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

• ClinicalTrials.gov Identifier: NCT01374425
• Recruitment Status: Completed
• First Posted: June 16, 2011
• Results First Posted: August 11, 2016
• Last Update Posted: August 11, 2016
• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Colorectal Cancer	Drug: 5-Fluorouracil; Drug: Bevacizumab; Drug: Irinotecan; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Capecitabine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 376 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: August 2011
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: July 2015

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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) ]
   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.
2. 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) ]
   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.
3. 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) ]
   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.
4. 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) ]
   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.
5. 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) ]
   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 :

1. 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) ]
   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.
2. 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) ]
   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.
3. 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) ]
   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.
4. 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) ]
   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.
5. Overall Survival (OS) [ Time Frame: From Baseline until death (maximum up to 45 months overall) ]
   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.
6. OS in Participants With High ERCC-1 Levels [ Time Frame: From Baseline until death (maximum up to 45 months overall) ]
   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.
7. OS in Participants With Low ERCC-1 Levels [ Time Frame: From Baseline until death (maximum up to 45 months overall) ]
   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.
8. 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) ]
   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.
9. 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) ]
   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.
10. 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) ]
    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.
11. 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) ]
    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.
12. 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) ]
    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.
13. 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) ]
    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.
14. 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) ]
    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.
15. 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) ]
    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.
16. 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) ]
    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.
17. Percentage of Participants With Liver Metastasis Resection [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ]
    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.
18. Percentage of Participants With Complete Liver Metastasis Resection [ Time Frame: At time of resective surgery during study (maximum up to 45 months overall) ]
    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.
19. 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) ]
    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.
20. 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) ]
    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.
21. 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) ]
    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.
22. 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) ]
    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.
23. 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) ]
    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.
24. 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) ]
    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.
25. 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) ]
    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.
26. 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) ]
    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.
27. OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS [ Time Frame: From Baseline until death (maximum up to 45 months overall) ]
    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.
28. 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) ]
    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.
29. 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) ]
    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.
30. 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) ]
    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.
31. 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) ]
    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.
32. 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) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, Alabama

Birmingham, Alabama, United States, 35294

United States, Arkansas

Little Rock, Arkansas, United States, 72205-7199

United States, California

Bellflower, California, United States, 90706

Duarte, California, United States, 91010

Fountain Valley, California, United States, 92708

Fresno, California, United States, 93720

Hayward, California, United States, 94545

Los Angeles, California, United States, 90033

Oakland, California, United States, 94611

Pleasant Hill, California, United States, 94523

Roseville, California, United States, 95661

Sacramento, California, United States, 95817

Sacramento, California, United States, 95825

San Francisco, California, United States, 94115

San Jose, California, United States, 95119

Santa Clara, California, United States, 95051

South San Francisco, California, United States, 94080

Vallejo, California, United States, 94589

Walnut Creek, California, United States, 94596

United States, Colorado

Denver, Colorado, United States, 80218

United States, Connecticut

Stamford, Connecticut, United States, 06902

Trumbull, Connecticut, United States, 06611

United States, Florida

Hollywood, Florida, United States, 33021

Jacksonville, Florida, United States, 32256

Miami, Florida, United States, 33136

Port Saint Lucie, Florida, United States, 34952

United States, Idaho

Boise, Idaho, United States, 83712

United States, Illinois

Joliet, Illinois, United States, 60435

Maywood, Illinois, United States, 60153

Peoria, Illinois, United States, 61615

United States, Indiana

Goshen, Indiana, United States, 46526

Indianapolis, Indiana, United States, 46237

Terre Haute, Indiana, United States, 47802

United States, Kansas

Fairway, Kansas, United States, 66205

United States, Kentucky

Elizabethtown, Kentucky, United States, 42791

United States, Maine

Scarborough, Maine, United States, 04074

United States, Massachusetts

Burlington, Massachusetts, United States, 01805

United States, Montana

Billings, Montana, United States, 59102

United States, Nebraska

Lincoln, Nebraska, United States, 68506

United States, New Jersey

Cherry Hill, New Jersey, United States, 08003

Manasquan, New Jersey, United States, 08736

United States, New Mexico

Albuquerque, New Mexico, United States, 87106

Albuquerque, New Mexico, United States, 87110

Albuquerque, New Mexico, United States, 87131-5636

Farmington, New Mexico, United States, 87401

Las Cruces, New Mexico, United States, 88011

Santa Fe, New Mexico, United States, 87505

United States, New York

Rochester, New York, United States, 14642

United States, North Carolina

Durham, North Carolina, United States, 27710

Greensboro, North Carolina, United States, 27403

High Point, North Carolina, United States, 27262

Washington, North Carolina, United States, 27889

Winston-salem, North Carolina, United States, 27103

United States, Ohio

Columbus, Ohio, United States, 43219

Toledo, Ohio, United States, 43623

United States, Oklahoma

Oklahoma City, Oklahoma, United States, 73142

United States, Pennsylvania

Dunmore, Pennsylvania, United States, 18512

Media, Pennsylvania, United States, 19063

Philadelphia, Pennsylvania, United States, 19107

Pittsburgh, Pennsylvania, United States, 15212

United States, South Carolina

Charleston, South Carolina, United States, 29414

United States, Texas

Corpus Christi, Texas, United States, 78404

Houston, Texas, United States, 77090

United States, Wisconsin

Madison, Wisconsin, United States, 53792

Wauwatosa, Wisconsin, United States, 53226

Canada, Alberta

Edmonton, Alberta, Canada, T6G 1Z2

Estonia

Tallinn, Estonia, 13419

Tartu, Estonia, 51014

Ireland

Cork, Ireland

Dublin, Ireland, 24

Galway, Ireland

Norway

Oslo, Norway, 0407

Portugal

Coimbra, Portugal, 3000-075

Lisboa, Portugal, 1649-035

Porto, Portugal, 4200-072

Switzerland

Aarau, Switzerland, 5000

Basel, Switzerland, 4031

Luzern, Switzerland, 6004

Zürich, Switzerland, 8063

Sponsors and Collaborators

Genentech, Inc.

Investigators

• Study Director: Christiane Langer, M.D.; Genentech, Inc.

More Information

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01374425
• Other Study ID Numbers: ML25710; 2011-004755-39 ( EudraCT Number )
• First Posted: June 16, 2011
• Results First Posted: August 11, 2016
• Last Update Posted: August 11, 2016
• Last Verified: June 2016

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; Leucovorin; Bevacizumab; Capecitabine; Fluorouracil; Oxaliplatin; Irinotecan; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Topoisomerase I Inhibitors