A Study of Picoplatin in Colorectal Cancer

Colorectal cancer is a type of cancer that begins in the large intestine (colon) or the rectum (end of the colon). Several drugs are often given in combination to treat colorectal cancer. One of the most active treatment combinations is known as FOLFOX, which is a combination of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. Oxaliplatin is a type of platinum drug and was approved by the FDA in 2004. While generally well-tolerated, oxaliplatin may cause toxicity to the nerves, such as sensory loss or cold sensitivity.

Picoplatin is a new type of platinum drug that has shown activity with 5-FU in pre-clinical studies and has undergone extensive Phase 1 and Phase 2 testing in a variety of cancers. No significant nerve toxicity has been seen in previous studies of picoplatin.

This study will review the safety and effectiveness of FOLPI, which is the combination of 5-FU and leucovorin with picoplatin in participants with colorectal cancer.

Subjects will be randomized centrally to treatment with picoplatin administered either every two or every four weeks and will be assigned a dose of picoplatin dependent on the study results to date. Each patient will also receive therapy every two weeks with 5-FU and leucovorin. In each schedule, the cohort size will be 3 subjects, to be expanded to 6 subjects if a dose-limiting toxicity is observed. If not dose-limiting toxicity observed among the 3 subjects within a cohort, picoplatin dose escalation may proceed, until the maximum tolerated dose is established.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the colon or rectum.
* Metastatic disease consistent with colorectal adenocarcinoma. Stage M1, and not amenable to curative surgery. Subjects with only locally persistent or only locally recurrent disease are not eligible.
* No prior systemic therapy for metastatic cancer. Prior adjuvant chemotherapy with a 5-FU-based treatment regimen not containing oxaliplatin or irinotecan is acceptable after a treatment-free interval of at least 6 months.
* ECOG performance score (PS) of 0 or 1.
* Life expectancy more than 3 months.
* Subject must have measurable disease, defined by the RECIST criteria.
* At least 28 days must have elapsed since prior surgery except venous access device placement.
* At least 28 days must have elapsed since prior radiotherapy.
* At least 28 days must have elapsed since a prior investigational agent.
* Absolute neutrophil count (ANC) equal to or greater than 1.5 x 10\^9/L.
* Platelet count equal to or greater than 100 x 10\^9/L.
* Hemoglobin equal or greater than 10g/dL (must be obtained at least 3 days after any transfusion).
* Serum AST and ALT levels less than or equal to 2.5 times upper limit of normal (ULN) or less than 5 times ULN if liver involvement is present.
* Serum bilirubin of less than or equal to 1.5 ULN.
* Serum creatinine of less than or equal to ULN.
* Women of childbearing potential must have a negative pregnancy test (serum or urine beta HCG).
* All subjects must agree to use appropriate birth control methods while on study and for 1 month after completion of study chemotherapy.

Exclusion Criteria:

* Concurrent use of EGFR inhibitors or anti-VEGF agents.
* No clinically significant obstructive symptoms or intestinal bleeding.
* Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g. Crohn's disease, ulcerative colitis, malabsorption syndrome, Grade 2+ diarrhea of any etiology at baseline).
* History of serious cardiac disease, defined as myocardial infarction within six months of enrollment, congestive heart failure classified by the New York Heart Association as class III or IV, uncontrolled cardiac arrhythmias, poorly controlled or unstable angina, or electrocardiographic evidence of acute ischemia.
* Clinical evidence of brain metastases or central nervous system disease.
* Symptomatic peripheral neuropathy (equivalent to Grade 2 or higher CTCAE toxicity criteria).
* Uncontrolled intercurrent illness (e.g. active infection).
* Pregnant or nursing.
* Serious medical or psychiatric illness that could potentially interfere with the completion of study treatment according to this protocol.
* Malignancy other than colorectal carcinoma within the past 5 years, except, curatively treated, superficial skin cancer or carcinoma in situ of the cervix or breast.