Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal Cancer

Prior treatment

• Prior treatment with irinotecan and/or bevacizumab
• Unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 14 days (fruits and juices for at least 7 days) prior to Day 1 of FOLFIRI + bevacizumab initiation (see section 11.2, Appendix B, for list of prohibited drugs)
• Prior history of hypertensive encephalopathy
• Active cardiac disease including any of the following:
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure (see section 11.3, Appendix C)
  • History of myocardial infarction or unstable angina within 6 months prior to Day 1
  • History of stroke or transient ischemic attack within 6 months prior to Day 1 of FOLFIRI + bevacizumab initiation
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of FOLFIRI + bevacizumab initiation
• History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1 of FOLFIRI + bevacizumab initiation
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of FOLFIRI + bevacizumab initiation or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1 of FOLFIRI + bevacizumab initiation
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 of FOLFIRI + bevacizumab initiation
• Other anti-cancer or investigational therapy while patients are on study therapy

Other illness

• Inadequately controlled hypertension (defined as systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg)
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Any serious uncontrolled medical disorder that would impair the ability of the subject to receive protocol-driven therapy

Lab values

• Proteinuria as demonstrated by:
  • Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening OR Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible)

Other

• UGT1A1 genotype other than \*1/\*1, \*1/\*28, or \*28/\*28
• Known dihydropyrimidine dehydrogenase (DPD) deficiency

• Subjects must meet all of the inclusion criteria to participate in this study:
• An Institutional Review Board-approved informed consent obtained and signed
• Age ≥ 18 years
• Histological or cytological documentation of adenocarcinoma of the colon or rectum
• Measurable or non-measurable (but evaluable) disease as defined via RECIST 1.1
• Metastatic disease not amenable to surgical resection with curative intent
• No prior chemotherapy for metastatic disease
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see section 11.1, Appendix A)
• Adequate bone marrow, renal and hepatic function, as evidenced by the following:
  • absolute neutrophil count (ANC) ≥1,500/mm3
  • platelets ≥100,000/mm3
  • hemoglobin ≥9.0 g/dL
  • serum creatinine ≤1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and Alanine transaminase (ALT) ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer
  • Bilirubin ≤1.5 X ULN
  • Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer)
• Willing to undergo UGT1A1 genotyping
• Negative pregnancy test (urine or serum), within 7 day prior to Day 1 of FOLFIRI in women of childbearing potential
• Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care.