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Study of REOLYSIN® in Combination With FOLFIRI and Bevacizumab in FOLFIRI Naive Patients With KRAS Mutant Metastatic Colorectal Cancer

NCT01274624

Description:

This is a Phase 1 dose-escalation study with three dose levels to determine the maximum tolerated dose of REOLYSIN® combined with FOLFIRI and bevacizumab.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Study of REOLYSIN in Combination With <span class="go-doc-concept go-doc-intervention">FOLFIRI</span> and <span class="go-doc-concept go-doc-intervention">Bevacizumab</span> in <span class="go-doc-concept go-doc-intervention">FOLFIRI</span> Naive Patients With <span class="go-doc-concept go-doc-biomarker">KRAS</span> <span class="go-doc-concept go-doc-keyword">Mutant</span> Metastatic <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span>

Title

  • Brief Title: Study of REOLYSIN in Combination With FOLFIRI and Bevacizumab in FOLFIRI Naive Patients With KRAS Mutant Metastatic Colorectal Cancer
  • Official Title: A Multicenter Phase 1 Study of Intravenous Administration of REOLYSIN (Reovirus Type 3 Dearing) in Combination With Irinotecan/Fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in FOLFIRI Naive Patients With KRAS Mutant Metastatic Colorectal Cancer
  • Clinical Trial IDs

    NCT ID: NCT01274624

    ORG ID: REO 022

    Trial Conditions

    KRAS Mutant Metastatic Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    Irinotecan
    Leucovorin
    Fluorouracil (5-FU)
    Bevacizumab

    Trial Purpose

    This is a Phase 1 dose-escalation study with three dose levels to determine the maximum
    tolerated dose of REOLYSIN combined with FOLFIRI and bevacizumab.

    Detailed Description

    Reovirus Serotype 3 - Dearing Strain (REOLYSIN) is a naturally occurring, ubiquitous,
    non-enveloped human reovirus. Reovirus has been shown to replicate selectively in
    Ras-transformed cells causing cell lysis. Activating mutations in ras or mutation in
    oncogenes signaling through the ras pathway may occur in as many as 80% of human tumors. The
    specificity of the reovirus for Ras-transformed cells, coupled with its relatively
    nonpathogenic nature in humans, makes it an attractive anti-cancer therapy candidate.
    Eligible patients for this study include those with histologically confirmed cancer of the
    colon or rectum with Kras mutation and measurable disease.

    Cetuximab and panitumumab have shown to be ineffective in patients whose tumors have a KRAS
    mutation. Therefore, currently, for patients with a KRAS mutation, the only option after
    failure of front-line therapy is irinotecan or FOLFIRI. Over the past year, two randomized
    phase III trials have demonstrated that OS and PFS for these patients increase when
    bevacizumab is combined with the standard FOLFIRI therapy.

    The trial is a Phase I dose escalation study with four dose levels, comprising cohorts of
    three to six patients, to determine a maximum tolerated dose and dose-limiting toxicities
    with the combination of REOLYSIN, bevacizumab, and FOLFIRI. FOLFIRI and bevacizumab will be
    administered on the first day of a two week (14-day) cycle, while REOLYSIN will be
    administered on days one through five of a four week (28-day) cycle.

    The study is expected to enroll 20 to 32 patients.

    Trial Arms

    Name Type Description Interventions

    Eligibility Criteria

    Inclusion Criteria: Each patient MUST:

    - Have histologically confirmed cancer of the colon or rectum with radiologically
    documented and measurable metastases (high CEA alone is insufficient for study
    entry).

    - Have received 3 or fewer regimens in the metastatic setting.

    - Not have received prior FOLFIRI or irinotecan in the metastatic setting.

    - Have his/her tumor assessed for KRAS status and found to be mutation positive.

    - Have NO continuing acute toxic effects (except alopecia) of any prior radiotherapy,
    chemotherapy, or surgical procedures, i.e., all such effects must have resolved.

    - Have an ECOG Performance Score of 2.

    - Have a life expectancy of at least 3 months.

    - Have baseline laboratory results as follows:

    - Absolute neutrophil count (ANC) 1.5 x 10^9 [SI unit 10^9/L]

    - Platelets 100 x10^9 [SI units 10^9/L] (without platelet transfusion)

    - Hemoglobin 9.0 g/dL [SI units gm/L] (with or without RBC transfusion)

    - Serum creatinine 1.5 x upper limit of normal (ULN)

    - Bilirubin ULN

    - AST/ALT 2.5 x ULN ( 5 x ULN if with liver metastases)

    - Negative pregnancy test for females with childbearing potential.

    - Proteinuria < grade 2.

    - Have signed an informed consent indicating that the patient is aware of the
    neoplastic nature of their disease and have been informed of the procedures of the
    protocol, the experimental nature of the therapy, alternatives, potential benefits,
    side effects, risks, and discomforts.

    - Be willing and able to comply with scheduled visits, the treatment plan, and
    laboratory tests.

    - Be medically eligible to receive bevacizumab

    Exclusion Criteria: No patient may:

    - Receive concurrent therapy with any other investigational anticancer agent while on
    study.

    - Have previously received irinotecan or FOLFIRI in the metastatic setting (patient is
    eligible if he/she had received irinotecan or FOLFIRI as adjuvant therapy more than 6
    months before entry into the study)

    - Have brain metastases.

    - Be on immunosuppressive therapy or have known HIV infection or active hepatitis B or
    C.

    - Have received chemotherapy, radiotherapy, immunotherapy or hormonal therapy or had
    surgery (except biopsies) within 28 days prior to receiving the study drug.

    - Be a pregnant or breast-feeding woman. Female patients of childbearing potential
    must agree to use effective contraception, be surgically sterile, or be
    postmenopausal. Male patients must agree to use effective contraception or be
    surgically sterile. Barrier methods are a recommended form of contraception.

    - Have clinically significant cardiac disease (New York Heart Association, Class III or
    IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial
    infarction within 1 year prior to study entry, or Grade 2 or higher compromised left
    ventricular ejection fraction.

    - Have dementia or altered mental status that would prohibit informed consent.

    - Have any other acute, or chronic medical or psychiatric condition or laboratory
    abnormality that may increase the risk associated with study participation or study
    drug administration or may interfere with the interpretation of study results and, in
    the judgment of the Principal Investigator, would make the patient inappropriate for
    this study.

    - Have uncontrolled hypertension, proteinuria, or recent major surgery (all clinical
    parameters related to bevacizumab use). Any other clinical parameter considered
    important should be discussed with the medical monitor.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Dose limiting toxicity to define maximum tolerated dose and recommended Phase 2 dose

    Pharmacokinetic parameters for irinotecan and 5-FU when combined with REOLYSIN

    Secondary Outcome Measures

    CEA and Objective Response, Clinical Benefit Rate (PR, CR, SD), progression-free survival, and overall survival (PFS and OS)

    Safety and tolerability of REOLYSIN when administered in combination with FOLFIRI and bevacizumab

    Correlative studies including determination of specific genetic mutations and aberrant signalling pathways from tumor tissue to identify novel biomarkers of response and efficacy

    In vitro studies in human-derived colorectal cancer cells including the isogenic cell lines, to study the mechanism and scientific basis of synergy between irinotecan and reovirus

    Trial Keywords

    Colorectal

    Cancer

    REOLYSIN

    Chemotherapy

    FOLFIRI

    Reovirus

    Oncolytic virus

    Fluorouracil

    Irinotecan

    Leucovorin

    Bevacizumab