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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02292758
Recruitment Status : Active, not recruiting
First Posted : November 17, 2014
Last Update Posted : March 13, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief 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.

Condition or disease Intervention/treatment Phase
Colorectal Adenocarcinoma RAS Wild Type Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7 Biological: Bevacizumab Biological: Cetuximab Drug: Irinotecan Other: Laboratory Biomarker Analysis Other: Placebo Phase 2

Detailed Description:

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, germline single nucleotide polymorphisms (SNPs), and gene expression signatures for cetuximab sensitivity and resistance.

III. Explore the predictive value of dynamic changes in mutation status and gene expression signatures 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: BOND-3: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Irinotecan, Cetuximab, and Bevacizumab Compared With Irinotecan, Cetuximab, and Placebo in RAS-Wildtype, Irinotecan-Refractory, Metastatic Colorectal Cancer
Actual Study Start Date : December 12, 2014
Estimated Primary Completion Date : June 1, 2019
Estimated Study Completion Date : December 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (cetuximab, bevacizumab, irinotecan)
Patients receive cetuximab 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.
Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Biological: Cetuximab
Given IV
Other Names:
  • Chimeric Anti-EGFR Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
  • Erbitux
  • IMC-C225

Drug: Irinotecan
Given IV

Other: Laboratory Biomarker Analysis
Correlative studies

Active Comparator: Arm II (cetuximab, placebo, irinotecan)
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.
Biological: Cetuximab
Given IV
Other Names:
  • Chimeric Anti-EGFR Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
  • Erbitux
  • IMC-C225

Drug: Irinotecan
Given IV

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given IV
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From the date of randomization to the date of 1st documented disease progression or death due to any cause, whichever occurs first, assessed up to 12 months ]
    The distribution of PFS by group will be estimated using the method of Kaplan-Meier. Six and 12 month PFS rates by treatment group with confidence intervals will be estimated based on Kaplan-Meier curves. The hazard ratio (HR) with confidence interval will be estimated based on stratified Cox models (stratified by levels of stratification factors), without and with adjusting for baseline clinical/pathological factors.


Secondary Outcome Measures :
  1. Disease control rate (DCR) maintaining complete response (CR) or partial response (PR) or stable disease [ Time Frame: Up to 3 years ]
    Will be compared between two treatment groups using Chi-square test (or Fisher?s exact test if the data in the contingency table is sparse). Logistic regression models will be used to estimate the odds ratio (OR) and confidence interval without and with adjusting for baseline clinical/pathological factors.

  2. Duration of response (DOR) [ Time Frame: From the date of first tumor assessment with the response status being CR or PR to the date of 1st documented progressive disease, assessed up to 12 months ]
    The distribution of DOR by treatment group will be estimated using the method of Kaplan-Meier. Six and 12 month durable response (i.e. maintaining CR or PR without progressive disease [PD]) rates by treatment group with confidence intervals will be estimated based on Kaplan-Meier curves. The HR with confidence interval will be estimated based on stratified Cox models (stratified by levels of stratification factors), without and with adjusting for baseline clinical/pathological factors.

  3. Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days from last dose of study treatment ]
    The maximum grade of each adverse event and its attribution will be recorded for each patient. The frequency tables will be reviewed to evaluate for patterns of toxicity. The overall adverse event rates for grade 3 or higher adverse events will be compared between the two treatment groups using Chi-square test (or Fisher?s exact test if the data in the contingency table is sparse).

  4. Overall response rate (ORR) defined as achieving complete response (CR) or partial response (PR) [ Time Frame: Up to 3 years ]
    Will be compared between the two treatment groups using Chi-square test (or Fisher?s exact test if the data in the contingency table is sparse). Logistic regression models will be used to estimate the odds ratio (OR) and confidence interval without and with adjusting for baseline clinical/pathological factors.

  5. Overall survival (OS) [ Time Frame: From randomization to the date of death due to any cause, assessed up to 24 months ]
    The distribution of OS by group will be estimated using the method of Kaplan-Meier. Twelve, 18- and 24-month survival rates by treatment group with confidence intervals will be estimated based on Kaplan-Meier curves. The HR with confidence interval will be estimated based on stratified Cox models (stratified by levels of stratification factors), without and with adjusting for baseline clinical/pathological factors.

  6. Relative dose intensity (RDI) [ Time Frame: Up to 3 years ]
    Separate RDIs will be calculated for irinotecan and cetuximab. Agent-specific RDI will be summarized by means, 25th percentiles, medians, 75th percentiles, and min and max values, all of which will be compared between the two treatment groups by the Wilcoxon Rank sum test.

  7. Time to treatment failure (TTF) [ Time Frame: Time from the date of randomization to the date of treatment discontinuation due to PD, death, or severe AE, assessed at 6 months ]
    The distribution of TTF by treatment group will be estimated using the method of Kaplan-Meier. Six month event-free rates by treatment group with confidence intervals will be estimated based on Kaplan-Meier curves. The HR with confidence interval will be estimated based on stratified Cox models (stratified by levels of stratification factors), without and with adjusting for baseline clinical/pathological factors.


Other Outcome Measures:
  1. Change in genotype concentrations of prespecified gene mutations in circulating cell-free deoxyribonucleic acid (DNA) (cfDNA) [ Time Frame: Baseline up to 3 years ]
    The mean and median change in mutation concentration for each prespecified gene, and provide the corresponding 95% confidence intervals will be estimated. Cox proportional hazards models will be applied to explore the predictive value of pretreatment mutation status for cetuximab sensitivity and resistance, using PFS and OS as the outcome variables.

  2. Dynamic change in mutation concentration while the patient is receiving cetuximab treatment [ Time Frame: Baseline up to 3 years ]
    Scatter plots and box plots will be used to illustrate such change.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1
  • Total serum bilirubin =< institutional upper limit of normal (ULN) obtained =<14 days prior to randomization
  • Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =<14 days prior to randomization
  • Platelet count >= 100,000/mm^3 obtained =<14 days prior to randomization
  • Hemoglobin >= 9.0 g/dL (hemoglobin may be supported by transfusion) obtained =<14 days prior to randomization
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) obtained =<14 days prior to randomization
  • Creatinine within institutional limits of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal obtained =<14 days prior to randomization
  • Urinary protein =< 1+ obtained =<14 days prior to randomization

    • 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 obtained =<14 days prior to randomization; 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 or other anticoagulant =< 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 blood samples for mandatory correlative and research purposes
  • Willing to provide tissue and blood samples for mandatory banking 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 a RAS mutation in exons 2, 3, or 4 of KRAS or NRAS (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
  • 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
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02292758


Locations
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United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, Iowa
Siouxland Regional Cancer Center
Sioux City, Iowa, United States, 51101
United States, Kansas
Cancer Center of Kansas - Wichita
Wichita, Kansas, United States, 67214
United States, Louisiana
Ochsner Medical Center Jefferson
New Orleans, Louisiana, United States, 70121
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Michigan Cancer Research Consortium NCORP
Ann Arbor, Michigan, United States, 48106
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Heartland Regional Medical Center
Saint Joseph, Missouri, United States, 64507
Missouri Baptist Medical Center
Saint Louis, Missouri, United States, 63131
United States, New Hampshire
New Hampshire Oncology Hematology PA-Hooksett
Hooksett, New Hampshire, United States, 03106
United States, New York
State University of New York Upstate Medical University
Syracuse, New York, United States, 13210
United States, Wisconsin
Saint Vincent Regional Cancer Center CCOP
Green Bay, Wisconsin, United States, 54301
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kimmie Ng Academic and Community Cancer Research United

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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT02292758     History of Changes
Other Study ID Numbers: RU021302I
NCI-2016-02063 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RU021302I ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: November 17, 2014    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: February 2018

Additional relevant MeSH terms:
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Colorectal Neoplasms
Colonic Neoplasms
Adenocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Bevacizumab
Antineoplastic Agents, Immunological
Cetuximab
Irinotecan
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs