This parallel, randomized, open-label, multi-centre study will evaluate the effect on overall survival of trastuzumab (Herceptin) in combination with a chemotherapy compared to the chemotherapy alone in patients with HER2-positive advanced gastric cancer. Trastuzumab (Herceptin) will be administered as intravenous infusion of 6 mg/kg (loading dose 8 mg/kg) every 3 weeks. The chemotherapy consists of a combination of 6 cycles of fluorouracil (800 mg/m2/day intravenous infusion every 3 weeks) and cisplatin (80 mg/m2 intravenous infusion every 3 weeks), or capecitabine (Xeloda, 1000 mg/m2 po twice daily for 14 days every 3 weeks) and cisplatin (80 mg/m2 intravenous infusion every 3 weeks). Treatment with trastuzumab (Herceptin) will continue until disease progression. The target sample size is 300-600 patients.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
584
Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression
800 mg/m2 i.v. infusion on Days 1 through 5 of cycle every 3 weeks for 6 cycles
80 mg/m2 i.v. infusion on Day 1 of cycle every 3 weeks for 6 cycles
1000 mg/m2 p.o. twice daily on Days 1 through 15 of cycle every 3 weeks for 6 cycles
Unnamed facility
Adelaide, Australia
Unnamed facility
Kurralta Park, Australia
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Melbourne, Australia
Unnamed facility
Milton, Australia
Unnamed facility
Perth, Australia
Unnamed facility
Sydney, Australia
Overall Survival (OS) - Percentage of Participants With an Event
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up.
Time frame: Baseline (BL), Days 1, 8, 15, 22, 43, 64, 85, 106, 127, and every 21 days until the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Overall Survival - Time to Event
The median time, in months, from the date of randomization to the date of an OS event. Participants were censored at the last date tumor measurement, the last date in the study drug log, or the date of last follow-up.
Time frame: BL, Days 1, 8, 15, 22, 43, 64, 85, 106, 127, and every 21 days until the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Progression-Free Survival (PFS) - Percentage of Participants With an Event
PFS was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or date of death, whichever occurs first. For target lesions (TL), PD was defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD) of TLs, taking as a reference the smallest SLD recorded since the treatment started, or the appearance of one or more lesions. For non-target lesions (NTL), PD was defined as an unequivocal progression of existing NTLs. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Progression-Free Survival - Time to Event
The median time, in months, from the date of randomization to the date of a PFS event. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Time to Progression (TTP) - Percentage of Participants With an Event
TTP was defined as the time from the date of randomization and the date of the first occurrence of PD. Participants were censored at the last date of tumor assessment, the last date in the study drug log, or the last date of follow-up.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Time to Progression - Time to Event
The median time, in months, from the date of randomized to the date of a TTP event. Participants were censored at the last date of tumor assessment, the last date in the study drug log, or the last date of follow-up.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Percentage of Participants With Confirmed Complete Response (CR) or Partial Response (PR) Determined by Response Evaluation Criteria in Solid Tumors (RECIST)
For TLs, a CR was defined as the disappearance of all TLs and a PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD. For NTLs, a CR was defined as the disappearance of all NTLs and normalization of tumor marker levels.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Duration of Response - Percentage of Participants With an Event
Duration of response was defined for responders as the time from the date on which the CR or PR was first recorded to the date on which PD is first noted. Participants were censored on the date of death, the date of last tumor measurement, the last date in study drug log, or the date of last follow-up.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Duration of Response
The median time, in months, of the duration of response. Participants were censored at the date of death, the date of last tumor measurement, the last date in study drug log, or the date of last follow-up.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Percentage of Participants With Clinical Benefit
Clinical benefit was defined as stable disease (SD), CR, or PR for 6 weeks or longer as determined by RECIST. For TLs, SD was defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, taking as a reference the smallest SLD recorded since treatment had started. For NTLs, SD was defined as a persistence of one or more NTLs and/or maintenance of tumor marker levels above the normal limits.
Time frame: BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
European Organisation For the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ C-30) Questionnaire Scores
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 equals (=) better level of functioning or greater degree of symptoms.
Time frame: BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
EORTC Quality of Life Questionnaire-Stomach Cancer Specific (QLQ STO22) Questionnaire Scores
The QLQ-STO22 is a gastric cancer quality of life questionnaire. There are 22 questions concerning disease, treatment related symptoms, side effects, dysphagia, nutritional aspects, and questions about the emotional problems of gastric cancer (dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image, and hair loss). The questions are grouped into five scales and 4 single items which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms.
Time frame: BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Pain Intensity Scores as Assessed By Visual Analog Scale (VAS)
The participant assessed their pain on a 0 to 100 millimeter (mm) horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". A negative change indicated improvement.
Time frame: BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Percentage of Participants With a Change in Analgesic Medication During the Study
Analgesic medications were recorded throughout the study until disease progression.
Time frame: BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Body Weight (Kilograms [kg]) at BL
Time frame: BL
Percentage of Participants With Change From Baseline in Body Weight by Percentage Change in Weight
Change in body weight was categorized as an increase of greater than (\>)5 percent (%), no change (plus or minus \[±\]5%), decrease of \>5-10%, or a decrease of \>10% from BL to the end of study. Time windows were applied in order to assign visits to weight measurements, and the lowest post-screening value recorded was used for the analysis. The percentage change in weight from screening was summarized over time.
Time frame: BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Steady State Trastuzumab Area Under the Concentration (AUC)
Individual steady state predicted exposure, as assessed by median AUC (measured as mg multiplied by \[\*\] day per liter \[L\]) calculated for all treated participants using the nominal dosage schedule administered as an IV infusion. Individual steady state AUC was calculated using all available PK samples from all timepoints.
Time frame: Predose and end of infusion on Days 1, 8, 15, and 64, and predose on Days 22 and 106
Trastuzumab Minimum Serum Concentration (Cmin)
Median Cmin (measured as milligrams per liter \[mg/L\]) calculated for all treated participants using the nominal dosage schedule administered as an IV infusion.
Time frame: Predose and end of infusion on Days 1, 8, 15, and 64, and predose on Days 22 and 106
Trastuzumab Maximum Serum Concentration (Cmax)
Median Cmax (measured as mg/L) calculated for all treated participants using the nominal dosage schedule administered as an IV infusion.
Time frame: Predose and end of infusion on Days 1, 8, 15, and 64, and predose on Days 22 and 106
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Unnamed facility
Leuven, Belgium
Unnamed facility
Barretos, Brazil
Unnamed facility
Rio de Janeiro, Brazil
Unnamed facility
São Paulo, Brazil
...and 132 more locations