Metastatic Colorectal Cancer
Conditions
Brief summary
The purpose of this study is to compare the rates of Progression-Free Survival (PFS) at 12 months for patients treated with Bev-FOLFOX versus patients treated with FOLF-CB for first line treatment of metastatic colorectal cancer.
Detailed description
This is a Phase III, open label, nonblinded study. A total of 240 eligible patients will be randomized on a 1:1 basis to either treatment Arm. In this trial, we will compare the efficacy, safety, and tolerability of this novel combination of biweekly infusional 5-FU/leucovorin plus cetuximab and bevacizumab (FOLF-CB) to the current standard of care, biweekly infusional 5-FU/leucovorin plus oxaliplatin and bevacizumab (Bev-FOLFOX). For practical purposes, this study will be a head to head comparison of oxaliplatin versus cetuximab, since the other components of both regimens will be the same.
Interventions
DRUGBevacizumab
5 mg/kg over 30 minutes on Days 1 and 15
DRUGOxaliplatin
85 mg/m2 on Days 1 and 15
DRUGLeucovorin
400 mg/m2 on Days 1 and 15
DRUGFluorouracil
400 mg/m2, IV bolus followed by: 1200 mg/m2/day via 24-hour continuous infusion, for 2 consecutive days (total 5-FU infusion dose = 2400 mg/m2 over the 48 hour period)
DRUGCetuximab
400 mg/m2 over 2 hours (Cycle 1 Day 1 only) All subsequent doses (Day 8, 15, 22 of Cycle 1 and Days 1, 8, 15, 22 other cycles)250 mg/m2 over 1 hour
Sponsors
Bristol-Myers Squibb
Memorial Sloan Kettering Cancer Center
Prologue Research International
US Oncology Research
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
* Histologically or cytologically confirmed colorectal cancer with metastatic disease * Measurable disease * Previously irradiated lesions will be considered evaluable, if they progressed since radiation * Has disease other than limited to surgically resectable liver-only or lung-only metastatic disease * Not received prior chemo and/or biotherapy for metastatic disease * Not received oxaliplatin, bevacizumab, or cetuximab in the adjuvant setting * May have received 5-FU, leucovorin, and/or irinotecan in the adjuvant setting, however must have remained free of disease recurrence (including free of abnormal CEA level) for 1- year or more * Is \>18 years of age * ECOG performance status 0 or 1 * Normal organ & marrow function * Use of an acceptable method of birth control * Not pregnant or breast feeding * Paraffin tissue block(s) or 12 (minimum) unstained slides available, for assessment of potential predictive markers related to the EGFR, VEGF, DNA repair, and fluoropyrimidine catabolism pathways. If no block is available, slides (typically 7 to 10 um sections, air dried on uncharged slides) may be sent * Signed a Patient Informed Consent Form * Signed a Patient Authorization Form (HIPAA) Form
Exclusion criteria
* Had prior chemotherapy for metastatic colorectal cancer * Received any prior treatment with oxaliplatin, bevacizumab, or cetuximab in the adjuvant treatment of their colorectal cancer * Currently receiving any other investigational anticancer agents or has participated in an experimental drug study within the past 4 weeks * History of primary CNS tumors, seizures not well-controlled with standard medical therapy, or stroke * Sustained hypertension, as characterized by persistent blood pressures greater than 150/100 despite medical management * New York Heart Association (NYHA) Grade II or greater congestive heart failure or has had angioplasty or placement of coronary stents within the past 6 months * Clinically significant peripheral vascular disease * History of serious allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, cetuximab, oxaliplatin, fluorouracil, leucovorin, or other agents used in the study * Received prior cetuximab or other EGFR-directed therapy, or history of prior anti-cancer murine or chimeric monoclonal antibody therapy; prior humanized and human monoclonal antibody therapy is also excluded. * Received prior treatment with bevacizumab or other agents specifically targeting VEGF or VEGF receptors * Uncontrolled intercurrent illness including, not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements in the opinion of the Investigator/Treating Physician * Serious or non-healing active wound ulcer, or active bone fracture * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of protocol treatment * Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 1 * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1 * Current or recent use of a thrombolytic agent within last 30 days. Use for clearance of central line catheter is permitted. * Evidence of bleeding diathesis (disorder) or clinically significant coagulopathy (Note that deep venous thrombosis is not regarded as a reason for exclusion from this trial) * Hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies * History of arterial thromboembolic events within 6 months * Urine protein:creatinine ratio greater than 1.0 at screening * Pregnant or lactating woman * Known to be HIV positive or receiving combination anti-retroviral therapy * Unable to comply with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | 12 months | From randomization to first progression or death, whichever comes first (event); or first new anti-cancer treatment if before or without progression / death (censoring); or last follow-up date otherwise (censoring). Kaplan-Meier median PFS time and PFS rate (at 12 months) |
| Progression-free Survival (PFS) Rate at 1 Year. | 12 months | From randomization to first progression or death, whichever comes first (event); or first new anti-cancer treatment if before or without progression / death (censoring); or last follow-up date otherwise (censoring). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | up to 4 years | From randomization to death (event); or last follow-up date if alive (censoring). Kaplan-Meier OS median time. |
| Objective Response Rate | 12 months | Percentage of patients with tumor response (by RECIST criteria, including complete response, or CR, i.e. disappearance of all target lesions; and partial response, or PR, i.e. at least a 30% decrease in the sum of the longest diameters of target lesions taking as reference the baseline sum of the longest diameters) among all per-protocol population patients. |
Countries
United States
Participant flow
Recruitment details
A total of 247 patients were recruited from multiple research sites and were randomly assigned to either Arm A or Arm B between December 2005 to June 2007.
Pre-assignment details
The patients were required to be in screening for up to 3 weeks prior to registering the patient for randomization
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Bev-FOLFOX): Bevacizumab, followed by oxaliplatin and LV given simultaneously via T connector over 2 hours, followed by bolus 5-FU followed by infusional 5-FU.
Bevacizumab --\> oxaliplatin and LV --\> bolus 5-FU --\> infusional 5-FU
Dosing on Days 1 and 15 of each 28-day cycle | 124 |
| Arm B (FOLF-CB): Cetuximab administered over 2 hours (first dose only; administer all other doses over 1 hour) followed by bevacizumab over 30 minutes, followed by LV over 30 minutes, followed by bolus 5-FU followed by infusional 5-FU.
Cetuximab --\> bevacizumab --\> LV --\> bolus 5-FU --\> infusional 5-FU | 123 |
| Total | 247 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 13 |
| Overall Study | Death | 0 | 3 |
| Overall Study | Disease Progression | 14 | 20 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Patient Request | 4 | 5 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Unrelated Complication | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Arm B | Total | Arm A |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 56 Participants | 107 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 67 Participants | 140 Participants | 73 Participants |
| Age, Continuous | 63 years STANDARD_DEVIATION 11 | 62 years STANDARD_DEVIATION 12 | 61 years STANDARD_DEVIATION 12 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 30 Participants | 15 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 | 6 Participants | 10 Participants | 4 Participants |
| Race (NIH/OMB) White | 99 Participants | 199 Participants | 100 Participants |
| Region of Enrollment United States | 123 participants | 247 participants | 124 participants |
| Sex: Female, Male Female | 50 Participants | 104 Participants | 54 Participants |
| Sex: Female, Male Male | 73 Participants | 143 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 117 / 118 | 120 / 121 |
| serious Total, serious adverse events | 40 / 118 | 49 / 121 |
Outcome results
Primary
Progression-Free Survival (PFS)
From randomization to first progression or death, whichever comes first (event); or first new anti-cancer treatment if before or without progression / death (censoring); or last follow-up date otherwise (censoring). Kaplan-Meier median PFS time and PFS rate (at 12 months)
Time frame: 12 months
Population: This analysis included all registered (or randomized) patients, i.e. intent-to-treat (ITT) population, regardless of patient's treatment status.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Progression-Free Survival (PFS) | 11.0 months |
| Arm B | Progression-Free Survival (PFS) | 8.3 months |
Primary
Progression-free Survival (PFS) Rate at 1 Year.
From randomization to first progression or death, whichever comes first (event); or first new anti-cancer treatment if before or without progression / death (censoring); or last follow-up date otherwise (censoring).
Time frame: 12 months
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Progression-free Survival (PFS) Rate at 1 Year. | 0.45 proportion of participants w/ PFS at 1yr |
| Arm B | Progression-free Survival (PFS) Rate at 1 Year. | 0.32 proportion of participants w/ PFS at 1yr |
Secondary
Objective Response Rate
Percentage of patients with tumor response (by RECIST criteria, including complete response, or CR, i.e. disappearance of all target lesions; and partial response, or PR, i.e. at least a 30% decrease in the sum of the longest diameters of target lesions taking as reference the baseline sum of the longest diameters) among all per-protocol population patients.
Time frame: 12 months
Population: This analysis included all eligible and treated patients, i.e. per-protocol population. A patient will be considered in the arm he/she is actually treated, not randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Objective Response Rate | 52.1 percentage of participants |
| Arm B | Objective Response Rate | 41.2 percentage of participants |
Secondary
Overall Survival (OS)
From randomization to death (event); or last follow-up date if alive (censoring). Kaplan-Meier OS median time.
Time frame: up to 4 years
Population: ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Overall Survival (OS) | 21.3 Months |
| Arm B | Overall Survival (OS) | 19.5 Months |