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

Genotype-Directed Phase II Study Of Higher Dose Of Irinotecan In First-Line Metastatic Colorectal Cancer Patients Treated With Folfiri Plus Bevacizumab

This study involves standard combination chemotherapy treatment for colon cancer, 5-Fluorouracil (5FU), leucovorin and irinotecan (known as FOLFIRI), plus bevacizumab (Avastin). The study is designed to test the FOLFIRI regimen based on certain characteristics of a person's genetic makeup or "genes". Genes are made of DNA and determine not only inherited traits or appearance (hair and eye color, height, body type, etc.) but also play an important role in health and how the body responds to illness and treatments for those illnesses.

In this study, the investigators will examine the relationship between a patient's genes (DNA), or "genotype", and how the patient's body breaks down and removes or "metabolizes" the anti-cancer drug irinotecan. Circulating blood level of irinotecan plays an important role in how well this drug works against a patient's cancer as well as the adverse side effects the patient may experience. The current standard dose of irinotecan was determined in clinical trials without knowing individual genotypes and thus does not take into account a patient's ability to metabolize irinotecan. This means that based on one genotype the current standard dose of irinotecan may be correct or based on other genotypes the standard dose could result in lower and possibly less effective blood levels and result in significant under-dosing of irinotecan.

Based on genotype the patient will be assigned to one of the following doses of irinotecan:

• 180 mg/m2 (standard dose)
• 260 mg/m2
• 310 mg/m2

The purpose of this research study is to determine if dosing irinotecan based on genotype is effective and safe for patients with colon cancer. Patient genotype will be determined from a small sample of blood and a laboratory test or "assay" performed at University of North Carolina Laboratories. For the purpose of this study, this assay is new and considered to be "investigational". This means that the genotype assay used in this study has not yet been approved by the FDA for determining irinotecan dose levels in patients with colon cancer.

This phase II multicenter clinical trial will use a genotype-guided dosing strategy for irinotecan to prospectively analyze efficacy in 100 metastatic colorectal cancer patients (mCRC) receiving FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) plus bevacizumab. Irinotecan is detoxified and excreted primarily by glucuronidation in the liver via the isoenzyme uridine diphosphate glucuronosyl transferase (UGT1A1). Common variants in UGT1A1 alter the rate of glucuronidation and thus alter exposure to irinotecan.

The UGT1A1 *28 allele results in slower irinotecan glucuronidation, and thus greater exposure to its active metabolite SN-38. At the standard irinotecan dose used in FOLFIRI (180 mg/m2; established prior to our understanding of the importance of genotype in the rate of this drug's metabolism), there is a small increased risk of neutropenia in *28 homozygotes. However, the risk of clinically important consequences of neutropenia, such as febrile neutropenia and infection, are not significantly increased. Patients with other genotypes have a quite low risk of adverse effects suggesting patients with these low risk genotypes may tolerate higher doses of irinotecan in FOLFIRI. This finding was demonstrated in a phase I study in which *1/*28 and *1/*1 genotypes were able to tolerate escalating doses of irinotecan up to 260 mg/m2 and 310 mg/m2, respectively.

The central hypothesis of this trial is that increasing the irinotecan dose in *1/*28 and *1/*1 genotypes will increase the overall benefit of FOLFIRI for patients with mCRC as these two groups are likely under-dosed with the current dosing regimen. Eligible patients will be genotyped for UGT1A1 and assigned into 1 of 3 different dosing groups, based on their relative rate of metabolism. The primary objective of this trial is to estimate progression-free survival (PFS), and secondary objectives include characterization of toxicity and objective response rate (OR; complete response (CR) + partial response (PR)).

Inclusion Criteria:

Subjects must meet all of the inclusion criteria to participate in this study:

1. An Institutional Review Board-approved informed consent obtained and signed

2. Age ≥ 18 years

3. Histological or cytological documentation of adenocarcinoma of the colon or rectum

4. Measurable or non-measurable (but evaluable) disease as defined via RECIST 1.1

5. Metastatic disease not amenable to surgical resection with curative intent

6. No prior chemotherapy for metastatic disease

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see section 11.1, Appendix A)

8. 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)

9. Willing to undergo UGT1A1 genotyping

10. Negative pregnancy test (urine or serum), within 7 day prior to Day 1 of FOLFIRI in women of childbearing potential

11. 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.

Exclusion Criteria

1. UGT1A1 genotype other than *1/*1, *1/*28, or *28/*28

2. Known dihydropyrimidine dehydrogenase (DPD) deficiency

3. Prior treatment with irinotecan and/or bevacizumab

4. 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)

5. Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg)

6. Prior history of hypertensive encephalopathy

7. 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

8. 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

9. History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1 of FOLFIRI + bevacizumab initiation

10. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

11. 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

12. 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

13. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 of FOLFIRI + bevacizumab initiation

14. Serious, non-healing wound, active ulcer, or untreated bone fracture

15. 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)

16. Any serious uncontrolled medical disorder that would impair the ability of the subject to receive protocol-driven therapy

17. Other anti-cancer or investigational therapy while patients are on study therapy