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

NCT02573220 | Withdrawn Phase 1

• 3 other identifiers: IRB15-0081NCI-2015-01432P30CA014599
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Response rate

  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)

  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

  Within 1 year of starting therapy

Study Arms (1)

Treatment (FOLFIRI and cetuximab)

EXPERIMENTAL

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.

Biological: Cetuximab; Drug: Fluorouracil; Drug: Irinotecan Hydrochloride; Drug: Leucovorin Calcium

Interventions

Cetuximab BIOLOGICAL

Given IV

Also known as: Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Erbitux

Treatment (FOLFIRI and cetuximab)

Fluorouracil DRUG

Given IV

Also known as: 5-Fluorouracil, 5-FU

Treatment (FOLFIRI and cetuximab)

Irinotecan Hydrochloride DRUG

Given IV

Also known as: Camptosar, Camptothecin 11

Treatment (FOLFIRI and cetuximab)

Leucovorin Calcium DRUG

Given IV

Also known as: Calcifolin, Wellcovorin

Treatment (FOLFIRI and cetuximab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• University of Chicago: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Centro di Riferimento Oncologico

Aviano, 33081, Italy

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Cetuximab; Fluorouracil; Irinotecan; Leucovorin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Camptothecin; Alkaloids; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Study Officials

• Manish Sharma

  University of Chicago Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2015
• First Posted: October 9, 2015
• Study Start: June 1, 2015
• Primary Completion: August 1, 2016
• Study Completion: August 1, 2016
• Last Updated: December 9, 2016

Record last verified: 2016-12

Locations

IT (1)