Genetic Testing in Determining Irinotecan Hydrochloride Dose in Patients with Metastatic Colorectal Cancer Receiving FOLFIRI and Bevacizumab

Status: closed to accrual

This phase II trial studies how well genetic testing works in determining irinotecan hydrochloride dose in patients with colorectal cancer that has spread to other areas of the body, who are receiving leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) and bevacizumab. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as bevacizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving monoclonal antibody therapy with chemotherapy may kill more tumor cells. Genetic testing may help doctors determine how the body breaks down and removes irinotecan hydrochloride. Using genetic testing to determine the dose of irinotecan hydrochloride may be more effective and safer than standard dosing.

Inclusion Criteria

Institutional Review Board (IRB)-approved informed consent obtained and signed
Histological or cytological documentation of adenocarcinoma of the colon or rectum
Measurable or non-measurable (but evaluable) disease as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (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
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelets >= 100,000/mm^3
Hemoglobin >= 9.0 g/dL
Serum creatinine =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5.0 x 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 comply with study procedures
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

Exclusion Criteria

UGT1A1 genotype other than *1/*1, *1/*28, or *28/*28
Patients of Asian descent
Known dihydropyrimidine dehydrogenase (DPD) deficiency
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
Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg); to control hypertension, the addition or increase of standard of care antihypertensive regimen is allowed
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 * 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
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
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
Serious, non-healing wound, active ulcer, or untreated bone fracture
Proteinuria as demonstrated by: * Urine protein: creatinine (UPC) ratio >= 1.0 at screening (patients discovered to have a UPC >= 1 should undergo a 24 hour urine collection and must demonstrate =< 1 g of protein in 24 hours to be eligible) OR * Urine dipstick for proteinuria >= 2+ (patients discovered to have >= 2+ proteinuria on dipstick urinalysis may either undergo urine protein: creatinine (UPC) testing, and may participate if ratio < 1. 0 or should undergo a 24 hour urine collection and must demonstrate =< 1 g of protein in 24 hours to be eligible)
Any serious uncontrolled medical disorder that would impair the ability of the subject to receive protocol-driven therapy
Other anti-cancer or investigational therapy while patients are on study therapy

PRIMARY OBJECTIVES:

I. Estimate progression free survival (PFS) in previously untreated metastatic colorectal cancer (mCRC) patients receiving FOLFIRI + bevacizumab when irinotecan (irinotecan hydrochloride) dose is based on UGT1A1 genotype.

II. Estimate the proportion of patients who complete all the Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) questions at least 80% of the time the patient questionnaire is available (on day [d]1 and d15 of each cycle) in the parent trial (1317). (Sub-study)

III. Estimate the proportion of patients who complete all the PRO-CTCAE Clinician forms (i.e. both patient and clinician fully complete) at least 80% of the time the patient questionnaire is available (on d1 and d15 of each cycle) in the parent trial (1317). (Sub-study)

SECONDARY OBJECTIVES:

I. Evaluate the toxicity profile when irinotecan is dosed according to UGT1A1 genotype.

II. Estimate objective response (OR) (complete response [CR] + partial response [PR]) in previously untreated metastatic colorectal cancer (mCRC) patients receiving FOLFIRI + bevacizumab when irinotecan dose is based on UGT1A1 genotype.

III. Estimate overall survival (OS) in previously untreated mCRC patients receiving FOLFIRI + bevacizumab when irinotecan dose is based on UGT1A1 genotype.

IV. Estimate concordance between PRO-CTCAE grades of toxicity and investigator-assigned CTCAE grades of toxicity for each symptom of interest separately. (Sub-study)

V. Compare proportion of patients with PRO-CTCAE maximum score (>= 2 for diarrhea, >= 3 for all other symptoms) to proportion of patients with investigator-assigned CTCAE maximum score (>= 2 for diarrhea, >= 3 for all other symptoms) for each symptom separately. (Sub-study)

VI. Compare time to first PRO-CTCAE score of >= 2 for diarrhea, >= 3 for all other symptoms to time to first investigator-assigned CTCAE score of >= 2 for diarrhea, >= 3 for all other symptoms. (Sub-study)

TERTIARY OBJECTIVES:

I. Explore associations between tumor and host genetic profiles and response or toxicity.

II. Explore association between PRO-CTCAE scores of >= grade 2 diarrhea or >= grade 3 for all other symptoms and dose modifications. (Sub-study)

III. Explore association between PRO-CTCAE maximum score (>= grade 2 diarrhea, >= grade 3 for all other symptoms) and irinotecan starting dose. (Sub-study)

OUTLINE: Patients are assigned to 1 of 3 doses of irinotecan hydrochloride based on genotyping results.

Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes, leucovorin calcium IV over 2 hours, fluorouracil IV over 46 hours, and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

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Genetic Testing in Determining Irinotecan Hydrochloride Dose in Patients with Metastatic Colorectal Cancer Receiving FOLFIRI and Bevacizumab

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