Clinical Trial Results:
A Randomized, Phase III, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Onartuzumab (MetMAb) in Combination with 5-Fluorouracil, Folinic Acid, and Oxaliplatin (mFOLFOX6) in Patients with Metastatic HER2-Negative, MET-Positive Gastroesophageal Cancer
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Summary
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EudraCT number |
2012-001402-23 |
Trial protocol |
ES IT BE GB DE CZ PL |
Global end of trial date |
15 Dec 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Dec 2016
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First version publication date |
29 Dec 2016
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Other versions |
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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 |
YO28322
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01662869 | ||
WHO universal trial number (UTN) |
- | ||
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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 |
F.Hoffmann-La Roche Ltd., Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com
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Scientific contact |
F.Hoffmann-La Roche Ltd., Roche Trial Information Hotline, 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 |
15 Dec 2015
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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 |
15 Dec 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
This is a Phase III, randomized, placebo-controlled, double-blind study which evaluates the efficacy and safety of onartuzumab + mFOLFOX6 compared with placebo + mFOLFOX6 as measured by overall survival (OS) in participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative metastatic gastroesophageal cancer (GEC) classified as Met-immunohistochemistry (IHC) 2 + or 3 + (Met 2 + /3 + subgroup), and Met-IHC 1 + , 2 +, or 3 + (intent-to-treat [ITT] population).
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Protection of trial subjects |
This study was conducted in full conformance with the International Conference on Harmonisation (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Nov 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
20 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Poland: 31
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Country: Number of subjects enrolled |
Spain: 50
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Country: Number of subjects enrolled |
United Kingdom: 35
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Country: Number of subjects enrolled |
Belgium: 9
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Country: Number of subjects enrolled |
Czech Republic: 13
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Country: Number of subjects enrolled |
France: 33
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Country: Number of subjects enrolled |
Germany: 27
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Country: Number of subjects enrolled |
Italy: 62
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Country: Number of subjects enrolled |
Hong Kong: 6
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Country: Number of subjects enrolled |
Korea, Democratic People's Republic of: 115
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Country: Number of subjects enrolled |
Malaysia: 2
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Country: Number of subjects enrolled |
Singapore: 2
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Country: Number of subjects enrolled |
Thailand: 29
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Country: Number of subjects enrolled |
Taiwan: 22
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Country: Number of subjects enrolled |
Australia: 16
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Country: Number of subjects enrolled |
Canada: 5
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Country: Number of subjects enrolled |
Guatemala: 3
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Country: Number of subjects enrolled |
Israel: 5
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Country: Number of subjects enrolled |
Mexico: 11
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Country: Number of subjects enrolled |
Russian Federation: 28
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Country: Number of subjects enrolled |
Switzerland: 5
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Country: Number of subjects enrolled |
Turkey: 27
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Country: Number of subjects enrolled |
United States: 27
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Worldwide total number of subjects |
563
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EEA total number of subjects |
260
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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) |
373
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From 65 to 84 years |
190
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Five hundred and sixty-three participants were enrolled in the study and received treatment with onartuzumab or placebo in combination with mFOLFOX6. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo + mFOLFOX6 | |||||||||||||||||||||||||||||||||
Arm description |
Placebo matched to onartuzumab was administered by intravenous (IV) infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 milligrams per meter square (mg/m^2) IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with placebo, further continued treatment with placebo until disease progression, unacceptable toxicity, or death. | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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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 |
Placebo matched to onartuzumab was administered by IV infusion.
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Arm title
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Onartuzumab + mFOLFOX6 | |||||||||||||||||||||||||||||||||
Arm description |
Onartuzumab 10 mg/kilogram (mg/kg) in 250 milliliter (mL) final 0.9% normal saline solution (NSS) was administered by IV infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 mg/m^2 IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-FU 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with onartuzumab, further continued treatment with onartuzumab until disease progression, unacceptable toxicity, or death. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Onartuzumab
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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 |
Onartuzumab in NSS was administered by IV infusion.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo + mFOLFOX6
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Reporting group description |
Placebo matched to onartuzumab was administered by intravenous (IV) infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 milligrams per meter square (mg/m^2) IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with placebo, further continued treatment with placebo until disease progression, unacceptable toxicity, or death. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Onartuzumab + mFOLFOX6
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Reporting group description |
Onartuzumab 10 mg/kilogram (mg/kg) in 250 milliliter (mL) final 0.9% normal saline solution (NSS) was administered by IV infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 mg/m^2 IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-FU 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with onartuzumab, further continued treatment with onartuzumab until disease progression, unacceptable toxicity, or death. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo + mFOLFOX6
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Reporting group description |
Placebo matched to onartuzumab was administered by intravenous (IV) infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 milligrams per meter square (mg/m^2) IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with placebo, further continued treatment with placebo until disease progression, unacceptable toxicity, or death. | ||
Reporting group title |
Onartuzumab + mFOLFOX6
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Reporting group description |
Onartuzumab 10 mg/kilogram (mg/kg) in 250 milliliter (mL) final 0.9% normal saline solution (NSS) was administered by IV infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 mg/m^2 IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-FU 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with onartuzumab, further continued treatment with onartuzumab until disease progression, unacceptable toxicity, or death. | ||
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End point title |
Percentage of Participants Who Died: Met 2 + /3 + Subgroup GEC Participants [1] | ||||||||||||
End point description |
Met 2+ /3+ subgroup included all randomized participants with previously untreated HER2–negative GEC classified as Met-IHC 2+ or 3+.
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End point type |
Primary
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End point timeframe |
Randomization until death due to any cause (up to approximately 1.5 years)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis section is not applicable for this end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
OS: Met 2 + /3 + Subgroup GEC Participants | ||||||||||||
End point description |
OS was defined as the time from randomization to death due to any cause. Data for participants who were not reported as having died at the time of analysis were censored at the date they were last known to be alive. Participants who do not have post-baseline information were censored at the date of randomization plus 1 day. OS was estimated using Kaplan-Meier methodology. 99999 refers to the upper limit of confidence interval (CI) which was not-estimable due to insufficient follow-up. Met 2+/3+ subgroup population.
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End point type |
Primary
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End point timeframe |
Baseline until death due to any cause (up to approximately 1.5 years)
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Statistical analysis title |
Stratified Analysis | ||||||||||||
Statistical analysis description |
Hazard ratios were estimated by Cox regression. The stratification factors are Met expression (level I, II, III, IV, or V), world region (Asia-Pacific vs. other), and prior gastrectomy (yes vs. no).
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Comparison groups |
Placebo + mFOLFOX6 v Onartuzumab + mFOLFOX6
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Number of subjects included in analysis |
214
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0311 [2] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.64
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.4 | ||||||||||||
upper limit |
1.03 | ||||||||||||
| Notes [2] - One-sided p-value |
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Statistical analysis title |
Unstratified Analysis | ||||||||||||
Statistical analysis description |
Hazard ratios were estimated by Cox regression.
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Comparison groups |
Placebo + mFOLFOX6 v Onartuzumab + mFOLFOX6
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Number of subjects included in analysis |
214
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1955 [3] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.82
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.52 | ||||||||||||
upper limit |
1.29 | ||||||||||||
| Notes [3] - One-sided p-value |
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End point title |
Percentage of Participants Who Died: ITT Population [4] | ||||||||||||
End point description |
ITT population included all randomized participants. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline until death due to any cause (up to approximately 1.5 years)
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis section is not applicable for this end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
OS: ITT Population | ||||||||||||
End point description |
OS was defined as the time from randomization to death due to any cause. Data for participants who were not reported as having died at the time of analysis were censored at the date they were last known to be alive. Participants who do not have post-baseline information were censored at the date of randomization plus 1 day. OS was estimated using Kaplan-Meier methodology. 99999 refers to the upper limit of CI which was not-estimable due to insufficient follow-up. ITT population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline until death due to any cause (up to approximately 1.5 years)
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Statistical analysis title |
Stratified Analysis | ||||||||||||
Statistical analysis description |
Hazard ratios were estimated by Cox regression. The stratification factors are Met expression (level I, II, III, IV, or V), world region (Asia-Pacific vs. other), and prior gastrectomy (yes vs. no).
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Comparison groups |
Onartuzumab + mFOLFOX6 v Placebo + mFOLFOX6
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Number of subjects included in analysis |
562
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1222 [5] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.82
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.59 | ||||||||||||
upper limit |
1.15 | ||||||||||||
| Notes [5] - One-sided p-value |
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Statistical analysis title |
Unstratified Analysis | ||||||||||||
Statistical analysis description |
Hazard ratios were estimated by Cox regression.
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Comparison groups |
Placebo + mFOLFOX6 v Onartuzumab + mFOLFOX6
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Number of subjects included in analysis |
562
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.3899 [6] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.95
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.69 | ||||||||||||
upper limit |
1.32 | ||||||||||||
| Notes [6] - One-sided p-value |
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End point title |
Progression-free survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1): Met 2 + /3 + Subgroup GEC Participants | ||||||||||||
End point description |
PFS is defined as the time between the date of randomization and the date of first documented disease progression (PD) or death, whichever occurs first. Participants who were alive and have not experienced PD at the time of analysis were censored at the time of the last tumor assessment. Participants with no post-baseline tumor assessment were censored at the randomization date plus 1 day. PD: at least 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and absolute increase of at least 5 millilmeters (mm), progression of existing non-target lesions, or presence of new lesions. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criteria was not met, the analysis was not performed.
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End point type |
Secondary
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End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 1.5 years)
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| Notes [7] - As the pre-specified criteria was not met, the analysis was not performed. [8] - As the pre-specified criteria was not met, the analysis was not performed. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PFS as Determined by Investigator Using RECIST v1.1: ITT Population | ||||||||||||
End point description |
PFS is defined as the time between the date of randomization and the date of first documented PD or death, whichever occurs first. Participants who were alive and have not experienced PD at the time of analysis were censored at the time of the last tumor assessment. Participants with no post-baseline tumor assessment were censored at the randomization date plus 1 day. PD: at least 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criteria was not met, the analysis was not performed.
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End point type |
Secondary
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End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 3 years)
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| Notes [9] - As the pre-specified criteria was not met, the analysis was not performed. [10] - As the pre-specified criteria was not met, the analysis was not performed. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants With Objective Response as Determined Using RECIST v1.1: Met 2 + /3 + Subgroup GEC Participants | ||||
End point description |
Objective response:complete response(CR) or partial response(PR) as determined by the Investigator using RECIST v1.1 on 2 consecutive occasions at least 6 weeks apart.Participants were assessed by computed tomography (CT) or magnetic resonance imaging (MRI).CR:complete disappearance of all target lesions&non-target disease,except nodal disease.All nodes,both target and non-target,must decrease to normal (short axis less than [<] 10 millimeter [mm]).No new lesions.PR:greater than or equal(>=)30% decrease from baseline in the sum of diameters of target lesions.The short axis was used in the sum for target nodes,while the longest diameter was used in the sum for all other target lesions.No unequivocal progression of non-target disease.No new lesions.As per protocol,the secondary efficacy endpoints(including patient-reported endpoint)were only to be analyzed if the primary outcome results in statistical significance.As the pre-specified criteria was not met,the analysis was not performed.
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End point type |
Secondary
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End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 1.5 years)
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| No statistical analyses for this end point | |||||
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End point title |
Percentage of Participants With Objective Response as Determined Using RECIST v1.1: ITT Population | ||||||||||||
End point description |
Objective response is defined as a CR or PR as determined by the Investigator using RECIST v1.1 on 2 consecutive occasions at least 6 weeks apart. Participants were evaluated for tumor response for target lesions and assessed by CT or MRI. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease from baseline in the sum of diameters of target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criteria was not met, the analysis was not performed.
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End point type |
Secondary
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End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 1.5 years)
|
||||||||||||
|
|||||||||||||
| Notes [11] - As the pre-specified criteria was not met, the analysis was not performed. [12] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants With Disease Control as Determined Using RECIST v1.1: Met 2 + /3 + Subgroup GEC Participants | ||||||||||||
End point description |
Disease Control: Participants with CR, PR or stable disease(SD)for at least 6 weeks by RECIST v1.1. CR: complete disappearance of all target lesions&non-target disease,except nodal disease. All nodes must decrease to normal.PR: >=30% decrease from baseline in the sum of diameters of target lesions.The short axis was used in the sum for target nodes&the longest diameter was used in the sum for all other target lesions.No unequivocal progression of non-target disease. SD:neither sufficient shrinkage nor increase to qualify for PR or PD.PD:at least 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and absolute increase of at least 5 mm,progression of existing non-target lesions,or new lesions.As per protocol,the secondary efficacy endpoints (including patient-reported endpoints)were only to be analyzed if the primary outcome results in statistical significance.As the pre-specified criteria was not met,the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 1.5 years)
|
||||||||||||
|
|||||||||||||
| Notes [13] - As the pre-specified criteria was not met, the analysis was not performed. [14] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants With Disease Control as Determined Using RECIST v1.1: ITT Population | ||||||||||||
End point description |
Disease control: Participants with CR, PR or SD for at least 6 weeks by RECIST v1.1. CR: complete disappearance of all target lesions & non-target disease, except nodal disease. All nodes must decrease to normal. PR: >=30% decrease from baseline in the sum of diameters of target lesions. The short axis was used in the sum for target nodes & the longest diameter was used in the sum for all other target lesions.No unequivocal progression of non-target disease. SD: neither sufficient shrinkage nor increase to qualify for PR or PD. PD: at least 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or new lesions. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criteria was not met,the analysis was not performed
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 1.5 years)
|
||||||||||||
|
|||||||||||||
| Notes [15] - As the pre-specified criteria was not met, the analysis was not performed. [16] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||||||||||
End point description |
An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. AEs included both serious as well as non-serious adverse events. Safety population included all randomized participants who received at least one dose of study treatment.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline up to 30 days after the last administration of study drug (approximately up to 3 years)
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) Against Onartuzumab | ||||||||||||||||||
End point description |
Safety population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this endpoint and "n" indicates total number of participants with evaluable data for a particular time point.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Pre-dose (within 1 hour before infusion start) on Day 1 of Cycles 1 and 4, (cycle length = 14 days), at study drug discontinuation visit (up to 3 years)
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||
End point title |
Minimum Observed Serum Onartuzumab Concentration (Cmin) [17] | ||||||||
End point description |
Safety population. "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Predose (0-1 hours) on Day 1 of Cycles 1, 2 and 4 (cycle length = 14 days), at study drug discontinuation visit (up to approximately 1.5 years)
|
||||||||
| Notes [17] - 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: Only participants who received onartuzumab were included in analysis; hence only Onartuzumab + mFOLFOX6 arm is reported. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Maximum Observed Serum Onartuzumab Concentration (Cmax) [18] | ||||||||
End point description |
Safety population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
30 minutes after end of infusion (duration of infusion = 60 minutes) on Cycle 1 Day 1 (cycle length = 14 days)
|
||||||||
| Notes [18] - 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: Only participants who received onartuzumab were included in analysis; hence only Onartuzumab + mFOLFOX6 arm is reported. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
European Organization for Research and Treatment Cancer Quality of Life Questionnaire (EORTC QLQ) Core 30 (EORTC QLQ-C30) Version 3 Score | ||||||||||||
End point description |
EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criterion was not met, the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 of each treatment Cycle up to end of treatment (EOT) (up to approximately 1.5 years) (1 Cycle= 21 days)
|
||||||||||||
|
|||||||||||||
| Notes [19] - As the pre-specified criteria was not met, the analysis was not performed. [20] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
EORTC QLQ-Gastric cancer Specific Quality of Life Questionnaire (EORTC QLQ-STOC22) Score | ||||||||||||
End point description |
EORTC QLQ-STOC22: included symptom or problem scale (eating problems, discomfort, pain, bloating, indigestion, nausea/vomiting, dry mouth). Questions used 4 point scale (1 'Not at all' to 4 'Very much'; higher score=better level of functioning or greater degree of symptoms. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criterion was not met, the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 of each treatment Cycle up to EOT (up to approximately 1.5 years) (1 Cycle= 21 days)
|
||||||||||||
|
|||||||||||||
| Notes [21] - As the pre-specified criteria was not met, the analysis was not performed. [22] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Score | ||||||||||||
End point description |
EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state ("confined to bed"). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criterion was not met, the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 of each treatment Cycle up to EOT (up to approximately 1.5 years) (1 Cycle= 21 days)
|
||||||||||||
|
|||||||||||||
| Notes [23] - As the pre-specified criteria was not met, the analysis was not performed. [24] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Duration of Response (DOR) as Determined by Investigator Using RECIST v1.1: Met 2 + /3 + Subgroup GEC Participants | ||||||||||||
End point description |
DOR is defined as the duration from the first tumor assessment that supports the participant's objective response (CR or PR, whichever is first recorded) to PD or death due to any cause, whichever occurs first. Participants who are alive and have not experienced PD at the time of analysis were censored at the time of the last tumor assessment. Participants with no post-baseline tumor assessment were censored at the randomization date plus 1 day. PD: at least 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. DOR was estimated using Kaplan-Meier methodology. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criterion was not met, the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 1.5 years)
|
||||||||||||
|
|||||||||||||
| Notes [25] - As the pre-specified criteria was not met, the analysis was not performed. [26] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DOR as Determined by Investigator Using RECIST v1.1: ITT Population | ||||||||||||
End point description |
DOR is defined as the duration from the first tumor assessment that supports the participant's objective response (CR or PR, whichever is first recorded) to PD or death due to any cause, whichever occurs first. Participants who are alive and have not experienced PD at the time of analysis were censored at the time of the last tumor assessment. Participants with no post-baseline tumor assessment were censored at the randomization date plus 1 day. PD: at least 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. DOR was estimated using Kaplan-Meier methodology. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criterion was not met, the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to disease progression or death due to any cause, whichever occurred first (up to approximately 3 years)
|
||||||||||||
|
|||||||||||||
| Notes [27] - As the pre-specified criteria was not met, the analysis was not performed. [28] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change from Baseline in ATAs Level of Onartuzumab | ||||||||||||
End point description |
Safety population. As per protocol, the secondary efficacy endpoints (including patient-reported endpoints) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criteria was not met, the analysis was not performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (pre-dose [within 1 hour before infusion start] on Cycle 1 Day 1), pre-dose on Cycle 4 Day 1 (cycle length = 14 days), at study drug discontinuation visit (up to 3 years)
|
||||||||||||
|
|||||||||||||
| Notes [29] - As the pre-specified criteria was not met, the analysis was not performed. [30] - As the pre-specified criteria was not met, the analysis was not performed. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
Baseline up to 30 days after the last administration of study drug (approximately up to 3 years)
|
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Adverse event reporting additional description |
Safety population
|
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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 |
Placebo + mFOLFOX6
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Reporting group description |
Placebo matched to onartuzumab was administered by IV infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 mg/m^2 IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-FU 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with placebo, further continued treatment with placebo until disease progression, unacceptable toxicity, or death. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Onartuzumab + mFOLFOX6
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Reporting group description |
Onartuzumab 10 mg/kg in 250 mL final 0.9% NSS was administered by IV infusion (first infusion for 60 minutes, and subsequently for 30 minutes) on Day 1 of each 14-day cycle followed by mFOLFOX6 regimen comprising of oxaliplatin 85 mg/m^2 IV, folinic acid (400 mg/m^2) or levofolinic acid (200 mg/m^2) or as deemed appropriate per investigator and 5-FU 400 mg/m^2 IV bolus, then 5-FU 2400 mg/m^2 continuous IV infusion over 46 to 48 hours until 12 cycles. Participants without disease progression after 12 cycles of mFOLFOX6 with onartuzumab, further continued treatment with onartuzumab until disease progression, unacceptable toxicity, or death. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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12 Sep 2012 |
- Met IHC stratification factor (formerly a clinical score of 1+ vs. 2+/3+ based on a >/= 50% analytical cutoff) and primary tumor location has been replaced with 5 stratification levels encompassing a >/=50% and >/=90% analytical cutoff (I, II, III, IV, and V).
- Baseline weight (rather than screening weight) was used to calculate onartuzumab/placebo dosage.
- The exclusion criterion regarding history of malignancy has been modified, and exclusion criterion regarding known sensitivity to components of study treatment has been updated to include known contraindications.
- Procedures for potential emergency unblinding have been revised.
- Live vaccines have been added to the list of prohibited concomitant medications.
- Text has been added to indicate that participants must receive the first dose of study drug within 3 days after randomization.
- Description of the tumor assessment schedule and text concerning chemotherapy dose modification has been updated.
- The protocol has been amended to specify pharmacokinetics (PK)/ATA evaluation at selected centers only.
- Text has been added to indicate that objective response rate has been evaluated in all randomized participants.
- The rationale for the study design has been updated.
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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. | |||
| As per protocol, the secondary efficacy outcomes (including patient-reported outcomes) were only to be analyzed if the primary outcome results in statistical significance. As the pre-specified criteria was not met, the analysis was not performed. | |||
