A Study of Avastin (Bevacizumab) in Combination With mFOLFOX-6 or FOLFOXIRI in Patients With Metastatic Colorectal Cancer.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00778102
First received: October 22, 2008
Last updated: August 7, 2015
Last verified: August 2015
  Purpose

This 2 arm study will compare the resection rate of liver metastases and safety of surgery in patients with metastatic colorectal cancer and primarily unresectable liver metastases receiving treatment with Avastin in combination with 5-FU, leucovorin and oxaliplatin with irinotecan (FOLFOXIRI) or without irinotecan (mFOLFOX-6) as first line treatment. Patients will be randomized to receive Avastin (5mg/kg iv every 2 weeks) in combination with each of these two standard neoadjuvant chemotherapy regimens. The anticipated time on study treatment is until surgery, disease progression, unacceptable toxicity or patient refusal, and the target sample size is <100 individuals.


Condition Intervention Phase
Colorectal Cancer
Drug: 5-FU
Drug: Irinotecan
Drug: Leucovorin
Drug: Oxaliplatin
Drug: bevacizumab [Avastin]
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicentre Randomised Phase II Study to Assess the Safety and Resectability in Patients With Initially Unresectable Liver Metastases Secondary to Colorectal Cancer Receiving First-line Treatment Either With mFOLFOX-6 Plus Bevacizumab or FOLFOXIRI Plus Bevacizumab (OLIVIA)

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery) ] [ Designated as safety issue: No ]
    Following resective surgery, participants were evaluated for complete resection (R0) or the presence of microscopic (R1) or macroscopic (R2) residual tumor. The percentage of participants within each residual tumor classification was calculated as [number of participants with R0, R1, and/or R2 divided by the total number of participants] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.


Secondary Outcome Measures:
  • Time to Resection [ Time Frame: Up to 5 years (at Screening; prior to each cycle, and within 7 days prior to surgery; and at time of surgery) ] [ Designated as safety issue: No ]
    Time to resection was defined as the time from randomization to the date of first resective surgery. For participants who did not undergo resective surgery, time to resection was censored at Day 1. Time to resection was estimated by Kaplan-Meier analysis.

  • Percentage of Participants With Histopathological Response [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery) ] [ Designated as safety issue: No ]
    At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, where 'Complete response' was considered for those with 0 percent (%) viable tumor cells, 'Major response' for those with 1% to 49% viable tumor cells, 'Minor response' for 50% to 99% viable tumor cells, and 'No response' for 100% viable tumor cells. The response could not be determined in some cases and was documented as 'Unknown.' The percentage of participants within each response category was calculated as [number of participants with a given response divided by the number of participants who completed the assessment] multiplied by 100.

  • Percentage of Participants With Complete or Major Histopathological Response [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery) ] [ Designated as safety issue: No ]
    At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, as described previously. The collective percentage of participants assessed as having a complete or major response was calculated as [number of participants with complete or major response divided by the number of participants who completed the assessment] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

  • Percentage of Participants Experiencing Relapse Following Curative Resection [ Time Frame: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually) ] [ Designated as safety issue: No ]
    Among participants with curative resection (complete resection [R0] or microscopic residual tumor [R1]), relapse was defined as the first new occurrence of cancer or death. The percentage of participants who experienced relapse was calculated as [number of participants with a relapse event divided by the number of participants initially classified as R0 or R1 following resective surgery] multiplied by 100.

  • Relapse-Free Survival (RFS) [ Time Frame: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually) ] [ Designated as safety issue: No ]
    RFS was defined as the time from curative resection (complete resection [R0] or microscopic residual tumor [R1]) to the date of first diagnosis of relapse. For participants with curative resection and without relapse, RFS was censored at the last known relapse-free assessment. RFS was estimated by Kaplan-Meier analysis.

  • Percentage of Participants Experiencing Death or Disease Progression [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2) ] [ Designated as safety issue: No ]
    PD was defined, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. The percentage of participants experiencing PD or death was calculated as [number of participants with event divided by the number of participants analyzed] multiplied by 100.

  • Progression-Free Survival (PFS) [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2) ] [ Designated as safety issue: No ]
    PFS was defined, using RECIST version 1.0, as the time from randomization to the date of first documented PD or death from any cause. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. For participants without documented PD or death, PFS was censored at the time of last tumor assessment. PFS was estimated by Kaplan-Meier analysis.

  • Percentage of Participants Who Died [ Time Frame: Up to 5 years (prior to each cycle, and within 7 days prior to surgery; at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually) ] [ Designated as safety issue: No ]
  • Overall Survival (OS) [ Time Frame: Up to 5 years (prior to each cycle, and within 7 days prior to surgery; at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually) ] [ Designated as safety issue: No ]
    OS was defined as the time from randomization to death from any cause. For participants without an event of death, OS was censored at the last-known alive date. OS was estimated by Kaplan-Meier analysis.

  • Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0 [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2) ] [ Designated as safety issue: No ]
    Using RECIST version 1.0, participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. The collective percentage of participants with confirmed best overall response of CR or PR was calculated as [number of participants meeting RECIST criteria for CR or PR divided by the number of participants analyzed] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

  • Time to Response [ Time Frame: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2) ] [ Designated as safety issue: No ]
    Time to response according to RECIST version 1.0 was defined as the time from randomization to the date of first documented CR or PR. Participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. For participants who did not complete a confirmatory tumor assessment, time to response was censored at the date of last tumor assessment, or if unavailable, at the date of first dose. Time to response was estimated by Kaplan-Meier analysis.

  • Percentage of Participants With Complications Related to First Resective Surgery [ Time Frame: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually) ] [ Designated as safety issue: No ]
    Complications related to the first resective surgery were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 equals (=) resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given adverse event (AE) by severity grade was calculated as [number of participants with an AE divided by the number of participants who underwent first resective surgery] multiplied by 100.

  • Percentage of Participants With Complications Related to Second Resective Surgery [ Time Frame: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually) ] [ Designated as safety issue: No ]
    Complications related to the second resective surgery were evaluated using the NCI-CTCAE version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 = resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given AE by severity grade was calculated as [number of participants with an AE divided by the number of participants who underwent second resective surgery] multiplied by 100.


Enrollment: 80
Study Start Date: October 2008
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: 5-FU
Bolus 400mg/m2, day 1 every 2 weeks
Drug: 5-FU
2400mg/m2 46-hour continuous iv infusion, day 1 every 2 weeks
Drug: Leucovorin
400mg/m2 2-hour iv infusion, day 1 every 2 weeks
Drug: Oxaliplatin
85mg/m2 2-hour iv infusion, day 1 every 2 weeks
Drug: bevacizumab [Avastin]
5mg/kg iv day 1 every 2 weeks
Active Comparator: 2 Drug: 5-FU
3200mg/m2 46-hour continuous iv infusion, day 1 every 2 weeks
Drug: Irinotecan
165mg/m2 1-hour iv infusion, day 1 every 2 weeks
Drug: Leucovorin
200mg/m2 2-hour iv infusion, day 1 every 2 weeks
Drug: Oxaliplatin
85mg/m2 2-hour iv infusion, day 1 every 2 weeks
Drug: bevacizumab [Avastin]
5mg/kg iv day 1 every 2 weeks

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • adult patients, >=18 years of age;
  • unresectable liver metastasis secondary to cancer of colon or rectum;
  • scheduled for standard first line chemotherapy;
  • ECOG performance score of 0 or 1;
  • condition feasible for major abdominal surgery after first line treatment.

Exclusion Criteria:

  • diagnosis of metastatic disease >3 months prior to study entry;
  • evidence of extrahepatic disease, diffuse peritoneal carcinosis or involvement of celiac lymph nodes;
  • prior systemic or local treatment of metastatic disease;
  • prior (neo)adjuvant chemotherapy/radiotherapy completed within 6 months prior to study entry;
  • history or evidence of CNS disease unrelated to cancer.
  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: NCT00778102

Locations
Austria
Wien, Austria, 1090
France
Bordeaux, France, 33075
Creteil, France, 94010
Le Mans, France, 72037
Lille, France, 59037
Lyon, France, 69373
Montpellier, France, 34298
Villejuif, France, 94804
Spain
San Sebastian, Guipuzcoa, Spain, 20080
Palma de Mallorca, Islas Baleares, Spain, 07198
Santiago de Compostela, La Coruña, Spain, 15706
Girona, Spain, 17007
Madrid, Spain, 28007
Madrid, Spain, 28046
Valencia, Spain, 46026
United Kingdom
London, United Kingdom, WC1E 6DD
Manchester, United Kingdom, M20 4BX
Sutton, United Kingdom, SM2 5PT
Wirral, United Kingdom, CH63 4JY
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00778102     History of Changes
Other Study ID Numbers: MO18725, 2007-007863-26
Study First Received: October 22, 2008
Results First Received: July 10, 2015
Last Updated: August 7, 2015
Health Authority: Austria: Ethikkommission

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on September 03, 2015