Irinotecan and Cetuximab with or without Bevacizumab in Treating Patients with RAS Wild-Type Locally Advanced or Metastatic Colorectal Cancer That Cannot Be Removed by Surgery

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IITreatmentActive18 and overRU021302I
NCI-2016-02063, NCT02292758

Trial Description

Summary

This randomized phase II trial studies how well irinotecan and cetuximab with or without bevacizumab work in treating patients with RAS wild-type colorectal cancer that has spread to other places in the body and cannot be removed by surgery. Irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab and bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving irinotecan and cetuximab with or without bevacizumab may work betting in treating patients with colorectal cancer.

Further Study Information

PRIMARY OBJECTIVES:

I. To assess and compare the progression-free survival (PFS) of patients receiving irinotecan, cetuximab, and bevacizumab with patients receiving irinotecan, cetuximab and placebo, in the population of patients with RAS wild-type, irinotecan-refractory metastatic colorectal cancer (mCRC) who also previously received bevacizumab in at least one prior line therapy.

SECONDARY OBJECTIVES:

I. To assess the adverse event (AE) profile and safety of the proposed treatment in this population.

II. To assess and compare the overall survival (OS) between treatment arms in this population.

III. To assess and compare the disease control rate (DCR) between treatment arms in this population.

IV. To assess and compare the overall response rate (ORR) between treatment arms in this population.

V. To assess and compare the duration of response between treatment arms in this population.

VI. To assess and compare time to treatment failure between treatment arms in this population.

VII. To assess relative dose intensity of treatment agents between treatment arms in this population.

TERTIARY OBJECTIVES:

I. Determine the change in genotype concentrations of prespecified gene mutations in circulating cell-free deoxyribonucleic acid (DNA) (cfDNA) collected serially during protocol treatment.

II. Explore the predictive value of pretreatment mutation status for cetuximab sensitivity and resistance.

III. Explore the predictive value of dynamic changes in mutation status for cetuximab sensitivity and resistance.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cetuximab intravenously (IV) over 90-120 minutes, bevacizumab IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 90-120 minutes, placebo IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 3 years.

Eligibility Criteria

Inclusion Criteria:

Metastatic or locally advanced (unresectable) colorectal cancer with histological confirmation of adenocarcinoma

Measurable disease

RAS wild-type tumor; Note: evidence of EGFR expression in the tumor is not required

Previous failure of at least one fluoropyrimidine- and irinotecan-containing chemotherapy regimen for metastatic disease; Note: previous failure is defined as disease progression while receiving treatment or within 6 weeks after the last dose of irinotecan; failure for this assessment is defined as any enlargement of measurable or assessable lesion(s) or the development of any new lesion; a rising tumor marker alone is not sufficient to define failure; patients can have received irinotecan in any previous line of therapy

Treatment with bevacizumab in at least one prior line of therapy for metastatic disease

Negative serum or urine pregnancy test done =< 7 days prior to registration, for women of childbearing potential only; Note: childbearing potential is defined as a female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not postmenopausal (defined as amenorrhea >= 12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level > 35 mIU/mL); women who are using oral, implanted, or injectable contraceptive hormones or mechanical products such as intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of childbearing potential

Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1

Total serum bilirubin =< institutional upper limit of normal (ULN)

Absolute neutrophil count (ANC) >= 1500/mm^3

Platelet count >= 100,000/mm^3

Hemoglobin >= 9.0 g/dL (hemoglobin may be supported by transfusion)

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)

Creatinine within institutional limits of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

Urinary protein =< 1+

Patients discovered to have >= 2+ proteinuria must have a spot urine protein:creatinine ratio (UPCR) < 1.0

Partial thromboplastin time (PTT) =< 1 x institutional ULN and international normalized ratio (INR) =< 1.5, unless participant is on full dose anticoagulation therapy; patients on full-dose anticoagulation are eligible if the following criteria are met:

Patient has an in-range INR (usually 2-3) on a stable dose of warfarin =< 14 days or is on a stable dose of low molecular weight heparin

Patient has no active bleeding or pathological condition that carries a high risk of bleeding (i.e., tumor involving major vessels or known varices)

Patients receiving anti-platelet agents are eligible; in addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible

Life expectancy > 3 months

Provide informed written consent

Willing to provide tissue and blood samples for mandatory correlative and research purposes

Any major surgery or open biopsy completed >= 4 weeks prior to randomization

Any minor surgery or core biopsy completed >= 1 week prior to randomization and patient must have fully recovered from the procedure; Note: insertion of a vascular access device is not considered major or minor surgery

Exclusion Criteria:

Presence of any RAS mutation

Patients with mutations in exons 2, 3, or 4 of KRAS and/or NRAS are excluded

Prior treatment with cetuximab or panitumumab

Prior intolerance to irinotecan and/or bevacizumab despite dose reduction

Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis; Note: participants with brain or CNS metastases are excluded from this clinical trial

Active, uncontrolled infection, including hepatitis B, hepatitis C

Concurrent anti-cancer therapy, including chemotherapy agents, targeted agents, or biological agents not otherwise specified in this protocol

Anti-cancer therapy =< 14 days prior to randomization

Prior radiotherapy to > 25% of bone marrow; Note: standard rectal cancer chemoradiation will not exclude subject from study protocol

Radiation therapy =< 2 weeks prior to randomization

Any of the following:

Pregnant women

Nursing women

Men or women of childbearing potential who are unwilling to employ adequate contraception

Co-morbid systemic illnesses or other severe concurrent disease, history of any psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

Patients known to be human immunodeficiency virus (HIV) positive; Note: HIV-positive individuals on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, symptomatic pulmonary fibrosis or interstitial pneumonitis, or psychiatric illness/social situations that, in the opinion of the investigator, may increase the risks associated with study participation or study treatment, or may interfere with the conduct of the study or the interpretation of the study results

Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanoma skin cancer, prostatic intraepithelial neoplasia without evidence of prostate cancer, lobular carcinoma in situ in one breast, or carcinoma-in-situ of the cervix that has been treated

History of prior malignancy for which patient is receiving other specific treatment for their cancer

History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, cetuximab, and/or bevacizumab that led to discontinuation of those agents

Significant history of bleeding events or pre-existing bleeding diathesis =< 6 months of randomization (unless the source of bleeding has been resected)

History of gastrointestinal perforation =< 12 months prior to randomization

Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of > 3 loose stools daily in subjects without a colostomy or ileostomy; subjects with a colostomy or ileostomy may be entered at investigator discretion

Arterial thrombotic events =< 6 months prior to randomization; Note: this includes transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI)

Clinically significant peripheral artery disease (e.g., claudication with < 1 block) or any other arterial thrombotic event

Serious or non-healing wound, ulcer, or bone fracture

History of hypertension not well-controlled (>= 160/90) even though on a regimen of anti-hypertensive therapy

Evidence of Gilbert’s syndrome or known homozygosity for the UGT1A1*28 allele (special screening not required)

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Academic and Community Cancer Research United

  • National Cancer Institute
Kimmie Ng, Principal Investigator

Trial Sites

U.S.A.

Iowa
Sioux City

Siouxland Regional Cancer Center

Donald B. Wender
Ph: 712-252-0088
Email: drednew@msn.com

Donald B. Wender
Principal Investigator

Kansas
Wichita

Cancer Center of Kansas - Wichita

Shaker R. Dakhil
Ph: 316-262-4467
Email: shaker.dakhil@cancercenterofkansas.com

Shaker R. Dakhil
Principal Investigator

Massachusetts
Boston

Dana-Farber Cancer Institute

Kimmie Ng
Ph: 617-632-4150
Email: Kimmie_Ng@dfci.harvard.edu

Kimmie Ng
Principal Investigator

Michigan
Ann Arbor

Michigan Cancer Research Consortium NCORP

Philip J. Stella
Ph: 734-712-5674
Email: philip.stella@stjoeshealth.org

Philip J. Stella
Principal Investigator

New Hampshire
Hooksett

New Hampshire Oncology Hematology PA-Hooksett

Douglas J. Weckstein
Ph: 603-622-6484
Email: dweckstein@nhoh.com

Douglas J. Weckstein
Principal Investigator

Wisconsin
Green Bay

Saint Vincent Regional Cancer Center CCOP

Anthony John Jaslowski
Ph: 920-884-3135
Email: tjaslowski@gboncology.com

Anthony John Jaslowski
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifier NCT02292758

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.