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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

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ClinicalTrials.gov Identifier: NCT01774786
Recruitment Status : Active, not recruiting
First Posted : January 24, 2013
Results First Posted : February 14, 2018
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Gastric Cancer Drug: 5-Fluorouracil Drug: Capecitabine Drug: Cisplatin Drug: Pertuzumab Drug: Placebo Drug: Trastuzumab Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 780 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : June 10, 2013
Actual Primary Completion Date : December 9, 2016
Estimated Study Completion Date : December 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Stomach Cancer

Arm Intervention/treatment
Experimental: Pertuzumab + Trastuzumab + Chemotherapy
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). Participants will continue to receive pertuzumab and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.
Drug: 5-Fluorouracil
Participants will receive 5-fluorouracil 800 milligrams per meter square (mg/m^2)/24 hour IV infusion for 120 hours (Days 1-5) q3w for 6 cycles.

Drug: Capecitabine
Participants will receive capecitabine 1000 mg/m^2 orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) q3w for 6 cycles.
Other Name: Xeloda

Drug: Cisplatin
Participants will receive cisplatin 80 mg/m^2 IV q3w for 6 cycles.

Drug: Pertuzumab
Participants will receive pertuzumab 840 mg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.
Other Name: Perjeta

Drug: Trastuzumab
Participants will receive 8 mg/kg IV initial dose on Day 1, followed by 6 mg/kg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.
Other Name: Herceptin

Placebo Comparator: Placebo + Trastuzumab + Chemotherapy
Participants will receive pertuzumab placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Participants will continue to receive pertuzumab placebo and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.
Drug: 5-Fluorouracil
Participants will receive 5-fluorouracil 800 milligrams per meter square (mg/m^2)/24 hour IV infusion for 120 hours (Days 1-5) q3w for 6 cycles.

Drug: Capecitabine
Participants will receive capecitabine 1000 mg/m^2 orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) q3w for 6 cycles.
Other Name: Xeloda

Drug: Cisplatin
Participants will receive cisplatin 80 mg/m^2 IV q3w for 6 cycles.

Drug: Placebo
Participants will receive pertuzumab placebo IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Drug: Trastuzumab
Participants will receive 8 mg/kg IV initial dose on Day 1, followed by 6 mg/kg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.
Other Name: Herceptin




Primary Outcome Measures :
  1. Overall Survival [ Time Frame: Baseline up to death (up to the 09 Dec 2016 data cutoff, approximately 3.5 years) ]
    Overall survival (OS) was defined as the time from randomization to death from any cause.


Secondary Outcome Measures :
  1. 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 up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years) ]
    Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause. Disease progression: 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.

  2. 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 disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years) ]
    Overall objective response (partial response [PR] or complete response [CR]) occurring on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1. 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 computed tomography (CT) or magnetic resonance imaging (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.

  3. Duration of Objective Response, as Determined by Investigator According to RECIST v1.1 Criteria [ Time Frame: Baseline up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years) ]
    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. Disease progression: 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.

  4. Percentage of Participants With Clinical Benefit, as Determined by the Investigator According to RECIST v1.1 Criteria [ Time Frame: Baseline up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years) ]
    Clinical benefit rate is defined as best response of CR or PR or stable disease 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. Stable Disease: 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.

  5. Percentage of Participants With Adverse Events [ Time Frame: Baseline up to the 09 Dec 2016 data cutoff, approximately 3.5 years ]
    An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.

  6. Percentage of Participants With Left Ventricular Systolic Dysfunction (LVSD, Symptomatic or Asymptomatic) [ Time Frame: Baseline up to the 09 Dec 2016 data cutoff, approximately 3.5 years ]
    Left ventricular systolic dysfunction may either be asymptomatic or have symptoms of heart failure. It is characterized by dilation of the left ventricle and vasoconstriction.

  7. 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) ]
    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).

  8. 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) ]
    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).

  9. Maximum Serum Concentration (Cmax) of Pertuzumab [ Time Frame: Post-dose (0.5 hour after end of 30-60 minutes infusion) on Day (D1) of Cycles 1, 2, 4, and 8 (1 cycle = 21 days; up to approximately 3.5 years) ]
  10. Cmax of Trastuzumab [ Time Frame: Post-dose (0.5 hour after end of 30-60 minutes infusion) on D1 of Cycles 1, 2, 4, and 8 (1 cycle = 21 days; up to approximately 3.5 years) ]
  11. Minimum Serum Concentration (Cmin) of Pertuzumab [ Time Frame: Pre-dose (0-6 hours before infusion) on D1 of Cycles 1, 2, 3, 4, 6, and 8; at 28 & 60-90 days (Post-Treatment [PT] Monitoring Visits 1 and 2, respectively) after D1 of last cycle (1 cycle = 21 days; up to approximately 3.5 years) ]
  12. Cmin of Trastuzumab [ Time Frame: Pre-dose (0-6 hours before infusion) on D1 of Cycles 1, 2, 3, 4, 6, and 8; at 28 & 60-90 days (Post-Treatment [PT] Monitoring Visits 1 and 2, respectively) after D1 of last cycle (1 cycle = 21 days; up to approximately 3.5 years) ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01774786


  Show 196 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01774786     History of Changes
Other Study ID Numbers: BO25114
2012-003554-83 ( EudraCT Number )
First Posted: January 24, 2013    Key Record Dates
Results First Posted: February 14, 2018
Last Update Posted: July 10, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Pertuzumab
Cisplatin
Capecitabine
Trastuzumab
Fluorouracil
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs