Colorectal Neoplasms
Conditions
Brief summary
This randomized, open-label, multicenter study will evaluate the efficacy and safety of folinic acid (leucovorin), 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) / bevacizumab regimens (concurrent and sequential) versus folinic acid (leucovorin), 5-fluorouracil, and oxaliplatin (FOLFOX) / bevacizumab in first-line in participants with metastatic colorectal cancer. Participants will be randomized to receive bevacizumab 5 milligrams per kilogram (mg/kg) intravenously every 2 weeks with either concurrent or sequential FOLFOXIRI or with FOLFOX for 4 to 6 months of induction therapy, followed by maintenance therapy with bevacizumab plus either leucovorin/5-fluorouracil or capecitabine until disease progression occurs. After disease progression, participants will receive treatment with a fluoropyrimidine-based chemotherapy plus bevacizumab.
Interventions
DRUG5-fluorouracil
Participants in Arm A will receive 3200 milligrams per square meter (mg/m\^2) by 48-hour continuous intravenous (IV) infusion every 2 weeks, during the 4-6 months' induction followed by maintenance therapy including bolus dose of 400 mg/m\^2, followed by a 46-hour continuous infusion (2400 mg/m\^2) every 2 weeks per investigator's discretion. Participants in Arm B and C will receive a bolus dose of 400 mg/m\^2, followed by a 46-hour continuous infusion (2400 mg/m\^2) every 2 weeks during the 4-6 months of induction and maintenance per investigator's discretion.
DRUGbevacizumab
Participants will receive 5 mg/kg IV every 2 weeks during the first 4-6 months induction phase, followed by 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks during maintenance therapy, and 2.5 mg/kg per week reinduction after disease progression.
DRUGcapecitabine
Participants will receive 1000 or 850 mg/kg orally twice daily as per investigator's discretion on Day 1 to 14, repeated every 3 weeks in maintenance phase.
DRUGirinotecan
Participants will receive IV infusion of 165 mg/m\^2 over 1 hour every 2 weeks (Arm A) or IV infusion of 180 mg/m\^2 over 1 hour in 2 x 2 weeks cycles alternating months (in Arm B), during 4-6 months induction phase.
DRUGfolinic acid
Participants will receive IV infusion of 200 mg/m\^² (Arm A) or 400 mg/m\^2 (Arm B or C) over 2 hours every 2 weeks, during 4-6 months induction phase followed by IV infusion of 400 mg/m\^2 in the maintenance therapy.
DRUGoxaliplatin
Participants will receive 85 mg/m\^2 over 2 hours as IV infusion every 2 weeks (Arm A, C ) or 2 x 2 week cycles alternating months (Arm B), during 4-6 months induction phase .
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed colorectal cancer with at least one measurable metastatic lesion by RECIST v 1.1, that is considered unresectable at baseline * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 if age less than (\<) 71 years; ECOG status of 0 if age 71 to 75 years * Adequate hematological, renal and liver function * Participants with treated brain metastases are eligible for study participation; participants may not receive ongoing treatment with steroids at screening, anticonvulsants (at stable dose) are allowed * Females of childbearing potential and males must agree to use effective contraception as defined by protocol during the treatment period and for at least 6 months after the last dose of study drug
Exclusion criteria
* Any prior treatment for metastatic colorectal cancer, except for use of palliative radiosensitizers * Adjuvant chemotherapy for colorectal cancer completed \< 12 months prior to study consent * Sensory peripheral neuropathy greater than or equal to (\>/=) Grade 2 * Evidence of Gilbert's Syndrome or homozygosity for the Uridine 5-diphospho-glucuronosyltransferase (UGT) 1A1\*28 allele * Positive for human immunodeficiency virus (HIV) infection * Malignancies other than metastatic colorectal cancer within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent * Radiotherapy to any site for any reason within 28 days prior to randomization, except for palliative radiotherapy to bone lesions within 14 days prior to randomization * Clinically significant third-space fluid collections (e.g. ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry * Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization * Any disease or condition or laboratory finding giving reasonable suspicion of disease or condition that contraindicates the use of bevacizumab or puts the participant at high risk for treatment-related complications * Inadequately controlled hypertension * Clinically significant (that is \[i.e.\] active) cardiovascular disease (For example \[e.g.\] cerebrovascular accident or myocardial infarction within 6 months prior to randomization), unstable angina, congestive heart failure (New York Heart Association Class \>/= II) or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with the administration of the study treatment * Known hypersensitivity to bevacizumab or any of its excipients or any other study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response During First-Line Therapy (ORR1) | Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) | ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to \<10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR |
| Progression-Free Survival During First-Line Therapy (PFS1) | Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) | PFS1 was defined as time from randomization to the first occurrence of disease progression during first-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Underwent Liver Metastases Resections | Randomization up to approximately 3 years | Reported here is the proportion of participants who underwent liver metastases resections calculated as follows: number of participants who underwent liver metastases resections divided by total number of participants in each arm. |
| Time to PFS2 | Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years) | Time to PFS2 was defined as time from randomization to the first occurrence of disease progression after reinduction of second-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5mm. |
| Percentage of Participants With Adverse Events | Randomization up to approximately 3 years | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases | Randomization up to approximately 3 years | The proportion of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases was calculated as follows: number of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases divided by total number of participants in each arm. This outcome represents a measure of the rate of conversion from unresectable to resectable disease. |
| Overall Survival (OS) | Randomization until death due to any cause (up to approximately 3 years) | OS was defined as the time from the date of randomization to the date of death from any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. | 93 |
| Arm B: Sequential FOLFOXIRI + Bevacizumab Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. | 92 |
| Arm C: FOLFOX + Bevacizumab Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. | 95 |
| Total | 280 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 31 | 36 | 33 |
| Overall Study | Lost to Follow-up | 2 | 2 | 1 |
| Overall Study | Other | 3 | 6 | 9 |
| Overall Study | Sponsor Decision | 46 | 42 | 42 |
| Overall Study | Withdrawal of Consent | 11 | 6 | 10 |
Baseline characteristics
| Characteristic | Arm A: Concurrent FOLFOXIRI + Bevacizumab | Arm B: Sequential FOLFOXIRI + Bevacizumab | Arm C: FOLFOX + Bevacizumab | Total |
|---|---|---|---|---|
| Age, Continuous | 56.0 Years STANDARD_DEVIATION 11.53 | 56.0 Years STANDARD_DEVIATION 10.46 | 57.9 Years STANDARD_DEVIATION 9.86 | 56.7 Years STANDARD_DEVIATION 10.63 |
| Sex: Female, Male Female | 42 Participants | 40 Participants | 36 Participants | 118 Participants |
| Sex: Female, Male Male | 51 Participants | 52 Participants | 59 Participants | 162 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 91 / 91 | 89 / 90 | 89 / 90 |
| serious Total, serious adverse events | 39 / 91 | 42 / 90 | 43 / 90 |
Outcome results
Primary
Percentage of Participants With Overall Response During First-Line Therapy (ORR1)
ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to \<10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR
Time frame: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Percentage of Participants With Overall Response During First-Line Therapy (ORR1) | 72.0 Percentage of participants |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Percentage of Participants With Overall Response During First-Line Therapy (ORR1) | 72.8 Percentage of participants |
| Arm C: FOLFOX + Bevacizumab | Percentage of Participants With Overall Response During First-Line Therapy (ORR1) | 62.1 Percentage of participants |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Percentage of Participants With Overall Response During First-Line Therapy (ORR1) | 72.4 Percentage of participants |
Comparison: Stratified by extent of metastatic disease (liver-limited disease versus non liver-limited disease) and tumor location (right versus left) after correction post-randomization.p-value: 0.13290% CI: [0.96, 2.71]Cochran-Mantel-Haenszel
Primary
Progression-Free Survival During First-Line Therapy (PFS1)
PFS1 was defined as time from randomization to the first occurrence of disease progression during first-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5 mm.
Time frame: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Progression-Free Survival During First-Line Therapy (PFS1) | 11.86 months |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Progression-Free Survival During First-Line Therapy (PFS1) | 11.37 months |
| Arm C: FOLFOX + Bevacizumab | Progression-Free Survival During First-Line Therapy (PFS1) | 9.46 months |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Progression-Free Survival During First-Line Therapy (PFS1) | 11.70 months |
Comparison: Stratified by extent of metastatic disease (liver-limited disease vs. non-liver-limited disease) and tumor location (right vs. left) after correction post-randomization.p-value: 0.00590% CI: [0.53, 0.88]Log Rank
Secondary
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death from any cause.
Time frame: Randomization until death due to any cause (up to approximately 3 years)
Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Overall Survival (OS) | 33.97 months |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Overall Survival (OS) | 28.32 months |
| Arm C: FOLFOX + Bevacizumab | Overall Survival (OS) | 30.65 months |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Overall Survival (OS) | 28.32 months |
Secondary
Percentage of Participants With Adverse Events
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Randomization up to approximately 3 years
Population: Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Percentage of Participants With Adverse Events | 100 Percentage of participants |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Percentage of Participants With Adverse Events | 98.9 Percentage of participants |
| Arm C: FOLFOX + Bevacizumab | Percentage of Participants With Adverse Events | 100 Percentage of participants |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Percentage of Participants With Adverse Events | 99.4 Percentage of participants |
Secondary
Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases
The proportion of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases was calculated as follows: number of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases divided by total number of participants in each arm. This outcome represents a measure of the rate of conversion from unresectable to resectable disease.
Time frame: Randomization up to approximately 3 years
Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases | 0.24 Proportion of participants |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases | 0.17 Proportion of participants |
| Arm C: FOLFOX + Bevacizumab | Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases | 0.14 Proportion of participants |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases | 0.21 Proportion of participants |
Secondary
Proportion of Participants Who Underwent Liver Metastases Resections
Reported here is the proportion of participants who underwent liver metastases resections calculated as follows: number of participants who underwent liver metastases resections divided by total number of participants in each arm.
Time frame: Randomization up to approximately 3 years
Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Proportion of Participants Who Underwent Liver Metastases Resections | 0.17 Proportion of participants |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Proportion of Participants Who Underwent Liver Metastases Resections | 0.10 Proportion of participants |
| Arm C: FOLFOX + Bevacizumab | Proportion of Participants Who Underwent Liver Metastases Resections | 0.08 Proportion of participants |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Proportion of Participants Who Underwent Liver Metastases Resections | 0.14 Proportion of participants |
Secondary
Time to PFS2
Time to PFS2 was defined as time from randomization to the first occurrence of disease progression after reinduction of second-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5mm.
Time frame: Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years)
Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Concurrent FOLFOXIRI + Bevacizumab | Time to PFS2 | 18.76 months |
| Arm B: Sequential FOLFOXIRI + Bevacizumab | Time to PFS2 | 13.17 months |
| Arm C: FOLFOX + Bevacizumab | Time to PFS2 | 14.75 months |
| Arms A + B: Pooled FOLFOXIRI + Bevacizumab | Time to PFS2 | 15.08 months |