Clinical Trial Results:
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
Summary
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EudraCT number |
2011-004755-39 |
Trial protocol |
IE EE PT |
Global end of trial date |
02 Jul 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Jul 2016
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First version publication date |
16 Jul 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ML25710
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01374425 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Jan 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Jul 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This was 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 consisted of participants with first-line metastatic colorectal cancer (mCRC).
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Protection of trial subjects |
The Investigator has ensured that this study was conducted in full conformance with the principles of the Declaration of Helsinki or with the laws and regulations of the country in which the research was conducted, whichever affords the greater protection to the individual. The study must have fully adhered to the principles outlined in the Guideline for Good Clinical Practice International Council for Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it affords greater protection to the participant. In other countries where the Guideline for Good Clinical Practice exists, Roche and the investigators have strictly ensured adherence to the stated provisions.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Aug 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Norway: 2
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Country: Number of subjects enrolled |
Portugal: 18
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Country: Number of subjects enrolled |
Estonia: 8
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Country: Number of subjects enrolled |
Ireland: 11
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Country: Number of subjects enrolled |
Canada: 11
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Country: Number of subjects enrolled |
Switzerland: 8
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Country: Number of subjects enrolled |
United States: 318
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Worldwide total number of subjects |
376
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EEA total number of subjects |
39
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
236
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From 65 to 84 years |
139
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85 years and over |
1
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The trial included a 21-day Screening period during which participants provided information for demographics, medical history and cancer/treatment history and completed urinalysis collection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Bevacizumab + mFOLFOX6 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Bevacizumab was given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.
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Investigational medicinal product name |
Leucovorin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
5-Fluorouracil
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
5-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Oxaliplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Oxaliplatin was given as 85 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Capecitabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.
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Arm title
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Bevacizumab + FOLFIRI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Bevacizumab was given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.
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Investigational medicinal product name |
Leucovorin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
5-Fluorouracil
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
5-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Irinotecan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Irinotecan was given as 180 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Capecitabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.
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Arm title
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Bevacizumab + mFOLFOX/FOLFIRI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Bevacizumab was given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.
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Investigational medicinal product name |
Leucovorin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
5-Fluorouracil
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
5-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Oxaliplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Oxaliplatin was given as 85 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Irinotecan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Irinotecan was given as 180 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.
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Investigational medicinal product name |
Capecitabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.
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Baseline characteristics reporting groups
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Reporting group title |
Bevacizumab + mFOLFOX6
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Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bevacizumab + FOLFIRI
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bevacizumab + mFOLFOX/FOLFIRI
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Bevacizumab + mFOLFOX6
|
||
Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||
Reporting group title |
Bevacizumab + FOLFIRI
|
||
Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||
Reporting group title |
Bevacizumab + mFOLFOX/FOLFIRI
|
||
Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||
Subject analysis set title |
Bevacizumab + mFOLFOX6 (ERCC-1 High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with excision repair cross-complementing (ERCC)-1 level greater than (>) 1.7 × 10^-3 ERCC-1/B-actin messenger ribonucleic acid (mRNA) at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + FOLFIRI (ERCC-1 High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX6 (ERCC-1 Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level less than or equal to (≤) 1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with vascular endothelial growth factor (VEGF)-A level >5 picograms per milliliter (pg/mL) at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle.Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with wild-type V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) at Baseline were included in separate analyses.
|
||
Subject analysis set title |
Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with mutant KRAS at Baseline were included in separate analyses.
|
|
|||||||||||||
End point title |
PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [1] | ||||||||||||
End point description |
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. Intent-to-Treat (ITT) Population: All randomized participants regardless of receiving any study drug.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by high/low ERCC-1 level and region of enrollment. Hazard ratio (HR, relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
|
||||||||||||
Number of subjects included in analysis |
376
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0555 [2] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.79
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.61 | ||||||||||||
upper limit |
1.01 | ||||||||||||
Notes [2] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
|
||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.3944 [3] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.84
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.56 | ||||||||||||
upper limit |
1.26 | ||||||||||||
Notes [3] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0786 [4] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.76
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.55 | ||||||||||||
upper limit |
1.03 | ||||||||||||
Notes [4] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.9576 [5] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.99
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.77 | ||||||||||||
upper limit |
1.28 | ||||||||||||
Notes [5] - P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
370
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.1658 [6] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.19
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.93 | ||||||||||||
upper limit |
1.53 | ||||||||||||
Notes [6] - P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio Stratified | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
|
||||||||||||
Number of subjects included in analysis |
59
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.3019 [7] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.73
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.41 | ||||||||||||
upper limit |
1.32 | ||||||||||||
Notes [7] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|||||||||||||
Statistical analysis title |
Hazard Ratio Unstratified | ||||||||||||
Statistical analysis description |
Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
|
||||||||||||
Number of subjects included in analysis |
59
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5308 [8] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.83
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.47 | ||||||||||||
upper limit |
1.47 | ||||||||||||
Notes [8] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio Stratified | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
70
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.6035 [9] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.86
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.48 | ||||||||||||
upper limit |
1.53 | ||||||||||||
Notes [9] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|||||||||||||
Statistical analysis title |
Hazard Ratio Unstratified | ||||||||||||
Statistical analysis description |
Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
70
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5026 [10] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.82
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.46 | ||||||||||||
upper limit |
1.46 | ||||||||||||
Notes [10] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio Stratified | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
|
||||||||||||
Number of subjects included in analysis |
125
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.4032 [11] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.83
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.54 | ||||||||||||
upper limit |
1.28 | ||||||||||||
Notes [11] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|||||||||||||
Statistical analysis title |
Hazard Ratio Unstratified | ||||||||||||
Statistical analysis description |
Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
|
||||||||||||
Number of subjects included in analysis |
125
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.235 [12] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.77
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.51 | ||||||||||||
upper limit |
1.18 | ||||||||||||
Notes [12] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio Stratified | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
115
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0647 [13] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.65
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.41 | ||||||||||||
upper limit |
1.03 | ||||||||||||
Notes [13] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|||||||||||||
Statistical analysis title |
Hazard Ratio Unstratified | ||||||||||||
Statistical analysis description |
Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
115
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0856 [14] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.67
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.43 | ||||||||||||
upper limit |
1.06 | ||||||||||||
Notes [14] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
Overall Survival (OS) [15] | ||||||||||||
End point description |
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. ITT Population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death (maximum up to 45 months overall)
|
||||||||||||
Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to Bevacizumab + mFOLFOX6)was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
|
||||||||||||
Number of subjects included in analysis |
376
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0861 [16] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.76
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.56 | ||||||||||||
upper limit |
1.04 | ||||||||||||
Notes [16] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
OS in Participants With High ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX6 (ERCC-1 High)
|
||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.3295 [17] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.51 | ||||||||||||
upper limit |
1.26 | ||||||||||||
Notes [17] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
OS in Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.1519 [18] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.74
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.49 | ||||||||||||
upper limit |
1.12 | ||||||||||||
Notes [18] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by region of enrollment. HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2774 [19] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.19
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.87 | ||||||||||||
upper limit |
1.62 | ||||||||||||
Notes [19] - P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
Percentage of Participants With Objective Response According to RECIST Version 1.1 [20] | ||||||||||||
End point description |
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. ITT Population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Objective Response Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
|
||||||||||||
Number of subjects included in analysis |
376
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in objective response rates | ||||||||||||
Point estimate |
4.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.5 | ||||||||||||
upper limit |
14 |
|
|||||||||||||
End point title |
Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Objective Response Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
|
||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in objective response rates | ||||||||||||
Point estimate |
9.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
7.2 | ||||||||||||
upper limit |
26.1 |
|
|||||||||||||
End point title |
Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Objective Response Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in objective response rates | ||||||||||||
Point estimate |
2.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-9.9 | ||||||||||||
upper limit |
14.1 |
|
|||||||||||||
End point title |
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 | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Objective Response Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with objective response in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in objective response rates | ||||||||||||
Point estimate |
-3.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-14 | ||||||||||||
upper limit |
6.6 |
|
|||||||||||||
End point title |
Percentage of Participants With Disease Control According to RECIST Version 1.1 [21] | ||||||||||||
End point description |
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. ITT Population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Disease Control Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
|
||||||||||||
Number of subjects included in analysis |
376
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in response rates | ||||||||||||
Point estimate |
2.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-7.6 | ||||||||||||
upper limit |
3.3 |
|
|||||||||||||
End point title |
Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Disease Control Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
|
||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in disease control rates | ||||||||||||
Point estimate |
-8.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-19.1 | ||||||||||||
upper limit |
1.7 |
|
|||||||||||||
End point title |
Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Disease Control Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in disease control rates | ||||||||||||
Point estimate |
2.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.7 | ||||||||||||
upper limit |
8.3 |
|
|||||||||||||
End point title |
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 | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Disease Control Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with disease control in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in disease control rates | ||||||||||||
Point estimate |
-4.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-10.6 | ||||||||||||
upper limit |
1.5 |
|
|||||||||||||
End point title |
Percentage of Participants With Liver Metastasis Resection [22] | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + FOLFIRI v Bevacizumab + mFOLFOX6
|
||||||||||||
Number of subjects included in analysis |
122
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in resection rates | ||||||||||||
Point estimate |
-4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-15.9 | ||||||||||||
upper limit |
7.8 |
|
|||||||||||||
End point title |
Percentage of Participants With Complete Liver Metastasis Resection [23] | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Complete Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
|
||||||||||||
Number of subjects included in analysis |
122
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in complete resection rates | ||||||||||||
Point estimate |
-6.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-16.3 | ||||||||||||
upper limit |
3.3 |
|
|||||||||||||
End point title |
Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
|
||||||||||||
Number of subjects included in analysis |
32
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in resection rates | ||||||||||||
Point estimate |
-11
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-33.1 | ||||||||||||
upper limit |
11.1 |
|
|||||||||||||
End point title |
Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Complete Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
|
||||||||||||
Number of subjects included in analysis |
32
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in complete resection rates | ||||||||||||
Point estimate |
-11
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-33.1 | ||||||||||||
upper limit |
11.1 |
|
|||||||||||||
End point title |
Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in resection rates | ||||||||||||
Point estimate |
-3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-10.1 | ||||||||||||
upper limit |
4.2 |
|
|||||||||||||
End point title |
Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Complete Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in complete resection rates | ||||||||||||
Point estimate |
-5.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-11.5 | ||||||||||||
upper limit |
0.4 |
|
|||||||||||||
End point title |
Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in resection rates | ||||||||||||
Point estimate |
-4.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-9.5 | ||||||||||||
upper limit |
0.6 |
|
|||||||||||||
End point title |
Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Complete Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with complete resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in complete resection rates | ||||||||||||
Point estimate |
-1.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-6.2 | ||||||||||||
upper limit |
3.1 |
|
|||||||||||||
End point title |
PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)
|
||||||||||||
Number of subjects included in analysis |
336
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [24] | ||||||||||||
P-value |
= 0.0593 [25] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.29
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.99 | ||||||||||||
upper limit |
1.69 | ||||||||||||
Notes [24] - Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression. [25] - P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
370
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.002 [26] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.64
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.2 | ||||||||||||
upper limit |
2.24 | ||||||||||||
Notes [26] - P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until death (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard Ratio | ||||||||||||
Statistical analysis description |
Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
|
||||||||||||
Number of subjects included in analysis |
336
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0955 [27] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.34
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.95 | ||||||||||||
upper limit |
1.88 | ||||||||||||
Notes [27] - P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons. |
|
|||||||||||||
End point title |
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 | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Objective Response Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with objective response in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
370
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in objective response rates | ||||||||||||
Point estimate |
-5.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-15.7 | ||||||||||||
upper limit |
3.8 |
|
|||||||||||||
End point title |
Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Objective Response Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with objective response in the KRAS Mutant subgroup minus the KRAS Wild-Type subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
|
||||||||||||
Number of subjects included in analysis |
336
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in objective response rates | ||||||||||||
Point estimate |
-5.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-16 | ||||||||||||
upper limit |
5.2 |
|
|||||||||||||
End point title |
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 | ||||||||||||
End point description |
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. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Disease Control Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with disease control in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
370
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in disease control rates | ||||||||||||
Point estimate |
-1.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-6.5 | ||||||||||||
upper limit |
4.3 |
|
|||||||||||||
End point title |
Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
370
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in resection rates | ||||||||||||
Point estimate |
-3.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-8.6 | ||||||||||||
upper limit |
2.1 |
|
|||||||||||||
End point title |
Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | ||||||||||||
End point description |
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. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At time of resective surgery during study (maximum up to 45 months overall)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference in Complete Resection Rates | ||||||||||||
Statistical analysis description |
The difference was calculated as the percentage of participants with complete resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
|
||||||||||||
Comparison groups |
Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
|
||||||||||||
Number of subjects included in analysis |
370
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in complete resection rates | ||||||||||||
Point estimate |
-4.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-9.6 | ||||||||||||
upper limit |
-0.2 |
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Adverse events information
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Timeframe for reporting adverse events |
Serious Adverse Events (AEs): Baseline until 3 months after last dose or study discontinuation/termination (up to 45 months overall); Non-Serious AEs: Baseline until 28 days after last dose or study discontinuation/termination (up to 45 months overall).
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Adverse event reporting additional description |
Safety Population: All randomized participants who received at least one partial or complete dose of study drug.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Bevacizumab + mFOLFOX6
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Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bevacizumab + FOLFIRI
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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03 Jul 2012 |
The protocol was modified to include geographic region (United States or non-United States) as a stratification factor for enrollment. The start of Screening was also changed to the date that biopsy tissue became available, and biomarker samplings were updated. |
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26 Oct 2012 |
The protocol was amended primarily to modify the requirement for follow-up after study discontinuation. Participants who discontinued bevacizumab or other study drug were to continue with the rest of the treatment regimen until progression or unacceptable toxicity, and the end of treatment was re-defined as the time at which all study drugs were discontinued or the participant progressed. Thereafter, participants could enter the survival follow-up phase. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |