Clinical Trials /

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

NCT02573220

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Irinotecan Hydrochloride</span> With <span class="go-doc-concept go-doc-intervention">FOLFIRI</span> and <span class="go-doc-concept go-doc-intervention">Cetuximab</span> as First-Line Therapy in Treating Patients With <span class="go-doc-concept go-doc-biomarker">RAS</span> Wild-Type <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span>

Title

  • Brief Title: Irinotecan Hydrochloride With FOLFIRI and Cetuximab as First-Line Therapy in Treating Patients With RAS Wild-Type Colorectal Cancer
  • Official Title: 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
  • Clinical Trial IDs

    NCT ID: NCT02573220

    ORG ID: IRB15-0081

    NCI ID: NCI-2015-01432

    Trial Conditions

    Stage IVA Colorectal Cancer

    Stage IVB Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    Fluorouracil 5-Fluorouracil, 5-FU Treatment (FOLFIRI and cetuximab)
    Irinotecan Hydrochloride Camptosar, Camptothecin 11 Treatment (FOLFIRI and cetuximab)
    Leucovorin Calcium Calcifolin, Wellcovorin Treatment (FOLFIRI and cetuximab)

    Trial Purpose

    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.

    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.

    Trial Arms

    Name Type Description Interventions
    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. Fluorouracil, Irinotecan Hydrochloride, Leucovorin Calcium

    Eligibility Criteria

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD)

    Secondary Outcome Measures

    Response rate

    Progression-free survival (PFS)

    metastectomy (with curative intent) rate

    Trial Keywords