Study of Bevacizumab + mFOLFOX6 Versus Bevacizumab + FOLFIRI With Biomarker Stratification in Participants With Previously Untreated Metastatic Colorectal Cancer (mCRC) (MAVERICC)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT01374425
First received: June 14, 2011
Last updated: June 30, 2016
Last verified: June 2016
  Purpose
This will be a randomized, open-label, multicenter, Phase II study with primary objectives to assess whether expression of select chemotherapy markers is associated with progression-free survival (PFS) in participants treated with bevacizumab plus leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) or bevacizumab plus leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI). The study population will consist of participants with first-line mCRC.

Condition Intervention Phase
Colorectal Cancer
Drug: 5-Fluorouracil
Drug: Bevacizumab
Drug: Irinotecan
Drug: Leucovorin
Drug: Oxaliplatin
Drug: Capecitabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: MAVERICC (Marker Evaluation for Avastin Research in CRC): A Randomized Phase II Study of Bevacizumab+mFOLFOX6 Vs. Bevacizumab+FOLFIRI With Biomarker Stratification in Patients With Previously Untreated Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as greater than or equal to (≥) 20 percent (%) increase in sum of largest diameters (LD) of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 millimeters (mm). Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.


Secondary Outcome Measures:
  • PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • Overall Survival (OS) [ Time Frame: From Baseline until death (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • OS in Participants With High ERCC-1 Levels [ Time Frame: From Baseline until death (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • OS in Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until death (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until death (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • Percentage of Participants With Objective Response According to RECIST Version 1.1 [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Objective response was defined as complete response (CR) or partial response (PR) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to less than (<) 10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Disease Control According to RECIST Version 1.1 [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Disease control was defined as CR, PR, or stable disease (SD) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Liver Metastasis Resection [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Complete Liver Metastasis Resection [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • PFS According to RECIST Version 1.1 in Participants With Wild-Type V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Versus Participants With Mutant KRAS [ Time Frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels [ Time Frame: From Baseline until death (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS [ Time Frame: From Baseline until death (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  • Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels [ Time Frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.

  • Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ] [ Designated as safety issue: No ]
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.


Enrollment: 376
Study Start Date: August 2011
Study Completion Date: July 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bevacizumab + mFOLFOX6
Participants will receive bevacizumab plus mFOLFOX6 by intravenous (IV) infusion on Day 1 of each 2-week cycle until disease progression or unacceptable toxicity. Participants may be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin, with bevacizumab continued in 3-week cycles.
Drug: 5-Fluorouracil
5-Fluorouracil 400 milligrams per meter-squared (mg/m^2) by IV bolus and subsequent 2400 mg/m^2 by IV infusion over 46 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab 5 milligrams per kilogram (mg/kg) of body weight via IV infusion will be administered every 2 weeks until disease progression or unacceptable toxicity. If participants are discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab may be given in 3-week cycles with capecitabine.
Other Name: Avastin
Drug: Leucovorin
Leucovorin 400 mg/m^2 or dose deemed appropriate by Investigator via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
Drug: Oxaliplatin
Oxaliplatin 85 mg/m^2 via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
Drug: Capecitabine
Capecitabine 850 or 1000 mg/m^2 may be offered in the event of unacceptable toxicity to oxaliplatin or irinotecan, to be given orally twice a day on Days 1 to 14 in 3-week cycles.
Experimental: Bevacizumab + FOLFIRI
Participants will receive bevacizumab plus FOLFIRI by IV infusion on Day 1 of each 2-week cycle until disease progression or unacceptable toxicity. Participants may be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan, with bevacizumab continued in 3-week cycles.
Drug: 5-Fluorouracil
5-Fluorouracil 400 milligrams per meter-squared (mg/m^2) by IV bolus and subsequent 2400 mg/m^2 by IV infusion over 46 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab 5 milligrams per kilogram (mg/kg) of body weight via IV infusion will be administered every 2 weeks until disease progression or unacceptable toxicity. If participants are discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab may be given in 3-week cycles with capecitabine.
Other Name: Avastin
Drug: Irinotecan
Irinotecan 180 mg/m^2 via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
Drug: Leucovorin
Leucovorin 400 mg/m^2 or dose deemed appropriate by Investigator via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
Drug: Capecitabine
Capecitabine 850 or 1000 mg/m^2 may be offered in the event of unacceptable toxicity to oxaliplatin or irinotecan, to be given orally twice a day on Days 1 to 14 in 3-week cycles.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed colorectal cancer (CRC) with at least one measurable metastatic lesion by RECIST Version 1.1
  • Archival tumor tissue sample must be requested and available prior to study entry. If no archival tumor tissue sample is available, a fresh biopsy tissue sample must be obtained but should be discussed first with the medical monitor. A copy of the local pathology report must be submitted along with the specimens.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • 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. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician. Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization.
  • Female participants should not be pregnant or breastfeeding. Female participants with childbearing potential should agree to use effective, non-hormonal means of contraception during the study and for a period of at least 6 months following the last administration of study drugs. Female participants with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study.
  • Male participants must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized.

Exclusion Criteria:

  • Any prior systemic treatment for mCRC
  • Adjuvant chemotherapy for CRC completed <12 months
  • Evidence of Gilbert's syndrome or of homozygosity for the UGT1A1*28 allele
  • Known positivity for human immunodeficiency virus (HIV)
  • Malignancies other than mCRC 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 detectable third-space fluid collections 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01374425

  Show 79 Study Locations
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Christiane Langer, M.D. Genentech, Inc.
  More Information

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01374425     History of Changes
Other Study ID Numbers: ML25710  2011-004755-39 
Study First Received: June 14, 2011
Results First Received: June 30, 2016
Last Updated: June 30, 2016
Health Authority: United States: Food and Drug Administration

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
Oxaliplatin
Irinotecan
Capecitabine
Fluorouracil
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Immunosuppressive Agents

ClinicalTrials.gov processed this record on August 25, 2016