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Study Comparing Veliparib Plus FOLFIRI Versus Placebo Plus FOLFIRI With or Without Bevacizumab in Previously Untreated Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT02305758
Recruitment Status : Completed
First Posted : December 3, 2014
Results First Posted : November 20, 2018
Last Update Posted : November 20, 2018
Sponsor:
Information provided by (Responsible Party):
AbbVie

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.

Condition or disease Intervention/treatment Phase
Untreated Metastatic Colorectal Cancer Drug: Veliparib Drug: Placebo Drug: Modified FOLFIRI Drug: FOLFIRI Drug: Bevacizumab Drug: Fluorouracil infusion Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Blinded, Multicenter, Phase 2 Study Comparing Veliparib Plus FOLFIRI ± Bevacizumab Versus Placebo Plus FOLFIRI ± Bevacizumab in Previously Untreated Metastatic Colorectal Cancer
Actual Study Start Date : December 2, 2014
Actual Primary Completion Date : September 22, 2017
Actual Study Completion Date : September 22, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Experimental: 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.
Drug: Veliparib
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
Other Name: ABT-888

Drug: Modified 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

Drug: Bevacizumab
At the discretion of the Investigator, 5 mg/kg may be administered intravenously immediately preceding FOLFIRI dosing
Other Name: Avastin

Drug: Fluorouracil infusion
2400 mg/m^2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle
Other Name: 5-FU

Placebo Comparator: 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.
Drug: Placebo
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

Drug: FOLFIRI
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

Drug: Bevacizumab
At the discretion of the Investigator, 5 mg/kg may be administered intravenously immediately preceding FOLFIRI dosing
Other Name: Avastin

Drug: Fluorouracil infusion
2400 mg/m^2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle
Other Name: 5-FU




Primary Outcome Measures :
  1. Progression-Free Survival (PFS): Time to Event [ 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. ]
    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 Outcome Measures :
  1. Overall Survival (OS): Time to Event [ 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. ]
    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.

  2. Objective Response Rate (ORR) [ 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. ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02305758


Sponsors and Collaborators
AbbVie
Investigators
Study Director: AbbVie Inc. AbbVie
  Study Documents (Full-Text)

Documents provided by AbbVie:
Study Protocol  [PDF] July 16, 2015
Statistical Analysis Plan  [PDF] February 23, 2017


Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02305758     History of Changes
Other Study ID Numbers: M14-217
2014-002866-65 ( EudraCT Number )
First Posted: December 3, 2014    Key Record Dates
Results First Posted: November 20, 2018
Last Update Posted: November 20, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by AbbVie:
PARP inhibitor
veliparib
metastatic colorectal cancer
ABT-888
first line
previously untreated
colorectal cancer
colon cancer
rectal cancer
FOLFIRI
fluorouracil
5-FU
leucovorin
irinotecan

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Irinotecan
Veliparib
Fluorouracil
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors