use of claim 44, wherein the amount is from about 40-45mg/m²The dose of picoplatin is administered at least once.

67. The use of any one of claims 41 to 46, wherein a cumulative dose greater than about 900mg/m is delivered to the patient²Picoplatin of (1).

68. The use of any one of claims 41 to 46, wherein at about 400mg/m²Is administered intravenously at a first dose of about 250mg/m once a week²The dosage of (a).

69. The use of claim 41, wherein the dose administered by 2 hour infusion is about 400mg/m²Leucovorin; after administration of leucovorin, the bolus dose is about 400mg/m²5-FU of (1); after a bolus of 5-FU, a continuous infusion of about 2,400mg/m for 46 hours was performed²5-FU of (1); wherein the leucovorin and 5-FU are administered to the patient every two weeks and about 60-150mg/m is administered to the patient with the leucovorin every 4 weeks²Wherein at least the initial dose of picoplatin is about 150mg/m²Wherein at about 400mg/m²Is administered with cetuximab once a week at about 250mg/m²The dose of (a) is administered with cetuximab.

70. The use of any one of claims 41 to 46, wherein the patient exhibits EGFR expression in cells of metastatic colorectal cancer.

71. The use of any one of claims 41-46, further comprising testing the patient for the presence of a K-ras mutation-positive genotype of mCRC in cells of metastatic colorectal cancer prior to administration of picoplatin.

72. About 5-150mg/m administered every 21 days²In combination with picoplatin at 400mg/m administered weekly²First dose of cetuximab and subsequent 250mg/m²Use of a dose of cetuximab to treat colorectal cancer in a patient having colorectal cancer who has failed the FOLFOX-4 and/or FOLPI regimen.

73. About 5-150mg/m administered every 21 days²In combination with picoplatin at 400mg/m administered weekly²First dose of cetuximab and subsequent 250mg/m²Use of a dose of cetuximab to prevent recurrence of colorectal cancer in a patient having colorectal cancer who has received an irinotecan, FOLFOX or FOLPI regimen with or without bevacizumab or cetuximab, wherein the cancer is in remission.

74. The method of any one of claims 72 or 73, further comprising administering 5-HT₃A receptor antagonist.

75. A kit suitable for intravenous administration of a FOLPI + cetuximab regimen to a patient; the kit comprises a first container containing a picoplatin solution and a second container containing a formyltetrahydrofolate solution; further comprising a coupling device adapted to be independently connected to the first container, the second container and a single intravenous administration tube, thereby enabling simultaneous administration of the contents of the first container and the second container to the patient; the kit further comprises a container containing a cetuximab solution suitable for intravenous administration to the patient and a container containing a 5-FU solution; instructions for use are also optionally included.

76. The kit of claim 75 wherein the first container comprises a picoplatin dosage form comprising an isotonic solution comprising water, an osmolyte comprising NaCl and about 0.5mg/ml dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostats.