Study of CS-7017 in Combination With FOLFIRI in Subjects With Metastatic Colorectal Cancer Who Failed First-Line Therapy

This phase 2, randomized, active-controlled, open-label, parallel group, multicenter study will be conducted at up to 18 study centers in the US, Central America, and South America. Adult subjects with metastatic colorectal cancer (CRC) who failed first-line chemotherapy will participate in the study, which will be conducted on an outpatient basis. It is anticipated that 100 subjects will be enrolled to obtain approximately 90 evaluable subjects.

• Colorectal Cancer
• Neoplasms, Colorectal

• Drug: CS7017
  CS-7017 (0.25mg tablet) Two CS-7017 tablets will be administered PO BID every 12 hours. FOLFIRI will be administered IV once every 2 weeks.
• Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)

  FOLFIRI will be administered IV once every 2 weeks.

  The FOLFIRI regimen consists of:

  • Irinotecan, 180 mg/m2 IV infusion over 30 to 120 minutes
  • Leucovorin, 400 mg/m2 IV infusion to match the duration of the irinotecan infusion
  • 5-FU, 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46 to 48 hours continuous infusion)
  Other Names:

  • Irinotecan
  • Leucovorin
  • 5-FU
  • 5-fluorouracil

• Experimental: CS7017 plus FOLFIRI
  CS7017 plus irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)
  Interventions:

  • Drug: CS7017
  • Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)
• Active Comparator: FOLFIRI
  irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)
  Intervention: Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)

Inclusion Criteria:

• Metastatic CRC that has progressed following first-line therapy.
• Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.0.34.
• Male or female = 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status = 2.
• Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 3.0, grade = 1.

• Adequate organ and bone marrow function as evidenced by:

  • Hemoglobin = 9 g/dL (transfusion and/or growth factor support allowed)
  • Absolute neutrophil count (ANC) = 1.5 x 109/L
  • Platelet count = 100 x 109/L Serum creatinine = 1.5 x the upper limit of normal (ULN) or creatinine clearance = 60 mL/min
  • Aspartate aminotransferase (AST) and alkaline phosphatase = 2.5 x ULN in subjects with no liver metastasis and = 5.0 x ULN in subjects with liver metastasis
  • Total bilirubin = 1.5 x ULN
• Women of childbearing potential must be willing to consent to using effective contraception (eg, hormonal contraceptives, bilateral tubal ligation, barrier with spermicide, intrauterine device) while on treatment and for at least 3 months thereafter. Men who are the partner of a woman of childbearing potential must be willing to consent to using effective contraception (e.g., vasectomy or barrier with spermicide) while on treatment and for 3 months thereafter.
• All female subjects of childbearing potential must have a negative pregnancy test (serum or urine) result before initiating study treatment.
• Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an IEC- or IRB-approved ICF (including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests.
• Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

• First-line treatment with an irinotecan-based regimen (eg, FOLFIRI).
• Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study.
• Treatment with chemotherapy, other TZDs, RT, surgery, immunotherapy, biological therapy, or any investigational anticancer agent within 4 weeks before start of study treatment.

• History of any of the following conditions within 6 months before initiating study treatment:

  • Diabetes mellitus requiring treatment with insulin or TZD agents
  • Myocardial infarction with significant impairment of cardiac function (e.g., ejection fraction = 50%)
  • Severe/unstable angina pectoris
  • Coronary/peripheral artery bypass graft
  • New York Heart Association (NYHA) class III or IV congestive heart failure
  • Malabsorption syndrome, chronic diarrhea (lasting > 4 weeks), inflammatory bowel disease, or partial bowel obstruction.
• Subjects with clinically active brain metastases (defined as untreated, symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms); uncontrolled seizure disorder; spinal cord compression; or carcinomatous meningitis. Subjects with treated brain metastasis will be included in the study if they have recovered from the acute, toxic effects of RT. A minimum of 15 days must have elapsed between the end of RT and enrollment into the study.
• History of malignancy other than CRC, unless there is an expectation that the malignancy has been cured, and tumor-specific treatment for the malignancy has not been administered within the previous 5 years.
• Clinically significant, severe, active infection requiring IV antibiotic or antiviral agents.
• Pericardial or pleural effusion (eg, requiring drainage) or pericardial involvement with the tumor. Subjects with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor.
• Need for concomitant use of other TZDs during the study.
• Previous administration of CS-7017.
• Pregnant or breast feeding.
• Known to be homozygous for the UGT1A1*28 allele.
• Known history of severe hypersensitivity reactions to any of the components of CS-7017, irinotecan, leucovorin, or 5-FU.
• Serious intercurrent medical or psychiatric illnesses or any other conditions that in the opinion of the Investigator would impair the ability to give informed consent or unacceptably reduce protocol compliance or safety of the study treatment.