HK1155089A

HK1155089A - Use of picoplatin and bevacizumab to treat colorectal cancer

Info

Publication number: HK1155089A
Application number: HK11109428.0A
Authority: HK
Inventors: 罗纳德‧A‧马特尔; 大卫‧A‧卡林
Original assignee: 帕纳德制药公司
Priority date: 2008-02-08
Filing date: 2009-02-06
Publication date: 2012-05-11

Description

Use of picoplatin and bevacizumab to treat colorectal cancer

Cross Reference to Related Applications

Priority of U.S. application No.61/027,387 filed on 8/2/2008, U.S. application No.61/027,382 filed on 8/2/2008, and U.S. application 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 for U.S. application nos. 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. application 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 metastatic colorectal cancer (MCRC) 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 past decade in the treatment of colorectal cancerIncluded are several new therapeutic agents including irinotecan (irinotecan), oxaliplatin (oxaliplatin), capecitabine (capecitabine), and recent approval of cetuximab (cetuximab) and bevacizumab (bevacizumab)^2，3. Importantly, new chemotherapeutic regimens have been devised using these drugs, which result in improved response rates and increased time to progression 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。

Avastin(bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds and inhibits the biological activity of human Vascular Endothelial Growth Factor (VEGF) as shown in vitro and in vivo assay systems. Bevacizumab binds VEGF and prevents VEGF from interacting with receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF and its receptors results in endothelial cell proliferation and the generation of new blood vessels in an in vitro model of angiogenesis. Administration of bevacizumab to a nude (athymic) mouse colon cancer xenograft model resulted in a reduction in microvascular growth and inhibition of metastatic disease progression.

Bevacizumab contains a human framework region and the complementarity determining regions of murine antibodies that bind VEGF (Presta LG, Chen H, O' Connor SJ, Chisholm V, Meng YG, Krummen L, etc., Humanization of an anti-vascular endothelial growth factor monoclonal antibodies for the therapy of solid tumors and other disorders. cancer Res.1997；57: 4593-9). Bevacizumab, having a molecular weight of about 149 kilodaltons, is produced in a chinese hamster ovary mammalian cell expression system in nutrient medium containing the antibiotic gentamicin.

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.

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, limiting the patient's disturbed cold sensitivity to the FOLFOX regimen^7-10。

The efficacy of platinum analogs is also limited by several (innate 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。

Disclosure of Invention

The invention relates to a method for preparing a new medicine by using picoplatin and bevacizumab (Avastin)) And optionally 5-fluorouracil and/or leucovorin for the treatment of colorectal cancer; also relates to the combination of picoplatin and bevacizumab (Avastin)) And optionally 5-fluorouracil and/or leucovorin for the treatment of metastatic colorectal cancer.

In various embodiments, the present invention provides methods of treating colorectal cancer comprising administering picoplatin, bevacizumab, 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 at the time of administration of the fluorouracil and leucovorin, and the bevacizumab is administered at least twice at one week intervals. 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, bevacizumab, 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 bevacizumab is administered at least twice at one week intervals, wherein the amount of picoplatin administered 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.

Another embodiment of the invention provides a method of treating colorectal cancer comprising administering picoplatin, bevacizumab, 5-FU, and leucovorin to a patient having metastatic colorectal cancer, wherein the administration is for about 2 weeksBy administering 5-FU and leucovorin intravenously, with picoplatin at about 45-120mg/m, each time fluorouracil and leucovorin are administered, with leucovorin and 5-FU²Wherein bevacizumab is administered at a dose of about 5-25mg/kg (preferably 10mg/kg) intravenously at two week intervals.

In another embodiment of the invention, the picoplatin is administered substantially concurrently with the leucovorin, and every other time (e.g., every four weeks) when the patient is treated with 5-FU and leucovorin. Bevacizumab is administered simultaneously with picoplatin, followed by biweekly administration. May be about 200-500mg/m²Preferably about 400mg/m²The dose of (a) is administered as leucovorin. At a rate of about 60-180mg/m²The dose of picoplatin is administered. Avastin as described above was formulated by infusion administration at a dose of 10mg/kg every 14 daysBevacizumab in solution. At about 1000-3000mg/m²The total dose of 5-FU is administered. A preferred treatment cycle for leucovorin and 5-FU is every two weeks, and picoplatin is administered every 4 weeks, e.g., about 60-75mg/m²Low dose (e.g., 60 mg/m)²) Or about 120-180mg/m²(preferably about 120-150 mg/m)²) High dosage of (e.g. about 150 mg/m)²。

The present invention also provides a method comprising administering picoplatin in a dosage form comprising an isotonic solution comprising water, an osmotic pressure regulator (osmotic adjuster), and about 0.5mg/ml dissolved picoplatin. The dosage form may further comprise an effective amount of dissolved or dispersed 5-FU and/or leucovorin according to the dosing regimen disclosed herein. The dosage form also contains no preservative or bacteriostatic agent. An appropriate volume of the dosage form may be administered to achieve the desired therapeutic dose.

The dosage form may also include a first container containing a picoplatin solution and a second container containing a bevacizumab solution. The two containers may also contain means for administering the contents to the patient simultaneously, for example, the containers may be plastic intravenous bags (intravenous bags) which are independently connectable to a single intravenous tube (single intravenous tube) so that the contents of each container may be administered to the patient simultaneously, e.g., via a Y-connector (Y-link). These containers may be packaged, for example, in a kit with instructions for their end use. Separately packaged formyltetrahydrofolate solution and/or separately packaged 5-FU solution can also be contained within the kit. The picoplatin solution can be in a picoplatin dosage form at a concentration of about 0.5mg/mL, optionally containing an osmotic pressure regulator such as sodium chloride, wherein no bacteriostatic preservative is present in the dosage form.

In one embodiment, the present invention provides the use of picoplatin in combination with bevacizumab, 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 at the time of administration of the fluorouracil and leucovorin, and bevacizumab is administered at least twice at two week intervals.

In one embodiment, the present invention provides the use of picoplatin in combination with bevacizumab, 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer, wherein the picoplatin is administered at least twice intravenously at intervals of about two weeks by administering the picoplatin, 5-FU and leucovorin at least twice at intervals of two weeks, wherein the amount of picoplatin, when administered in said combination, is below the maximum tolerated dose of picoplatin.

In one embodiment, the present invention provides the use of picoplatin in combination with bevacizumab, 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at intervals of about 2 weeks, picoplatin is administered with the leucovorin and 5-FU each time the fluorouracil and leucovorin are administered, wherein about 45-120mg/m²Wherein bevacizumab is administered at a dose of 5-25mg/kg intravenously at two week intervals.

In one embodiment, the present invention provides about everyAbout 5-150mg/m for 21 days administration²Use of picoplatin in combination with bevacizumab at a dose of about 10mg/kg administered about every other week (every other week) to treat metastatic colorectal cancer in a patient with colorectal cancer who has failed an irinotecan, FOLFOX and/or FOLPI regimen.

In one embodiment, the invention provides about 5-150mg/m administered about every 21 days²In combination with bevacizumab at a dose of about 10mg/kg administered about every other week, for treating metastatic colorectal cancer in a patient suffering from colorectal cancer who has received an irinotecan, FOLFOX and/or FOLPI regimen with or without bevacizumab or cetuximab to prevent relapse, wherein the cancer is in remission.

Detailed Description

In one embodiment, the present invention provides a method of treating colorectal cancer, comprising administering picoplatin, bevacizumab, 5-fluorouracil (5-FU) and leucovorin to a patient having metastatic colorectal cancer, wherein the 5-FU and leucovorin are administered at least twice intravenously at intervals of about 2-6 weeks, the picoplatin is administered with the leucovorin and 5-FU every other time while the fluorouracil and leucovorin are administered, and the bevacizumab is administered at least twice at intervals of two weeks.

In another embodiment, the present invention provides a method of treating colorectal cancer, comprising administering to a patient having metastatic colorectal cancer an effective amount of a combination of picoplatin, bevacizumab, 5-FU and leucovorin, wherein the picoplatin, 5-FU and leucovorin are administered intravenously at least twice at intervals of about two weeks, and the bevacizumab is administered at least twice at intervals of two weeks (every two weeks), wherein the amount of picoplatin, when administered in the combination, is below the maximum tolerated dose of picoplatin.

Another embodiment of the invention provides a method of treating colorectal cancer, comprising administering picoplatin, bevacizumab, 5-FU, and leucovorin to a patient having metastatic colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at intervals of about two weeksPicoplatin is administered with leucovorin and 5-FU each time fluorouracil and leucovorin are administered, at about 45-120mg/m²Wherein bevacizumab is administered at a dose of about 5-25mg/kg (preferably 10mg/kg) intravenously at two week intervals.

Thus, in one embodiment of the invention, the leucovorin is present at 200-500mg/m²Is administered by infusion for about 2 hours, concurrently with picoplatin if administered, wherein the dose of picoplatin is 120-180mg/m²E.g. about 150mg/m²(ii) a After administration of leucovorin and picoplatin, about 400mg/m was administered by bolus injection²5-FU at a dose; after administration of 5-FU, a dose of 600mg/m was administered²Or 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 4 week alternating intervals.

Bevacizumab was administered as described above with an initial dose of 10mg/kg, followed by a dose of 10mg/kg every two weeks. 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 the FOLPI regimen, and in the present invention, is supplemented with infusion of bevacizumab.

In another embodiment of the invention, at 400mg/m²The leucovorin is administered by infusion for 2 hours; after administration of leucovorin at 400mg/m²Bolus injection of 5-FU; after bolus injection of 5-FU, the dose was 400mg/m administered parenterally²Or 2,400mg/m²Preferably in the form of a 22 hour or 46 hour continuous infusion, respectively; administration of leucovorin and 5-FU is performed every two weeks; wherein at a rate of up to about 50mg/m²(e.g., about 40-50 mg/m)²E.g. about 45mg/m²) The dose of (a) is administered biweekly, preferably simultaneously, with leucovorin. Also, about 45-105mg/m may be administered²The picoplatin dose of (c). Bevacizumab was administered weekly as described previously.

It has unexpectedly been found that in certain cases, the administration of low doses of picoplatin in combination with leucovorin and 5-FU in each treatment cycle is as effective or more effective in producing corresponding aspects of treatment as higher doses, such as the Maximum Tolerated Dose (MTD), given at the same intervals. The MTD for the 2-and 4-week picoplatin administration schedules is discussed below. Preferably, such dose in the initial treatment is below or significantly below the MTD. Such dosage may range from about 40 to 60mg/m biweekly²Picoplatin, which is administered with leucovorin and bevacizumab, followed by 5-FU, as described below.

It has unexpectedly been found that the total cumulative dose exceeds about 900mg/m²The picoplatin can be tolerated by the patient without secondary or above neuropathy observed.

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

In one embodiment, the present invention provides the use of picoplatin in combination with bevacizumab, 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 upon administration of the fluorouracil and leucovorin, and bevacizumab is administered at least twice at intervals of two weeks.

In one embodiment, the present invention provides the use of picoplatin in combination with bevacizumab, 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer, wherein the 5-FU and leucovorin are administered intravenously at intervals of about two weeks, picoplatin is administered with the leucovorin and 5-FU each time the fluorouracil and leucovorin are administered, wherein about 45-120mg/m²Wherein bevacizumab is administered at a dose of 5-25mg/kg intravenously at two week intervals.

The use may be a use wherein the patient having metastatic colorectal cancer has not previously been treated for metastatic disease.

Alternatively, the use may be one wherein the patient having metastatic colorectal cancer has previously been treated with an irinotecan regimen, a FOLFOX regimen or a FOLPI regimen, wherein the cancer is refractory to treatment, or wherein the cancer has progressed within 6 months of completing the regimen.

Alternatively, the use may be one wherein a patient having metastatic colorectal cancer has previously been treated sequentially with at least two of an irinotecan regimen, a FOLFOX regimen, and a FOLPI regimen, wherein the cancer is refractory, or wherein the cancer has progressed within 6 months of completion of the regimen. The irinotecan regimen or FOLFOX regimen or both may have been concomitantly administered bevacizumab.

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 least 6 months prior to the picoplatin regimen of the invention) at the time of primary tumor treatment.

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

In various embodiments, picoplatin and leucovorin may be administered simultaneously.

In various embodiments, 5-FU may be administered after picoplatin, leucovorin, and bevacizumab.

In various embodiments, the leucovorin and 5-FU may be administered about every two weeks, the picoplatin may be administered with the leucovorin about every 4 weeks, and the bevacizumab may be administered about every two weeks.

In various embodiments, picoplatin can be administered substantially simultaneously with leucovorin, followed by 5-FU, and bevacizumab at two week intervals, each time the patient is treated.

In various embodiments, may be about 200-400mg/m²Administering leucovorin.

In various embodiments, about 1000-3000mg/m per administration may be used²The total dose of 5-FU is administered.

In various embodiments, it may be from about 60 to about 180mg/m²At a dose of about 120-180mg/m²The dose of picoplatin is administered.

In various embodiments, it may be about 15-30mg/m lower than the previous dose²The subsequent picoplatin dose is administered.

In various embodiments, it may be about 150mg/m²The dose of (A) is administered at least once, or may be about 60-75mg/m²The dose of (A) is administered at least once, or may be about 40-45mg/m²The dose of picoplatin is administered at least once.

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

In various embodiments, bevacizumab may be administered intravenously at a first dose of about 10mg/kg, followed by a dose of about 10mg/kg every other week.

In various embodiments, a dose of about 400mg/m can be administered by 2 hour infusion²Leucovorin; after administration of leucovorin, the bolus dose is about 400mg/m²5-FU of (1); after a bolus of 5-FU, a continuous infusion dose of about 2,400mg/m for 46 hours²5-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 bevacizumab is administered at an initial dose of about 10mg/kg and then at a dose of about 10mg/kg once every other week.

In various embodiments, the invention provides about 5-150mg/m administered about every 21 days²In combination with bevacizumab at a dose of about 10mg/kg administered about every other week, for the treatment of metastatic colorectal cancer in a patient suffering from colorectal cancer who has failed an irinotecan, FOLFOX and/or FOLPI regimen. 5-FU or leucovorin or both may be administered every other week. In various embodiments, the use of the present invention may further comprise the use of 5-HT₃A receptor antagonist.

In various embodiments, the invention provides about 5-150mg/m administered about every 21 days²In combination with bevacizumab at a dose of about 10mg/kg administered about every other week, for the treatment of metastatic colorectal cancer in a patient suffering from colorectal cancer who has received an irinotecan, FOLFOX and/or FOLPI treatment regimen with or without bevacizumab or cetuximab to prevent relapse, wherein the cancer is in remission. 5-FU or leucovorin or both may be administered every other week. In various embodiments, the use of the present invention may further comprise the use of 5-HT₃A receptor antagonist.

Picoplatin is a third-generation platinum analog that has been shown to act synergistically with 5-FU in vitro in preclinical studies, and has been extensively tested in phase 1 and phase 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. 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. Several human ovarian and colon cell lines with induced resistance to oxaliplatin retain sensitivity to picoplatin^16-18。

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

Picoplatin (SP-4-3) (cis-aminodichloro (2-methylpyridine) platinum (II)) and useful prodrugs and analogs thereof are disclosed in U.S. Pat. nos. 5,665,771; 6,518,428, respectively; 6,413,953, respectively; U.S. patent application No.11/982,891 and PCT/GB/01/02060, filed 11/5/2007, which are incorporated herein by reference. The dosages disclosed herein can be provided by oral administration of an effective amount of a combination of picoplatin and a pharmaceutically acceptable carrier, and can also be provided by intravenous infusion.

Avastin(bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds and inhibits the biological activity of human Vascular Endothelial Growth Factor (VEGF) as shown in vitro and in vivo assay systems. Bevacizumab, having a molecular weight of about 149 kilodaltons, is produced in a chinese hamster ovary mammalian cell expression system in nutrient medium containing the antibiotic gentamicin.

AvastinIs a clear to light milky, colorless to light brown, sterile, Intravenous (IV) infusion solution having a pH of 6.2. AvastinProvided in the form of 100mg and 400mg preservative-free, single-use vials delivering 4ml or 16ml Avastin(25 mg/ml). 100mg of the product was formulated in 240mg of alpha, alpha-trehalose dihydrate, 23.2mg of sodium dihydrogen phosphate (monohydrate), 4.8mg of sodium hydrogen phosphate (anhydrous), 1.6mg of polysorbate 20 and USP water for injection. 400mg of the product was prepared in 960mg of alpha, alpha-trehalose dihydrate 92.8mg of sodium dihydrogen phosphate (monohydrate), 19.2mg of sodium hydrogen phosphate (anhydrous), 6.4mg of polysorbate 20, and USP water for injection. The recommended dosage regimen is to administer 10mg/kg every two weeks in combination with the FOLFOX regimen (oxaliplatin, Leucovorin (LV) and 5-fluorouracil (5-FU)).

Bevacizumab is currently combined with chemotherapy based on intravenous administration of 5-fluorouracil as a first or second line treatment for patients with metastatic colon or rectal cancer (MCRC). In MCRC treatment, the recommended dose of bevacizumab to be used in combination with chemotherapy based on intravenous administration of 5-FU is administered by intravenous infusion (5mg/kg or 10mg/kg) every 14 days. When used in combination with the FOLFOX4 regimen for the treatment of metastatic colorectal cancer (MCRC), the recommended dose of bevacizumab is 10mg/kg (http:// www.gene.com/gene/products/information/interaction/activity/insulin/insert.jsp # administration) every two weeks (14 days).

Bevacizumab has been evaluated in combination with oxaliplatin, an organic platinum drug, and irinotecan, a polycyclic alkaloid derivative, for the treatment of MCRC (see http:// www.gene.com/gene/products/information/oncology/avastin/insert. In one clinical trial with oxaliplatin, bevacizumab in combination with 5-fluorouracil (5-FU) and Leucovorin (LV) in combination with oxaliplatin (85 mg/m)²) (FOLFOX4 regimen) in comparison to patients who received only FOLFOX4 regimen as second line treatment after first line treatment with irinotecan/5-FU. In the bevacizumab treatment group, Avastin was received compared to those patients receiving FOLFOX4 onlyPatients combined with FOLFOX4 had significantly longer total survival time (OS) (median OS 13.0 vs. 10.8 mos; risk ratio 0.75[ 95% CI 0.63, 0.89%]And p is 0.001 hierarchical log rank test (stritified logrank test)). In addition, there are reports of Avastin based on investigator's evaluationPatients treated in combination with FOLFOX4 had significantly longer progression free survival times and higherTotal response rate (average response rate).

The FOLFOX protocols FOLFOX4, FOLFOX6 and FOLFOX7 commonly used all used in combination with the same bioactive agent, but at different doses, as shown in table 1.

Table 1: brief summary of FOLFOX protocol

Replacement of oxaliplatin with picoplatin in the FOLFOX regimen is referred to as the FOLPI regimen, and then studies evaluating the FOLPI regimen with or without bevacizumab for treatment of metastatic colorectal cancer will be conducted in three sections. Phase 1 is a dose escalation study to determine the Maximum Tolerated Dose (MTD) of picoplatin, which may be administered every two weeks or four weeks, in combination with 5-FU and Leucovorin (LV) administered every two weeks, as initial treatment for patients with colorectal metastatic cancer who have not previously received treatment for metastatic disease. Phase 2 was a randomized study. In one aspect of the study, the dose is 150mg/m every four weeks²Picoplatin is administered in combination with bi-weekly administration of 5-FU and leucovorin (FOLPI). In another aspect, a modified FOLFOX6 regimen is used, wherein 100mg/m of FOLFOX6 is²The oxaliplatin dose of (a) is 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 present regimen using picoplatin in place of cisplatin, carboplatin, or oxaliplatin may be more effective in treating cancer patients because they will exhibit fewer side effects (e.g., neuropathy) and preferably receive a higher dose of the platinum drug. Stage 3 will be a comparison of Avastin with and without two weeksStudy of the FOLPI protocol for infusion.

Subjects eligible for the phase 1 study had colorectal cancer at stage IV and did not receive systemic treatment for metastatic cancer. Previous adjuvant chemotherapy (without oxaliplatin or irinotecan) with a 5-FU based treatment regimen is acceptable if there is 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/m²Increasing dose levels of picoplatin until unacceptable Dose Limiting Toxicity (DLT) occurs to determine MTD.

The MTD is defined as the dose of picoplatin below the dose at which at least 1/3 exhibited DLT in at least 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 schedule) subjects were treated with picoplatin (q4 weeks every other cycle). If the treatment is well tolerated, subjects assigned to subsequent order groups in the plan 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. Subject (about 100)Subject with metastatic CRC, about 25 clinical points) was randomly assigned to modified FOLFOX6⁶Or 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 (400 mg/m in D5W) was administered as an infusion for 2 hours every two weeks²) Or picoplatin in separate bags administered simultaneously via 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 FOLFOX6 protocol was as follows:

administered at 85mg/m in the form of infusion for 2 hours every two weeks²Oxaliplatin. Folic acid folinate (400 mg/m in D5W) was administered as an infusion for 2 hours every two weeks²). Oxaliplatin is administered simultaneously with leucovorin in a separate bag through a Y-tube. After administration of leucovorin + oxaliplatin, a bolus of 400mg/m²5-FU followed by a 46 hour continuous infusion of 2,400mg/m in D5W² 5-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 neuropathy scale, but not for dose variation. 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 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

^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) Picoplatin, in combination with other myelosuppressive chemotherapeutic agentsCombinations are usually tolerated. 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 vein or central line (central line); administration by intramuscular or subcutaneous routes is not necessary. The initial dose is calculated based on the body surface area of the patient's height and weight. 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 IV²Formyltetrahydrofolate, if picoplatin is to be administered the same day, is administered simultaneously with picoplatin in separate bags using a Y-tube, followed by a bolus injection of 5-FU 400mg/m²Then 2,400mg/m in D5W as a 46 hour continuous IV infusion²5-FU (recommended).

Dose variation

Dose variation of picoplatin

Dose reduction is forced if any of the following hematological events were observed in the previous cycle: absolute Neutrophil Count (ANC) < 0.5x10⁹L for at least 5 days; absolute neutrophil count < 1.0x10⁹L has the heating (higher than 38.5 ℃) with the grade of more than or equal to 2; platelet count < 25x10⁹L; on day 15, the platelet count not reaching 100X10⁹/L and ANC is more than or equal to 1.5X10⁹/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 dosage 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 variation 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 variation 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 changes must be made for grade 3 or 4 non-hematological events. Treatment was continued only when toxicity had subsided to < 3 grade.

Dose variation of formyltetrahydrofolic acid

There was no dose change of leucovorin unless it was speculated to be due to drug sensitivity due to 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 150mg/m in the q4 week schedule². Patients received up to 24 cycles and were well tolerated by the 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 responses and 1 had total responses (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%).

Stage 3

A phase 3 study will compare the FOLPI regimen with FOLPI + bevacizumab, wherein bevacizumab is administered according to the dose recommendation provided by Genentech for FOLFOX regimen in MCRC treatment. In the study, tumor assessments were performed at baseline and after every fourth 5-FU/formyltetrahydrofolate (every 8 weeks, unless there is a delay) treatment. According to RECIST criteria, the efficacy end point will include the objective response rate²⁶. Response duration, time to progression, progression free survival and overall survival were also assessed.

Reference to the literature

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

1.Jemal et al.，Cancer Statstics，2004.CA Cancer J Clin 54(1)：8-29，2004.

2.Hoff et al.，Oncology(Huntingt)18(6)：705-708，2004.

3.Meyerhardt et al.，N Engl J Med 352(5)：476-87，2005.

4.Penland et al.，Oncology(Huntingt)18(6)：715-722，2004.

5.Saltz et al.，N Engl J Med，343(13)：905-14，2000.

6.Tournigand et al.，J Clin Oncol，22(2)：229-37，2004.

7.de Gramont et al.，J Clin Oncol，18(16)：2938-47，2000.

8.Rothenberg et al.，J Clin Oncol，21(11)：2059-69，2003.

9.Andre et al.，N Engl J Med，350(23)：2343-51，2004.

10.Hwang et al.，In：Clinical Use of Oxaliplatin：Case Studies and Roundtable Discussion，Editor Marshall J，CMP Healthcare Media，Oncology Publishing Group，Manhasset，NY 2004.

11.Douillard，JY，Schiller，J.，Eur J Cancer 38(Suppl 8)：S25-S31，2002.

12.Beale，P，et al.，Br J Cancer 88(7)：1128-1134，2003.

13.Raynaud FI，et al.，Clin Cancer Res 3(11)：2063-2074，1997.

14.Holford J，et al.，Anticancer Drug Des 13(1)：1-18，1998.

15.Holford J，et al.，Br J Cancer 77(3)：366-373，1998.

16.Rogers P，et al.，Eur J Cancer 38(12)：1653-1660，2002.

17.Sharp SY，et al.，Eur J Cancer 38(17)：2309-15，2002.

18.Plasencia C，et al.，Invest New Drugs 22(4)：399-409，2004.

19.Murakami H，et al.，Eur J Cancer 38(Suppl 8)：S1-S5，2002

20.Giaccone G，et al.，Eur J Cancer 38(Suppl 8)：S19-S24，2002.

21.Gore ME，et al.，Eur J Cancer 38(18)：2416-2420，2002.

22.Treat J，et al.，Eur J Cancer 38(Suppl 8)：S13-18，2002.

23.Perez RP，et al.，Eur J Cancer 34(10)：1535-42，1998.

24.Gelmon KA，et al.，Ann Oncol 15(7)：1115-22，2004.

25.Gelmon KA，et al.，National Cancer Institute of Canada-Clinical Trials Group trial，IND 129.Ann Oncol 14：543-548，2003.

26.Therasse P，et al.，New Guidelines to Evaluate the Response to Treatment in Solid Tumors.European Organization for Research and Treatment of Cancer，National Cancer Institute of the United States，National Cancer Institute of Canada.J Natl Cancer Inst 92(3)：205-216，2000.

27.J.M.Tabernero et al.，J.Clin.Oncol.，22(145)，3512(2004).

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 platinum and non-platinum anti-cancer drugs as disclosed 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

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

PCT Ser. No. __________, filing date 2/6 in 2009, office docket No.295.115wo1

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

1. A method of treating colorectal cancer, comprising:

administering picoplatin, bevacizumab, 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 an interval 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 the bevacizumab is administered at least twice at an interval of one week.

2. RightsThe method of claim 1, wherein the concentration is from about 60 to about 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 having colorectal cancer an effective amount of a combination of picoplatin, bevacizumab, 5-FU and leucovorin, wherein the picoplatin and the 5-FU and leucovorin are administered intravenously at least twice at an interval of about 2-6 weeks and the bevacizumab is administered at least twice at an interval of one week, 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 picoplatin is administered at the dosage of (a).

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

7. The method of any one of claims 1-6, wherein the patient having metastatic colorectal cancer has not previously been treated for metastatic disease.

8. The method of any one of claims 1-6, wherein the patient with metastatic colorectal cancer was previously treated with an irinotecan regimen, a FOLFOX regimen, or a FOLPI regimen, wherein the cancer is refractory, or wherein the cancer has progressed within 6 months of completing the regimen.

9. The method of any one of claims 1-6, wherein the patient having metastatic colorectal cancer has previously been treated sequentially with at least two of an irinotecan regimen, a FOLFOX regimen, and a FOLPI regimen, wherein the cancer is refractory, or wherein the cancer has progressed within 6 months of completing the regimen.

10. 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 osmotic pressure regulating agent, and about 0.5mg/ml dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostats.

11. The method of claim 8, wherein the irinotecan regimen or the FOLFOX regimen or both are accompanied by administration of bevacizumab.

12. The method of claim 11 wherein the picoplatin and the leucovorin are administered concurrently.

13. The method of claim 9, wherein the irinotecan regimen or the FOLFOX regimen or both are accompanied by administration of bevacizumab.

14. The method of claim 13 wherein the picoplatin and the leucovorin are administered concurrently.

15. The method of any one of claims 1-6, wherein the 5-FU is administered after the picoplatin, leucovorin, and bevacizumab are administered.

16. The method of claim 1, wherein said leucovorin and said 5-FU are administered about every two weeks, said picoplatin is administered with said leucovorin about every 4 weeks, and said bevacizumab is administered every two weeks.

17. The method of claim 4 wherein said picoplatin is administered substantially concurrently with said leucovorin at each treatment of the patient, followed by administration of said 5-FU, and said bevacizumab is administered at two week intervals.

18. The method of any one of claims 1-6, wherein the concentration is about 200-²Is administered with the leucovorin.

19. The method of any one of claims 1-6, wherein about 1000 and 3000mg/m are administered at each administration²Is administered with said 5-FU.

20. The method of any one of claims 1-6, wherein the concentration is about 120-²The picoplatin is administered at the dosage of (a).

21. 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.

22. The method of any one of claims 1-6, wherein at about 150mg/m²The dose of picoplatin is administered at least once.

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

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

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

26. The method of any one of claims 1-6, wherein bevacizumab is administered intravenously at a first dose of about 10mg/kg, followed by a dose of about 10mg/kg every other week.

27. The method of claim 1, wherein the formyltetrahydrofolate is about 400mg/m by infusion for 2 hours²The dosage of (a); a bolus dose of about 400mg/m following administration of the leucovorin²5-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 said leucovorin and said 5-FU are administered to said patient every two weeks with about 60-150mg/m of said leucovorin every 4 weeks²Wherein at least the initial dose of picoplatin is about 150mg/m²Wherein the bevacizumab is administered at an initial dose of about 10mg/kg and then at a dose of about 10mg/kg once every other week.

28. A method of treating colorectal cancer, comprising:

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

(b) administering to said patient about 5-150mg/m every 21 days²And administering bevacizumab in a dose of about 10mg/kg in combination every other week.

29. A method of treating colorectal cancer, comprising:

(a) determining a patient with 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 said patient about 5-150mg/m every 21 days²And administering bevacizumab in a dose of about 10mg/kg in combination every other week, with or without 5-FU or leucovorin or both, as an adjunct therapy to prevent relapse.

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

31. Use of picoplatin in combination with bevacizumab, 5-fluorouracil (5-FU) and leucovorin for the treatment of colorectal cancer, wherein the 5-FU and leucovorin are administered at least twice intravenously at an interval 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 an interval of one week.

32. The use of claim 31, wherein the amount is from about 60 to 180mg/m²Preferably about 150mg/m²The picoplatin is administered at the dosage of (a).

33. The use of claim 31 wherein the administration interval of said 5-FU and said leucovorin is about two weeks and the administration interval of said picoplatin is about four weeks.

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

35. The use of claim 34, wherein the amount is from about 45 to 150mg/m²Preferably about 135-150mg/m²The picoplatin is administered at the dosage of (a).

36. The use of claim 34 wherein the interval between administration of said picoplatin, said 5-FU and said leucovorin is about two weeks.

37. The use of any one of claims 31-36, wherein the patient having metastatic colorectal cancer has not previously been treated for metastatic disease.

38. The use of any one of claims 31-36, wherein the patient with metastatic colorectal cancer has previously been treated with an irinotecan regimen, a FOLFOX regimen, or a FOLPI regimen, wherein the cancer is refractory, or wherein the cancer has progressed within 6 months of completing the regimen.

39. The use of any one of claims 31-36, wherein the patient having metastatic colorectal cancer has previously been treated sequentially with at least two of an irinotecan regimen, a FOLFOX regimen, and a FOLPI regimen, wherein the cancer is refractory, or wherein the cancer has progressed within 6 months of completing the regimen.

40. The use of claim 38, wherein the irinotecan regimen or the FOLFOX regimen or both are accompanied by administration of bevacizumab.

41. The use of claim 40 wherein the picoplatin and leucovorin are administered concurrently.

42. The use of claim 39, wherein the irinotecan regimen or the FOLFOX regimen or both are accompanied by administration of bevacizumab.

43. The use of claim 42 wherein the picoplatin and leucovorin are administered concurrently.

44. The use of any one of claims 31-36, wherein the 5-FU is administered after the picoplatin, leucovorin, and bevacizumab are administered.

45. The use of claim 31, wherein said leucovorin and said 5-FU are administered about every two weeks, said picoplatin is administered with said leucovorin about every 4 weeks, and said bevacizumab is administered every two weeks.

46. The use of claim 34 wherein said picoplatin is administered substantially concurrently with said leucovorin at each treatment of the patient, followed by administration of said 5-FU, with said bevacizumab being administered at two week intervals.

47. The use as claimed in any one of claims 31 to 36, wherein the concentration is about 200-400mg/m²Is administered with the leucovorin.

48. The use as claimed in any one of claims 31 to 36, wherein about 1000-3000mg/m per administration²Is administered with said 5-FU.

49. The use of any one of claims 31-36, wherein at about 60-180mg/m²The picoplatin is administered at the dosage of (a).

50. The use as claimed in claim 49, wherein the concentration is about 120-150mg/m²The picoplatin is administered at the dosage of (a).

51. The use of any one of claims 31-36, wherein the dose is about 15-30mg/m lower than the previous dose²The subsequent picoplatin dose is administered.

52. The use of claim 50, wherein at about 150mg/m²The picoplatin is administered at least once.

53. The use of claim 31, wherein the amount is from about 60 to 75mg/m²The picoplatin is administered at least once.

54. The use of claim 34, wherein the amount is from about 40-45mg/m²The picoplatin is administered at least once.

55. The use of any one of claims 31-36, wherein the cumulative dose administered to the patient is greater than about 900mg/m²Picoplatin of (1).

56. The use of any one of claims 31-36, wherein the bevacizumab is administered intravenously at a first dose of about 10mg/kg, followed by a dose of about 10mg/kg every other week.

57. The use of claim 31, wherein the formyltetrahydrofolate is about 400mg/m by infusion for 2 hours²The dosage of (a); a bolus dose of about 400mg/m following administration of the leucovorin²5-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 said leucovorin and said 5-FU are administered to said patient every two weeks with leucovorin about 60-150mg/m every 4 weeks²Wherein at least the initial dose of picoplatin is about 150mg/m²Wherein the bevacizumab is administered at an initial dose of about 10mg/kg and then at a dose of about 10mg/kg once every other week.

58. About every 21 daysAbout 5-150mg/m of the active ingredient²In combination with bevacizumab at a dose of about 10mg/kg administered about every other week, for use in the treatment of metastatic colorectal cancer in a patient suffering from colorectal cancer who has failed the regimen of irinotecan, FOLFOX and/or FOLPI.

59. The use of claim 58, further comprising the use of 5-FU or formyltetrahydrofolate or both administered every other week.

60. The use of claim 58, further comprising the use of 5-HT₃A receptor antagonist.

61. About 5-150mg/m administered about every 21 days²Is used in combination with bevacizumab at a dose of about 10mg/kg about every other week for the treatment of metastatic colorectal cancer in a patient suffering from colorectal cancer who has received an irinotecan, FOLFOX and/or FOLPI regimen with or without bevacizumab or cetuximab to prevent relapse, wherein the cancer is in remission.

62. The use of claim 61, further comprising the use of 5-FU or formyltetrahydrofolate or both administered every other week.

63. The use of claim 61, further comprising the use of 5-HT₃A receptor antagonist.

64. A kit suitable for intravenous administration of a FOLPI + bevacizumab regimen to a patient; the kit includes a first container containing a picoplatin solution and a second container containing bevacizumab (Avastin)) A second container of 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 and second containers to the patient; the medicine box is also provided withComprising a container suitable for intravenous administration to said patient containing a solution of formyltetrahydrofolate and/or a container containing a solution of 5-FU; instructions for use are also optionally included.

65. The kit of claim 64 wherein the first container comprises a dosage form comprising an isotonic solution containing water, an osmotic pressure regulating agent, and about 0.5mg/ml dissolved picoplatin, wherein the dosage form is free of preservatives or bacteriostats.