Untreated Metastatic Colorectal Cancer
Conditions
Keywords
PARP inhibitor, veliparib, metastatic colorectal cancer, ABT-888, first line, previously untreated, colorectal cancer, colon cancer, rectal cancer, FOLFIRI, fluorouracil, 5-FU, leucovorin, irinotecan
Brief summary
This was a blinded, randomized, placebo-controlled Phase 2 multicenter study evaluating the efficacy and tolerability of veliparib plus irinotecan, fluorouracil, and leucovorin chemotherapy regimen (FOLFIRI) compared to placebo plus FOLFIRI in participants with previously untreated metastatic colorectal cancer. Participants could also have been treated with bevacizumab at the discretion of the Investigator.
Detailed description
Participants were randomized to one of 2 groups: veliparib plus FOLFIRI ± bevacizumab (veliparib group) or placebo plus FOLFIRI ± bevacizumab (placebo group), and stratified by planned use of bevacizumab (planned bevacizumab use compared to unplanned use of bevacizumab) and regions of the world (North America versus rest of world). In this study, the term FOLFIRI was used to describe both the standard regimen containing a fluorouracil bolus that was administered to participants randomized to the placebo arm, and a modified regimen with a saline bolus that was administered to participants randomized to the veliparib arm. One cycle of protocol therapy consisted of 14 days, defined as Day -2 through Day 12. Dosing of oral veliparib/placebo began 2 days prior to the start of FOLFIRI and continued twice a day for a total of 7 consecutive days. At the discretion of the Investigator, bevacizumab could be administered intravenously immediately preceding FOLFIRI. Study visits were conducted on Day 1 and Day 8 of the first and second cycles, then on Day 1 of each subsequent cycle. Participants were to continue protocol therapy and study visits until they met one of the defined discontinuation criteria. When the Investigator determined that a participant met the criteria for discontinuation, a final visit was conducted. Participants were to have had one follow-up visit approximately 30 days after the last dose of protocol therapy. Sites began collecting post-treatment and survival information 4 weeks after the last clinical assessment. Post-baseline radiographic tumor assessment was to be conducted every 8 weeks from Cycle 1, Day 1 (prior to the start of a new cycle) until radiographic progression.
Interventions
DRUGVeliparib
200 mg oral dose beginning 2 days prior to the start of FOLFIRI and continuing twice a day (BID) for a total of 7 consecutive days
DRUGPlacebo
200 mg oral dose beginning 2 days prior to the start of FOLFIRI and continuing twice a day (BID) for a total of 7 consecutive days
DRUGModified FOLFIRI
Irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and saline bolus (up to 15-minute infusion) on Day 1 of each 14-day cycle
DRUGFOLFIRI
Irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and fluorouracil bolus 400 mg/m\^2 (up to 15-minute infusion) on Day 1 of each 14-day cycle
DRUGBevacizumab
At the discretion of the Investigator, 5 mg/kg may be administered intravenously immediately preceding FOLFIRI dosing
DRUGFluorouracil infusion
2400 mg/m\^2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum * At least 1 unresectable lesion on a CT (Computerized Tomography) scan that is measurable as defined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 * ECOG (Eastern Cooperative Oncology Group) performance score of 0 or 1 * Adequate hematologic, renal and hepatic function
Exclusion criteria
* Prior anti-cancer treatment for metastatic colorectal cancer * Prior exposure to PARP (poly ADP-ribose polymerase) inhibitors * The last course of adjuvant or neoadjuvant chemotherapy must have ended \> 12 months prior to Cycle 1 Day -2 * Any clinically significant and uncontrolled major medical condition * Participant is pregnant or lactating * Any medical condition, which in the opinion of the study Investigator, places the participant at an unacceptably high risk for toxicities * For those receiving bevacizumab, standard medical exclusionary conditions apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS): Time to Event | Every 8 weeks from Cycle 1, Day 1 until radiographic progression was observed. The maximum observed follow up duration at the progression-free survival analysis time was 579 days. | PFS was defined as the number of days from the date the participant was randomized to the date the participant experienced an event of disease progression or death, whichever occurred first. All events of disease progression were included, whether the participant was still taking or had discontinued study drug. Events of death were included for participants who had not experienced an event of disease progression, if the death occurred within 8 weeks of the last evaluable disease progression assessment. If the participant did not have an event of disease progression and the participant had not died as defined above, data were censored at the date of the participant's last evaluable disease progression assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Point estimates and 95% confidence intervals (95% CIs) for the PFS distribution quartiles are provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS): Time to Event | Survival information was to be collected 4 wks after the last study visit, continuing every 4 wks for 1 yr, then every 8 wks for up to 2 more yrs or until death. The maximum observed follow up duration at the overall survival analysis time was 914 days. | Overall survival was defined as the number of days from the date that the participant was randomized to the date of the participant's death. All events of death were included, regardless of whether the event occurred while the participant was still taking or had discontinued study drug. If a participant had not died, the data were censored at the date last known to be alive. The OS distribution was estimated using Kaplan-Meier methodology. Point estimates and 95% confidence intervals (95% CIs) for the OS distribution quartiles are provided. |
| Objective Response Rate (ORR) | Per protocol, post-baseline tumor assessment was conducted every 8 weeks from Cycle 1 Day 1 until radiographic progression. The maximum observed follow up duration at the progression-free survival analysis time was 579 days. | ORR was defined as the proportion of participants with a complete (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) for target lesions, assessed by computed tomography (CT). Complete response (CR) was defined as disappearance of all target lesions; partial response (PR) ≥30% decrease in the the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who underwent surgery, ORR was not evaluated after surgery. |
Participant flow
Pre-assignment details
All randomized participants. Although the study was terminated by the Sponsor, because all participants were evaluated for the primary end point, the study was considered to have Completed as planned.
Participants by arm
| Arm | Count |
|---|---|
| Veliparib + Modified FOLFIRI ± Bevacizumab Dosing of oral veliparib (200 mg) began 2 days prior to the start of FOLFIRI and continued twice a day (BID) for a total of 7 consecutive days. At the discretion of the Investigator, bevacizumab (5 mg/kg) could be administered intravenously (IV) immediately preceding FOLFIRI. Modified FOLFIRI was administered as irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and saline bolus (up to 15-minute infusion) immediately followed by fluorouracil 2400 mg/m\^2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle. | 65 |
| Placebo + FOLFIRI ± Bevacizumab Dosing of oral placebo (200 mg) began 2 days prior to the start of FOLFIRI and continued twice a day (BID) for a total of 7 consecutive days. At the discretion of the Investigator, bevacizumab (5 mg/kg) could be administered intravenously (IV) immediately preceding FOLFIRI. Standard FOLFIRI was administered as irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and fluorouracil bolus 400 mg/m\^2 (up to 15-minute infusion) immediately followed by fluorouracil 2400 mg/m\^2 (46-hour continuous infusion ± 4 hours) on Day 1 of each 14-day cycle. | 65 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 27 | 27 |
| Overall Study | Lost to Follow-up | 6 | 1 |
| Overall Study | Other, not specified | 2 | 1 |
| Overall Study | Study Terminated by Sponsor | 21 | 34 |
| Overall Study | Withdrew consent | 9 | 2 |
Baseline characteristics
| Characteristic | Placebo + FOLFIRI ± Bevacizumab | Total | Veliparib + Modified FOLFIRI ± Bevacizumab |
|---|---|---|---|
| Age, Continuous | 63.8 years STANDARD_DEVIATION 9.04 | 61.3 years STANDARD_DEVIATION 11.4 | 58.9 years STANDARD_DEVIATION 13.06 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 64 Participants | 126 Participants | 62 Participants |
| Sex: Female, Male Female | 25 Participants | 46 Participants | 21 Participants |
| Sex: Female, Male Male | 40 Participants | 84 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 27 / 65 | 27 / 65 |
| other Total, other adverse events | 59 / 65 | 60 / 65 |
| serious Total, serious adverse events | 30 / 65 | 33 / 65 |
Outcome results
Primary
Progression-Free Survival (PFS): Time to Event
PFS was defined as the number of days from the date the participant was randomized to the date the participant experienced an event of disease progression or death, whichever occurred first. All events of disease progression were included, whether the participant was still taking or had discontinued study drug. Events of death were included for participants who had not experienced an event of disease progression, if the death occurred within 8 weeks of the last evaluable disease progression assessment. If the participant did not have an event of disease progression and the participant had not died as defined above, data were censored at the date of the participant's last evaluable disease progression assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Point estimates and 95% confidence intervals (95% CIs) for the PFS distribution quartiles are provided.
Time frame: Every 8 weeks from Cycle 1, Day 1 until radiographic progression was observed. The maximum observed follow up duration at the progression-free survival analysis time was 579 days.
Population: All randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Veliparib + Modified FOLFIRI ± Bevacizumab | Progression-Free Survival (PFS): Time to Event | 50th Quartile | 361 days |
| Veliparib + Modified FOLFIRI ± Bevacizumab | Progression-Free Survival (PFS): Time to Event | 25th Quartile | 221 days |
| Veliparib + Modified FOLFIRI ± Bevacizumab | Progression-Free Survival (PFS): Time to Event | 75th Quartile | 534 days |
| Placebo + FOLFIRI ± Bevacizumab | Progression-Free Survival (PFS): Time to Event | 25th Quartile | 213 days |
| Placebo + FOLFIRI ± Bevacizumab | Progression-Free Survival (PFS): Time to Event | 50th Quartile | 337 days |
| Placebo + FOLFIRI ± Bevacizumab | Progression-Free Survival (PFS): Time to Event | 75th Quartile | 512 days |
Comparison: Comparisons between treatment groups were performed using the Cox Proportional Hazard Model, stratified by planned bevacizumab use (planned use versus no planned use).95% CI: [0.596, 1.48]
Secondary
Objective Response Rate (ORR)
ORR was defined as the proportion of participants with a complete (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) for target lesions, assessed by computed tomography (CT). Complete response (CR) was defined as disappearance of all target lesions; partial response (PR) ≥30% decrease in the the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who underwent surgery, ORR was not evaluated after surgery.
Time frame: Per protocol, post-baseline tumor assessment was conducted every 8 weeks from Cycle 1 Day 1 until radiographic progression. The maximum observed follow up duration at the progression-free survival analysis time was 579 days.
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Veliparib + Modified FOLFIRI ± Bevacizumab | Objective Response Rate (ORR) | 37 Participants |
| Placebo + FOLFIRI ± Bevacizumab | Objective Response Rate (ORR) | 40 Participants |
Comparison: Comparisons between treatment groups were performed using the Mantel-Haenszel method, stratified by planned bevacizumab use (planned use versus no planned use).95% CI: [-21.4, 12.1]Mantel Haenszel
Secondary
Overall Survival (OS): Time to Event
Overall survival was defined as the number of days from the date that the participant was randomized to the date of the participant's death. All events of death were included, regardless of whether the event occurred while the participant was still taking or had discontinued study drug. If a participant had not died, the data were censored at the date last known to be alive. The OS distribution was estimated using Kaplan-Meier methodology. Point estimates and 95% confidence intervals (95% CIs) for the OS distribution quartiles are provided.
Time frame: Survival information was to be collected 4 wks after the last study visit, continuing every 4 wks for 1 yr, then every 8 wks for up to 2 more yrs or until death. The maximum observed follow up duration at the overall survival analysis time was 914 days.
Population: All randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Veliparib + Modified FOLFIRI ± Bevacizumab | Overall Survival (OS): Time to Event | 25th Quartile | 557 days |
| Veliparib + Modified FOLFIRI ± Bevacizumab | Overall Survival (OS): Time to Event | 50th Quartile | 770 days |
| Veliparib + Modified FOLFIRI ± Bevacizumab | Overall Survival (OS): Time to Event | 75th Quartile | NA days |
| Placebo + FOLFIRI ± Bevacizumab | Overall Survival (OS): Time to Event | 25th Quartile | 512 days |
| Placebo + FOLFIRI ± Bevacizumab | Overall Survival (OS): Time to Event | 50th Quartile | 811 days |
| Placebo + FOLFIRI ± Bevacizumab | Overall Survival (OS): Time to Event | 75th Quartile | NA days |
Comparison: Comparisons between treatment groups were performed using the Cox Proportional Hazard Model, stratified by planned bevacizumab use (planned use versus no planned use).95% CI: [0.738, 2.156]