Colorectal Cancer
Conditions
Keywords
mucinous adenocarcinoma of the colon, recurrent colon cancer, signet ring adenocarcinoma of the colon, stage III colon cancer, stage IV colon cancer, mucinous adenocarcinoma of the rectum, recurrent rectal cancer, signet ring adenocarcinoma of the rectum, stage III rectal cancer, stage IV rectal cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and ramucirumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab and ramucirumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet know whether giving cetuximab and irinotecan hydrochloride together is more effective with or without ramucirumab in treating colorectal cancer. PURPOSE: This randomized phase II trial is studying the side effects and how well giving cetuximab and irinotecan hydrochloride with or without ramucirumab work in treating patients with advanced colorectal cancer with progressive disease after treatment with bevacizumab-containing chemotherapy.
Detailed description
OBJECTIVES: * To evaluate the progression-free survival of patients with advanced K-ras wild-type colorectal cancer, following progression on bevacizumab-contained chemotherapy, treated with irinotecan hydrochloride and cetuximab with versus without ramucirumab as second-line therapy. * To evaluate the response rate in patients treated with these regimens. * To evaluate the grade 3-4 toxicity rates of these regimens in these patients. * To evaluate the overall survival of patients treated with these regimens. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to performance status (0 vs 1), discontinuation of oxaliplatin before disease progression (yes vs no), and time to disease progression since last treatment (≤ 6 months vs \> 6 months). Patients are randomized to 1 of 2 treatment arms. * Arm A: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride over 60-90 minutes on day 1. * Arm B: Patients receive ramucirumab IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Arm B was closed early due to excessive toxicities and Arm C was then added to the study with reduced dose of protocol drugs. * Arm C: Patients receive reduced dose of ramucirumab, cetuximab and irinotecan hydrochloride as in arm B. In all arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up periodically for 5 years.
Interventions
BIOLOGICALcetuximab
Given IV
BIOLOGICALramucirumab
Given IV
DRUGirinotecan hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Measurable disease * Histologically confirmed adenocarcinoma of the colon or rectum * K-ras wild type based on either primary or metastatic tumor * Must have received prior first-line therapy comprising oxaliplatin-based fluoropyrimidine-containing chemotherapy and bevacizumab for metastatic colorectal cancer * Registration within 42 days since confirmed disease progression * Performance status 0-1 * ANC ≥ 1,500/μL * Platelet count ≥ 75,000/μL * Hemoglobin ≥ 9 g/dL * Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 40 mL/min * Urine protein ≤ 1+ on dipstick or routine urinalysis (if ≥ 2+, a 24-hour urine collection must demonstrate \< 1,000 mg of protein) * Total bilirubin ≤ 2.0 mg/dL * AST and ALT ≤ 3.0 times ULN (5.0 times ULN for patients with liver metastases) * INR ≤ 1.6 (≤ 3.0 for patients on warfarin and no active bleeding \[i.e., no bleeding within the past 14 days\]) * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after completion of study therapy * At least 28 days and no more than 90 days since prior bevacizumab * Concurrent stable dose of oral anticoagulant or low-molecular weight heparin allowed
Exclusion criteria
* Brain or CNS metastases * Pregnant or nursing * Prior therapy with drugs other than oxaliplatin and a fluoropyrimidine plus bevacizumab for colorectal cancer * Clinically significant (equivalent to NCI CTCAE grade 3-4) bleeding episodes within the past 3 months * Active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Symptomatic or poorly controlled cardiac arrhythmia * Uncontrolled thrombotic or hemorrhagic disorder * Uncontrolled or poorly controlled hypertension despite standard medical management (e.g., consistently systolic BP \> 160 mm Hg and diastolic BP \> 90 mm Hg) * Acute arterial thrombotic events within the past 6 months, including cerebrovascular accident, transient ischemic attack, myocardial infarction, or unstable angina * Other cancer requiring therapy within the past 3 years except in situ carcinoma or nonmelanoma skin cancer * Acute or subacute intestinal obstruction * History of inflammatory bowel disease requiring pharmacological and/or surgical intervention within the past 12 months * Known allergy to any of the treatment components * Major surgery within the past 28 days * Subcutaneous venous access device placement within the past 7 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years | Progression-fee survival is defined as the time from randomization to disease progression or death without documentation of progression. Censoring occurred at the date of last disease assessment without progression for cases without documentation of progression, except for cases where death occurred within a short period of time (4 months) following the date last known progression-free, in which case the death was considered an event. Progression is defined as appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With an Objective Response Rate (CR or PR) | Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years | Objective response is defined as either complete response or partial response. Complete response is defined as disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Proportion of Patients With Grade 3 or Higher Treatment-related Adverse Events | Assessed every 2 weeks while on treatment and for 30 days after the end of treatment | Adverse events were assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE). Treatment-related adverse events are defined as those that are possibly, probably, or definitely related to protocol therapy. |
| Overall Survival | Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years | Overall survival is defined as the time from randomization to death or date last known alive. |
Countries
United States
Participant flow
Recruitment details
The first patient was accrued on January 18, 2011.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (IC) Patients receive cetuximab (500 mg/m\^2) intravenously (IV) over 60-120 minutes and irinotecan hydrochloride (180 mg/m\^2) over 60-90 minutes on day 1. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities. | 62 |
| Arm B (ICR) Patients receive ramucirumab (8 mg/kg) IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities. | 16 |
| Arm C (mICR) Patients receive reduced dose of ramucirumab (6 mg/kg) IV over 60 minutes on day 1 and cetuximab (150 mg/m\^2) and irinotecan hydrochloride (400 mg/m\^2) as in arm B. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities. | 45 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 5 | 7 |
| Overall Study | Alternative therapy | 2 | 0 | 2 |
| Overall Study | Death | 2 | 0 | 2 |
| Overall Study | Disease progression | 43 | 7 | 31 |
| Overall Study | Error made in lesion measurement | 1 | 0 | 0 |
| Overall Study | Never started treatment | 1 | 0 | 2 |
| Overall Study | Patient had surgery | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Treatment cycle delay | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 4 | 4 |
Baseline characteristics
| Characteristic | Arm A (IC) | Arm B (ICR) | Arm C (mICR) | Total |
|---|---|---|---|---|
| Age, Continuous | 59.8 years | 60.0 years | 60.4 years | 60.3 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 13 Participants | 38 Participants | 105 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 1 Participants | 3 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 47 Participants | 15 Participants | 37 Participants | 99 Participants |
| Sex: Female, Male Female | 25 Participants | 7 Participants | 13 Participants | 45 Participants |
| Sex: Female, Male Male | 37 Participants | 9 Participants | 32 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 55 / 70 | 15 / 16 | 43 / 50 |
| other Total, other adverse events | 64 / 68 | 16 / 16 | 46 / 48 |
| serious Total, serious adverse events | 33 / 68 | 13 / 16 | 27 / 48 |
Outcome results
Primary
Progression-free Survival
Progression-fee survival is defined as the time from randomization to disease progression or death without documentation of progression. Censoring occurred at the date of last disease assessment without progression for cases without documentation of progression, except for cases where death occurred within a short period of time (4 months) following the date last known progression-free, in which case the death was considered an event. Progression is defined as appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years
Population: Only eligible patients are included in this analysis. For the comparison between arms A and C, only eligible patients that were concurrently randomized were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (IC) | Progression-free Survival | 5.98 months |
| Arm B (ICR) | Progression-free Survival | 7.03 months |
| Arm C (mICR) | Progression-free Survival | 9.20 months |
Secondary
Overall Survival
Overall survival is defined as the time from randomization to death or date last known alive.
Time frame: Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years
Population: Only eligible patients are included in this analysis. For the comparison between arms A and C, only eligible patients that were concurrently randomized were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (IC) | Overall Survival | 19.3 months |
| Arm B (ICR) | Overall Survival | 15.0 months |
| Arm C (mICR) | Overall Survival | 19.2 months |
p-value: 0.55Log Rank
Secondary
Proportion of Participants With an Objective Response Rate (CR or PR)
Objective response is defined as either complete response or partial response. Complete response is defined as disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years
Population: Only eligible patients are included in this analysis. For the comparison between arms A and C, only eligible patients that were concurrently randomized were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (IC) | Proportion of Participants With an Objective Response Rate (CR or PR) | 0.23 proportion of participants |
| Arm B (ICR) | Proportion of Participants With an Objective Response Rate (CR or PR) | 0.44 proportion of participants |
| Arm C (mICR) | Proportion of Participants With an Objective Response Rate (CR or PR) | 0.36 proportion of participants |
p-value: 0.27Chi-squared
Secondary
Proportion of Patients With Grade 3 or Higher Treatment-related Adverse Events
Adverse events were assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE). Treatment-related adverse events are defined as those that are possibly, probably, or definitely related to protocol therapy.
Time frame: Assessed every 2 weeks while on treatment and for 30 days after the end of treatment
Population: All patients who received protocol therapy and had toxicity data were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (IC) | Proportion of Patients With Grade 3 or Higher Treatment-related Adverse Events | 0.49 proportion of participants |
| Arm B (ICR) | Proportion of Patients With Grade 3 or Higher Treatment-related Adverse Events | 0.81 proportion of participants |
| Arm C (mICR) | Proportion of Patients With Grade 3 or Higher Treatment-related Adverse Events | 0.56 proportion of participants |