Colorectal Adenocarcinoma, RAS Wild Type, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7, Stage IV Colorectal Cancer AJCC v7
Conditions
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.
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. 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.
Interventions
BIOLOGICALBevacizumab
Given IV
BIOLOGICALCetuximab
Given IV
DRUGIrinotecan
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo
Given IV
Sponsors
National Cancer Institute (NCI)
Academic and Community Cancer Research United
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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 | 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) | 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 |
| Relative Dose Intensity (RDI) | 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. |
| Duration of Response (DOR) | 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 | 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 |
| Overall Response Rate (ORR) | 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 |
| Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Events | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Genotype Concentrations of Prespecified Gene Mutations in Circulating Cell-free Deoxyribonucleic Acid (DNA) (cfDNA) | 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 | Baseline up to 2 years | Scatter plots and box plots will be used to illustrate such change. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) Patients receive 500 mg/m\^2 cetuximab IV over 90-120 minutes, 5 mg/kg bevacizumab IV over 30-90 minutes, and 180 mg/m\^2 irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 19 |
| Arm II (Irinotecan, Cetuximab, Placebo) Patients receive 500 mg/m\^2 cetuximab IV over 90-120 minutes, 5 mg/kg placebo IV over 30-90 minutes, and 180 mg/m\^2 irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 17 |
| Total | 36 |
Baseline characteristics
| Characteristic | Arm II (Irinotecan, Cetuximab, Placebo) | Total | Arm I (Irinotecan, Cetuximab, Bevacizumab) |
|---|---|---|---|
| Age, Continuous | 54 years | 55 years | 58 years |
| ECOG Performance Status 0 | 12 Participants | 26 Participants | 14 Participants |
| ECOG Performance Status 1 | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 15 Participants | 30 Participants | 15 Participants |
| Sex: Female, Male Female | 7 Participants | 16 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 19 | 17 / 17 |
| other Total, other adverse events | 19 / 19 | 17 / 17 |
| serious Total, serious adverse events | 5 / 19 | 5 / 17 |
Outcome results
Primary
6-month and 12-month Progression-free Survival (PFS) Rates
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).
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | 6-month and 12-month Progression-free Survival (PFS) Rates | 6-month PFS rate | 76.5 percentage of participants |
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | 6-month and 12-month Progression-free Survival (PFS) Rates | 12-month PFS rate | 27.5 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | 6-month and 12-month Progression-free Survival (PFS) Rates | 6-month PFS rate | 41.2 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | 6-month and 12-month Progression-free Survival (PFS) Rates | 12-month PFS rate | 17.6 percentage of participants |
Primary
Progression-Free Survival (PFS)
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).
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Progression-Free Survival (PFS) | 9.7 months |
| Arm II (Irinotecan, Cetuximab, Placebo) | Progression-Free Survival (PFS) | 5.5 months |
p-value: 0.760995% CI: [0.431, 1.93]Log Rank
95% CI: [0.249, 1.656]
Secondary
12-month, 18-month, and 24-month Overall Survival (OS) Rates
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.
Time frame: From randomization to the date of death due to any cause, assessed up to 24 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | 12-month, 18-month, and 24-month Overall Survival (OS) Rates | 12-month OS rate | 77.2 percentage of participants |
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | 12-month, 18-month, and 24-month Overall Survival (OS) Rates | 18-month OS rate | 56.1 percentage of participants |
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | 12-month, 18-month, and 24-month Overall Survival (OS) Rates | 24-month OS rate | 14.0 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | 12-month, 18-month, and 24-month Overall Survival (OS) Rates | 24-month OS rate | 5.9 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | 12-month, 18-month, and 24-month Overall Survival (OS) Rates | 12-month OS rate | 47.1 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | 12-month, 18-month, and 24-month Overall Survival (OS) Rates | 18-month OS rate | 11.8 percentage of participants |
Secondary
Disease Control Rate (DCR)
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
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Disease Control Rate (DCR) | 68.4 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | Disease Control Rate (DCR) | 52.9 percentage of participants |
p-value: 0.3415Chi-squared
Secondary
Duration of Response (DOR)
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
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
Population: Participants who responded to treatment (CR or PR) are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Duration of Response (DOR) | 9.2 months |
| Arm II (Irinotecan, Cetuximab, Placebo) | Duration of Response (DOR) | 9.7 months |
p-value: 0.447Log Rank
Secondary
Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Events
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.
Time frame: Up to 30 days from last dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Events | 9 Participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Events | 6 Participants |
Secondary
Overall Response Rate (ORR)
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
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Overall Response Rate (ORR) | 36.8 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | Overall Response Rate (ORR) | 11.8 percentage of participants |
p-value: 0.1279Fisher Exact
Secondary
Overall Survival (OS)
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.
Time frame: From randomization to the date of death due to any cause, assessed up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Overall Survival (OS) | 19.7 months |
| Arm II (Irinotecan, Cetuximab, Placebo) | Overall Survival (OS) | 10.2 months |
p-value: 0.044695% CI: [0.209, 1.062]Log Rank
95% CI: [0.151, 1.089]
Secondary
Percentage of Participants With Treatment Failure 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
Time frame: assessed at 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Percentage of Participants With Treatment Failure at 6 Months | 72.7 percentage of participants |
| Arm II (Irinotecan, Cetuximab, Placebo) | Percentage of Participants With Treatment Failure at 6 Months | 38.4 percentage of participants |
p-value: 0.373895% CI: [0.345, 1.655]Log Rank
Secondary
Relative Dose Intensity (RDI)
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.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Relative Dose Intensity (RDI) | Cetuximab | 98.5 percentage of dose received |
| Arm I (Irinotecan, Cetuximab, Bevacizumab) | Relative Dose Intensity (RDI) | Irinotecan | 89 percentage of dose received |
| Arm II (Irinotecan, Cetuximab, Placebo) | Relative Dose Intensity (RDI) | Cetuximab | 95.5 percentage of dose received |
| Arm II (Irinotecan, Cetuximab, Placebo) | Relative Dose Intensity (RDI) | Irinotecan | 90 percentage of dose received |
Comparison: Cetuximab comparisonp-value: 0.4283Wilcoxon (Mann-Whitney)
Comparison: Irinotecan comparisonp-value: 0.5262Wilcoxon (Mann-Whitney)
Other Pre-specified
Change in Genotype Concentrations of Prespecified Gene Mutations in Circulating Cell-free Deoxyribonucleic Acid (DNA) (cfDNA)
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.
Time frame: Baseline up to 2 years
Other Pre-specified
Dynamic Change in Mutation Concentration While the Patient is Receiving Cetuximab Treatment
Scatter plots and box plots will be used to illustrate such change.
Time frame: Baseline up to 2 years