Description:
This double-blind, placebo-controlled, randomized, multicenter, international, parallel arm
study will evaluate the efficacy and safety of pertuzumab in combination with trastuzumab,
fluoropyrimidine and cisplatin as first-line treatment in participants with HER2-positive
metastatic gastroesophageal junction (GEJ) or gastric cancer (GC). Participants will be
randomized to receive pertuzumab 840 milligrams (mg) or placebo intravenously every 3 weeks
(q3w) in combination with trastuzumab (initial dose of 8 milligrams per kilogram [mg/kg]
intravenously [IV] followed by 6 mg/kg IV q3w) and cisplatin and fluoropyrimidine
(capecitabine or 5-fluorouracil) for the first 6 treatment cycles. Participants will continue
to receive pertuzumab or placebo and trastuzumab until disease progression occurrence of
unacceptable toxicity or withdrawal from the study for another reason.
Title
- Brief Title: A Study of Pertuzumab in Combination With Trastuzumab and Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Gastroesophageal Junction or Gastric Cancer
- Official Title: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Phase III Study Evaluating the Efficacy and Safety of Pertuzumab in Combination With Trastuzumab and Chemotherapy in Patients With HER2-Positive Metastatic Gastroesophageal Junction and Gastric Cancer
Clinical Trial IDs
- ORG STUDY ID:
BO25114
- SECONDARY ID:
2012-003554-83
- NCT ID:
NCT01774786
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| 5-Fluorouracil | | Pertuzumab + Trastuzumab + Chemotherapy |
| Capecitabine | Xeloda | Pertuzumab + Trastuzumab + Chemotherapy |
| Cisplatin | | Pertuzumab + Trastuzumab + Chemotherapy |
| Pertuzumab | Perjeta, RO4368451 | Pertuzumab + Trastuzumab + Chemotherapy |
| Placebo | | Placebo + Trastuzumab + Chemotherapy |
| Trastuzumab | Herceptin, RO0452317 | Pertuzumab + Trastuzumab + Chemotherapy |
Purpose
This double-blind, placebo-controlled, randomized, multicenter, international, parallel arm
study will evaluate the efficacy and safety of pertuzumab in combination with trastuzumab,
fluoropyrimidine and cisplatin as first-line treatment in participants with HER2-positive
metastatic gastroesophageal junction (GEJ) or gastric cancer (GC). Participants will be
randomized to receive pertuzumab 840 milligrams (mg) or placebo intravenously every 3 weeks
(q3w) in combination with trastuzumab (initial dose of 8 milligrams per kilogram [mg/kg]
intravenously [IV] followed by 6 mg/kg IV q3w) and cisplatin and fluoropyrimidine
(capecitabine or 5-fluorouracil) for the first 6 treatment cycles. Participants will continue
to receive pertuzumab or placebo and trastuzumab until disease progression occurrence of
unacceptable toxicity or withdrawal from the study for another reason.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Pertuzumab + Trastuzumab + Chemotherapy | Experimental | Participants will receive pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, participants will continue to receive pertuzumab and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason. | - 5-Fluorouracil
- Capecitabine
- Cisplatin
- Pertuzumab
- Trastuzumab
|
| Placebo + Trastuzumab + Chemotherapy | Placebo Comparator | Participants will receive placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, participants will continue to receive placebo and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason. | - 5-Fluorouracil
- Capecitabine
- Cisplatin
- Placebo
- Trastuzumab
|
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed metastatic adenocarcinoma of the stomach or GEJ
- Measurable or evaluable non-measurable disease as assessed by the investigator
according to RECIST v1.1 criteria
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Life expectancy greater than equal to (>/=) 3 months
Exclusion Criteria:
- Previous cytotoxic chemotherapy for advanced (metastatic) disease
- Evidence of disease progression documented within 6 months after completion of prior
neoadjuvant or adjuvant cytotoxic chemotherapy, or both, or radiotherapy for GEJ
adenocarcinoma
- Previous treatment with any HER2-directed therapy, at any time, for any duration
- Previous exposure to any investigational treatment within 30 days before the first
dose of study treatment
- Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks
if given as palliation to bone metastases, if recovered from all toxicities)
- History or evidence of brain metastases
- Clinically significant active gastrointestinal (GI) bleeding (Grade >/=2 according to
National Cancer Institute [NIC]-Common Terminology Criteria for Adverse Events Version
4.0 [CTCAEv.4.0])
- Residual toxicity resulting from previous therapy (for example, hematologic,
cardiovascular, or neurologic toxicity that is Grade >/=2). Alopecia is permitted
- Other malignancy (in addition to gastric cancer [GC]) within 5 years before
enrollment, except for carcinoma in situ of the cervix or squamous or basal cell
carcinoma of the skin that has been previously treated with curative intent
- Inadequate hematologic, renal or liver function
- Pregnant or lactating women
- History of congestive heart failure of any New York Heart Association (NYHA) criteria
- Angina pectoris requiring treatment
- Myocardial infarction within the past 6 months before the first dose of study drug
- Clinically significant valvular heart disease or uncontrollable high-risk cardiac
arrhythmia
- History or evidence of poorly controlled hypertension
- Baseline left ventricular ejection fraction (LVEF) value less than (<) 55 percent (%)
- Any significant uncontrolled intercurrent systemic illness
- Positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall Survival |
| Time Frame: | From Baseline until death from any cause (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.4 [0-42] months vs. 25.0 [0-41] months; Final Analysis: 46.1 [0-70] months vs. 44.4 [0-68] months) |
| Safety Issue: | |
| Description: | Overall survival (OS) was defined as the time from randomization to death from any cause. For participants who were still alive on the date of clinical data cut-off for the OS analysis, the last date when the participant was known to be alive on, or prior to the clinical cut-off date, was used to determine the censoring date. Participants who did not have any post-baseline data (e.g., dosing records, imaging dates, visit dates) were censored at the date of randomization plus 1 day. |
Secondary Outcome Measures
| Measure: | Progression-Free Survival, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria |
| Time Frame: | Baseline to death or progressive disease (PD), whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] vs. 21.3 [0-39] months; Final Analysis: 50.4 [0-70] vs. 47.4 [0-66] months) |
| Safety Issue: | |
| Description: | Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first. Tumor assessments with CT or MRI scans of the chest, abdomen, and pelvis were performed every 9 weeks. Participants without documented PD or death were censored at the tumor assessment date for which the participant was last known to be progression-free. Participants who did not have any post-baseline tumor assessment data were censored at the date of randomization plus 1 day. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 millimeters (mm) in the sum of diameters of target lesions; the appearance of one or more new lesions. |
| Measure: | Primary Analysis of the Percentage of Participants With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria |
| Time Frame: | Baseline up to death or progressive disease, whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] months vs. 21.3 [0-39] months) |
| Safety Issue: | |
| Description: | The overall objective response rate was defined as the percentage of participants with partial response (PR) or complete response (CR) occurring on two consecutive occasions ≥4 weeks apart, as determined by the investigator using RECIST v1.1. Tumor assessments with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed every 9 weeks. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be greater than or equal to (≥) 15 mm in short axis when assessed by CT scan. |
| Measure: | Final Analysis of the Percentage of Participants With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria |
| Time Frame: | Baseline up to death or progressive disease, whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Final Analysis: 50.4 [0-70] months vs. 47.4 [0-66] months) |
| Safety Issue: | |
| Description: | The overall objective response rate was defined as the percentage of participants with partial response (PR) or complete response (CR) occurring on two consecutive occasions ≥4 weeks apart, as determined by the investigator using RECIST v1.1. Tumor assessments with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed every 9 weeks. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be greater than or equal to (≥) 15 mm in short axis when assessed by CT scan. |
| Measure: | Duration of Objective Response, as Determined by Investigator According to RECIST v1.1 Criteria |
| Time Frame: | Baseline to death or progressive disease (PD), whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] vs. 21.3 [0-39] months; Final Analysis: 50.4 [0-70] vs. 47.4 [0-66] months) |
| Safety Issue: | |
| Description: | Duration of objective response is defined as the time from first occurrence of documented objective response to documented disease progression, as determined by the investigator using RECIST v1.1, or death from any cause. Objective response: PR or CR occurring on 2 consecutive occasions ≥4 weeks apart. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. Measurable disease defined as tumor lesions with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node, it must be ≥15 mm in short axis when assessed by CT scan. |
| Measure: | Percentage of Participants With Clinical Benefit, as Determined by the Investigator According to RECIST v1.1 Criteria |
| Time Frame: | Baseline up to death or progressive disease, whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] months vs. 21.3 [0-39] months) |
| Safety Issue: | |
| Description: | The clinical benefit rate was defined as best response of complete response (CR) or partial response (PR) or stable disease (SD) for 6 weeks or longer, as determined by the investigator using RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum diameters while on study. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be >/=15 mm in short axis when assessed by CT scan. The clinical benefit rate was not updated at the final analysis. |
| Measure: | Overview of Safety: Number of Participants With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03 |
| Time Frame: | From Baseline until end of post-treatment follow-up (up to 70 months) |
| Safety Issue: | |
| Description: | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. |
| Measure: | Number of Participants With Symptomatic or Asymptomatic Left Ventricular Systolic Dysfunction (LVSD) |
| Time Frame: | From Baseline until end of post-treatment follow-up (up to 70 months) |
| Safety Issue: | |
| Description: | The number and percentage of participants with symptomatic left ventricular systolic dysfunction (LVSD) and asymptomatic LVSD events (defined as a left ventricular ejection fraction [LVEF] ≥10% decrease from baseline to an absolute value <50%) at any time during the study was summarized by treatment arm. |
| Measure: | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score |
| Time Frame: | Day 1 of each 21-day treatment cycle up to 28 and 60-90 days (post-treatment [PT] monitoring visits 1 and 2, respectively) after Day 1 of last treatment cycle (up to approximately 3.5 years) |
| Safety Issue: | |
| Description: | The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1). |
| Measure: | Change From Baseline in EORTC QLQ-Gastric Cancer Module (EORTC QLQ-STO22) Score |
| Time Frame: | Day 1 of each 21-day treatment cycle up to 28 and 60-90 days (post-treatment [PT] monitoring visits 1 and 2, respectively) after Day 1 of last treatment cycle (up to approximately 3.5 years) |
| Safety Issue: | |
| Description: | The EORTC 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. A positive value means an increase, while a negative values means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1). |
| Measure: | Maximum Serum Concentration (Cmax) of Pertuzumab |
| Time Frame: | Post-dose (0.5 hour after end of 30-60 minutes infusion) on Day 1 of Cycles 1, 2, 4, and 8 (1 cycle = 21 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Cmax of Trastuzumab |
| Time Frame: | Post-dose (0.5 hour after end of 30-60 minutes infusion) on Day 1 of Cycles 1, 2, 4, and 8 (1 cycle = 21 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Minimum Serum Concentration (Cmin) of Pertuzumab |
| Time Frame: | Pre-dose (0-6 hours before infusion) on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (1 cycle = 21 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Cmin of Trastuzumab |
| Time Frame: | Pre-dose (0-6 hours before infusion) on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (1 cycle = 21 days) |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Hoffmann-La Roche |
Last Updated
December 30, 2020
