Irinotecan Hydrochloride With FOLFIRI and Cetuximab as First-Line Therapy in Treating Patients With RAS Wild-Type Colorectal Cancer

A UGT1A1 Genotype-Guided Dosing Study of Irinotecan Administered in Combination With 5-Fluorouracil/Leucovorin (FOLFIRI) and Cetuximab as First-Line Therapy in RAS Wild-Type Metastatic Colorectal Cancer Patients

This phase I trial studies the side effects and the best dose of irinotecan hydrochloride, based on a genetic test, when given in combination with fluorouracil, leucovorin calcium, and cetuximab as first-line therapy in treating patients with an abnormal gene called RAS wild-type that has spread to other parts of the body (metastatic). Patients may also have a gene called uridine diphosphate glucuronosyltransferase (UGT1A1) that may interfere with the way irinotecan hydrochloride is absorbed by the body and may not be able to tolerate it. Determining the presence of this gene may help determine the best dose of irinotecan hydrochloride when given with fluorouracil and leucovorin calcium (FOLFIRI). Combination chemotherapy, such as FOLFIRI, works 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. Cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving FOLFIRI together with cetuximab may be a better treatment for patients with colorectal cancer.

Study Overview

• Status: Withdrawn
• Conditions: Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer
• Intervention / Treatment: Drug: Fluorouracil; Drug: Leucovorin Calcium; Biological: Cetuximab; Drug: Irinotecan Hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the phase II recommended dosage of irinotecan (irinotecan hydrochloride) administered in the FOLFIRI regimen plus cetuximab in metastatic colorectal cancer (mCRC) patients with *1/*1 and *1/*28 uridine diphosphate glucuronosyltransferase (UGT1A1) genotype treated as first line chemotherapy.

SECONDARY OBJECTIVE:

To estimate the response rate, progression-free survival (PFS) and metastasectomy (with curative intent) rate in the overall patient population (both genotype cohorts).

OTHER OBJECTIVES:

I. To evaluate the variability of irinotecan pharmacokinetics, in combination with cetuximab, in patients with *1/*1 and *1/*28 genotype and the effect of the pharmacokinetic profile on toxicity and response rate.

II. To evaluate the pharmacokinetic profile of irinotecan and its major metabolites in the absence and the presence of cetuximab administration, in order to define the effect of the chimeric monoclonal antibody on irinotecan pharmacokinetics.

OUTLINE: This is a dose-escalation study of irinotecan hydrochloride in patients with UGT1A1.

Patients receive irinotecan hydrochloride intravenously (IV) over 1-2 hours, fluorouracil IV continuously over 46 hours, and leucovorin calcium IV on days 1 and 15. Patients also receive cetuximab IV over 2 hours on days 3 and 15 of course 1 and days 1 and 15 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Aviano, Italy, 33081
    • Centro Di Riferimento Oncologico

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of mCRC
• RAS wild-type status (by a Clinical Laboratory Improvement Amendments [CLIA] certified assay that includes all known mutations in Kirsten rat sarcoma viral oncogene homolog [KRAS], Harvey rat sarcoma viral oncogene homolog [HRAS], and neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS])
• No prior chemotherapy for metastatic disease
• Able to understand and provide written informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy > 3 months
• Measurable or evaluable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria, i.e. lesions that can be accurately measured in at least one dimension with the longest diameter >= 20 mm using conventional techniques or >= 10 mm using spiral computed tomography (CT) scan
• Absolute neutrophil count (ANC) > l500/ul
• Hemoglobin > 9g/dL
• Platelets > 100,000/ul
• Total bilirubin =< 1.5 times upper limit of normal
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times upper limit of normal
• Alkaline phosphatase < 2.5 times the upper limit of normal, unless bone metastasis is present in the absence of liver metastasis
• Creatinine < 1.5 mg/dL
• Patients genotyped for UGT1A1*28 polymorphism with *1/*1 or *1/*28 genotype
• Men and women of childbearing potential must agree to use adequate contraception (double barrier birth control) for the duration of study therapy
• Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of childbearing potential

Exclusion Criteria:

• Patients with both variant alleles (*28/*28)
• Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g, *6)
• Uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease or cardiac amyloidosis
• Patients with specific contraindications to the use of anti-EGFR therapy such as pulmonary fibrosis, interstitial pneumonia history
• Unresolved diarrhea and bowel obstruction
• Active bleeding
• Documented cerebral metastasis
• Serious active infectious disease
• Pregnancy
• Radiotherapy or major surgery within 4 weeks
• Psychiatric illness or social situations that would limit compliance with study requirements
• Presence of previous or concomitant neoplasm with exclusion of in situ cervical cancer
• Patients taking substrates, inhibitors and inducers of CYP3A4 should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with irinotecan

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (FOLFIRI and cetuximab); Patients receive irinotecan hydrochloride IV over 1-2 hours, fluorouracil IV continuously over 46 hours, and leucovorin calcium IV on days 1 and 15. Patients also receive cetuximab IV over 2 hours on days 3 and 15 of course 1 and days 1 and 15 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Fluorouracil; Given IV; Other Names: 5-FU; 5-Fluorouracil; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; Calcifolin; Biological: Cetuximab; Given IV; Other Names: Erbitux; Chimeric Anti-EGFR Monoclonal Antibody; Chimeric MoAb C225; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Camptosar; Camptothecin 11

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	The MTD recommended for phase II studies will be defined as the dose level immediately below the one at which 1 out of 3 patients or 1 out of 6 patients experienced DLT. Therefore at the MTD, 1/3 out of at least 10 patients experienced DLT. No intra-patient dose escalation is allowed. There will be two genotype cohorts of patients: one for each genotype. The cumulative hematological and non-hematological toxicities as well as the number of dose reductions and a delay in starting the next cycle of treatment will be used as secondary indicators to differentiate the two genotype cohorts of patients. Patients can continue receiving the same dose of irinotecan in the absence of major toxicity if before retreatment they fully recover from any non-hematological toxicity, absolute neutrophil count is 1500 microliters and platelet count is 100,000 microliters. Chemotherapy is discontinued on evidence of disease progression by RECIST version 1.1.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	Response rate is the number of patients with a partial response (by RECIST version 1.1) divided by the total number of patients.	Every 2 cycles (every 8 weeks), from the beginning of the study until disease progression or death, which ever comes first (up to on average 60 months)
Progression-free survival (PFS)	PFS is the time (in days) between study enrollment and disease progression (by RECIST version 1.1) or death, whichever comes first.	From beginning of the study until disease progression or death, which every comes first (up to on average 60 months)
metastectomy (with curative intent) rate	Metastatectomy rate is the number of patients who undergo a surgical resection with curative intent divided by the total number of patients	Within 1 year of starting therapy

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Manish Sharma, University of Chicago Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: September 21, 2015
• First Submitted That Met QC Criteria: October 7, 2015
• First Posted (Estimate): October 9, 2015

Study Record Updates

• Last Update Posted (Estimate): December 9, 2016
• Last Update Submitted That Met QC Criteria: December 8, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Cetuximab; Camptothecin
• Other Study ID Numbers: IRB15-0081 (Other Identifier: University of Chicago Comprehensive Cancer Center); P30CA014599 (U.S. NIH Grant/Contract); NCI-2015-01432 (Registry Identifier: CTRP (Clinical Trial Reporting Program))