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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| ClinicalTrials.gov Identifier: NCT02292758 |
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Recruitment Status :
Completed
First Posted : November 17, 2014
Results First Posted : February 28, 2020
Last Update Posted : January 31, 2022
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Sponsor:
Academic and Community Cancer Research United
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United
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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 (locally advanced/metastatic) and cannot be removed by surgery. Irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab and bevacizumab, may help the body?s immune system attack the cancer, and 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 |
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.
CORRELATIVE 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. Cycles 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. Cycles 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 2 years.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 36 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 |
| Actual Primary Completion Date : | March 20, 2019 |
| Actual Study Completion Date : | September 27, 2019 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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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. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
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Biological: Bevacizumab
Given IV
Other Names:
Biological: Cetuximab Given IV
Other Names:
Drug: Irinotecan Given IV Other: Laboratory Biomarker Analysis Correlative studies |
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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. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
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Biological: Cetuximab
Given IV
Other Names:
Drug: Irinotecan Given IV Other: Laboratory Biomarker Analysis Correlative studies Other: Placebo Given IV
Other Names:
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Primary Outcome Measures :
- 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 24 months ]The distribution of PFS by group will be estimated using the method of Kaplan-Meier. Median 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. Progression (PD) is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD: Any new lesion or increase by ≥50% of previously involved sites from nadir).
- 6-month and 12-month Progression-free Survival (PFS) Rates [ 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 24 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. Progression (PD) is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD: Any new lesion or increase by ≥50% of previously involved sites from nadir).
Secondary Outcome Measures :
- Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Events [ Time Frame: Up to 30 days from last dose of study treatment ]The number of participants who experienced at least one grade 3 or higher adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
- 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. Median OS 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.
- 12-month, 18-month, and 24-month Overall Survival (OS) Rates [ 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.
- Disease Control Rate (DCR) [ Time Frame: Up to 2 years ]Disease control is defined as maintaining Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) as the tumor assessment result during the defined time window. DCR (percentage) is defined as number of patients with success of disease control divided by total number of patients in the analysis population multiplied by 100, excluding patients who refuse treatment before the initiation of any treatment. CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by ≥50% of previously involved sites from nadir, SD: Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD
- Overall Response Rate (ORR) [ Time Frame: Up to 2 years ]The response rate (percentage) is the percent of participants whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. Response rates (including complete and partial response) will be tested using Fisher's exact test. CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites
- 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.CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by ≥50% of previously involved sites from nadir
- Percentage of Participants With Treatment Failure at 6 Months [ Time Frame: assessed at 6 months ]TTF is defined as the time from the date of randomization to the date of treatment discontinuation due to PD, death, or severe AE. 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. PD: Any new lesion or increase by ≥50% of previously involved sites from nadir
- Relative Dose Intensity (RDI) [ Time Frame: Up to 2 years ]RDI is defined as the total dose of protocol therapy a patient actually received (i.e., summation of actually received dose at each cycle) divided by the total planned dose (i.e., summation of planned dose level at each cycle) multiplied by 100. Separate RDIs will be calculated for irinotecan and cetuximab. Agent-specific RDI will be summarized by medians, and min and max values, all of which will be compared between the two treatment groups by the Wilcoxon Rank sum test.
Other Outcome Measures:
- Change in Genotype Concentrations of Prespecified Gene Mutations in Circulating Cell-free Deoxyribonucleic Acid (DNA) (cfDNA) [ Time Frame: Baseline up to 2 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.
- Dynamic Change in Mutation Concentration While the Patient is Receiving Cetuximab Treatment [ Time Frame: Baseline up to 2 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
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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
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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
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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
| United States, Arizona | |
| Mayo Clinic in Arizona | |
| Scottsdale, Arizona, United States, 85259 | |
| United States, Idaho | |
| Saint Luke's Mountain States Tumor Institute | |
| Boise, Idaho, United States, 83712 | |
| 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
| Principal Investigator: | Kimmie Ng | Academic and Community Cancer Research United |
Study Documents (Full-Text)
Documents provided by Academic and Community Cancer Research United:
Documents provided by Academic and Community Cancer Research United:
Study Protocol and Statistical Analysis Plan [PDF] May 24, 2019
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Academic and Community Cancer Research United |
| ClinicalTrials.gov Identifier: | NCT02292758 |
| 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 |
| Results First Posted: | February 28, 2020 |
| Last Update Posted: | January 31, 2022 |
| Last Verified: | August 2019 |
Additional relevant MeSH terms:
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Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Rectal Diseases 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 Growth Inhibitors Immunologic Factors Topoisomerase I Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors |