Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal 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. IRB-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)

- AST and 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