A Phase I/III, Randomized, Double-Blind, Placebo-Controlled Study of Carboplatin Plus Etoposide With or Without Atezolizumab (Anti-PD-L1 Antibody) in Patients With Untreated Extensive-Stage Small Cell Lung Cancer
Overview
- Phase
- Phase 3
- Intervention
- Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
- Conditions
- Small Cell Lung Carcinoma
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 503
- Locations
- 114
- Primary Endpoint
- Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study was designed to evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin plus (+) etoposide compared with treatment with placebo + carboplatin + etoposide in chemotherapy-naive participants with ES-SCLC. Participants will be randomized in a 1:1 ratio to receive either atezolizumab + carboplatin + etoposide or placebo + carboplatin + etoposide on 21-day cycles for four cycles in the induction phase followed by maintenance with atezolizumab or placebo until progressive disease (PD) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Treatment can be continued until persistent radiographic PD or symptomatic deterioration.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung Study Group \[VALG\] staging system)
- •No prior systemic treatment for ES-SCLC
- •Eastern Cooperative Oncology Group performance status of 0 or 1
- •Measurable disease, as defined by RECIST v1.1
- •Adequate hematologic and end organ function
- •Treatment-free for at least 6 months since last chemo/radiotherapy, among those treated (with curative intent) with prior chemo/radiotherapy for limited-stage SCLC
Exclusion Criteria
- •Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation
- •Malignancies other than SCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
- •Pregnant or lactating women
- •History of autoimmune disease
- •History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- •Positive test result for human immunodeficiency virus (HIV)
- •Active hepatitis B or hepatitis C
- •Severe infections at the time of randomization
- •Significant cardiovascular disease
- •Prior treatment with cluster of differentiation (CD) 137 agonists or immune checkpoint blockade therapies, anti-programmed death-1 (PD-1), and anti-PD-L1 therapeutic antibody
Arms & Interventions
Atezolizumab + Carboplatin + Etoposide
Participants received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m\^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
Atezolizumab + Carboplatin + Etoposide
Participants received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m\^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
Intervention: Carboplatin
Atezolizumab + Carboplatin + Etoposide
Participants received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m\^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
Intervention: Etoposide
Placebo + Carboplatin + Etoposide
Participants received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m\^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
Intervention: Carboplatin
Placebo + Carboplatin + Etoposide
Participants received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m\^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
Intervention: Etoposide
Placebo + Carboplatin + Etoposide
Participants received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m\^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
Intervention: Placebo
Outcomes
Primary Outcomes
Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population
Time Frame: Baseline until PD or death, whichever occurs first (up to approximately 23 months)
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least 20% increase in the sum of the longest diameter of target lesions compared to baseline, or unequivocal progression in non-target lesion(s), or the appearance of new lesion(s).
Duration of Overall Survival (OS) in the Global Population
Time Frame: Baseline until death from any cause (up to approximately 23 months)
OS is defined as the time from randomization to death from any cause.
Secondary Outcomes
- Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population(Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 23 months))
- OS Rate at 1 Year and 2 Years in the Global Population(1 year, 2 years)
- Percentage of Participants With at Least One Adverse Event in the Global Population(Baseline until up to 90 days after end of treatment (up to approximately 49 months))
- Plasma Concentration of Carboplatin in the Global Population(Predose, before end of infusion, and after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days))
- Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population(First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 23 months))
- PFS Rate at 6 Months and at 1 Year in Global Population(6 months, 1 year)
- Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population(Baseline until deterioration per symptom subscale (up to approximately 23 months))
- Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population(Predose (0 hours [H]) on Day (D) 1 of Cycles (C) 1, 2, 3, 4, 8, 16, and every 8 cycles (Q8C) thereafter (cycle = 21 days) until treatment discontinuation (up to 23 months) and 120 days after last dose (up to approximately 23 months overall))
- Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population(Post-dose Day 1 of Cycle 1 (cycle length = 21 days))
- Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population(Predose on Day 1 of Cycles 1, 3, 4, 8, 16 and 24 (cycle length = 21 days))
- Plasma Concentration of Etoposide in the Global Population(Predose, before end of infusion, 1 and 4 hours after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days))