A Study of Carboplatin Plus Etoposide With or Without Atezolizumab in Participants With Untreated Extensive-Stage (ES) Small Cell Lung Cancer (SCLC) (IMpower133)

• ClinicalTrials.gov Identifier: NCT02763579
• Recruitment Status: Active, not recruiting
• First Posted: May 5, 2016
• Results First Posted: June 13, 2019
• Last Update Posted: January 27, 2021
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: May 4, 2016
• First Posted Date: May 5, 2016
• Results First Submitted Date: April 19, 2019
• Results First Posted Date: June 13, 2019
• Last Update Posted Date: January 27, 2021
• Actual Study Start Date: June 7, 2016
• Actual Primary Completion Date: April 24, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 21, 2019)

• Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 [ 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) [ Time Frame: Baseline until death from any cause (up to approximately 23 months) ]

Original Primary Outcome Measures (submitted: May 4, 2016)

• Duration of Overall Survival [ Time Frame: Baseline until death from any cause (up to approximately 37 months) ]
• Duration of Progression-Free Survival as Assessed by Investigator Using RECIST v1.1 [ Time Frame: Baseline until disease progression or death, whichever occurred first (up to approximately 37 months) ]

Current Secondary Outcome Measures (submitted: May 21, 2019)

• Percentage of Participants With Objective Response (OR) as Assessed by the Investigator Using RECIST v1.1 [ Time Frame: Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 46 months) ]
• Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 [ Time Frame: First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 46 months) ]
• Percentage of Participants Alive and Without PD, as Assessed by the Investigator Using RECIST v1.1, at 6 Months and 1 Year [ Time Frame: 6 months, 1 year (up to approximately 46 months) ]
• Percentage of Participants Alive at 1 Year and 2 Years [ Time Frame: 1 year, 2 years (up to approximately 46 months) ]
• Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Score [ Time Frame: Baseline until deterioration per symptom subscale (up to approximately 46 months) ]
• TTD Per EORTC QLQ Lung Cancer Module (LC13) Score [ Time Frame: Baseline until deterioration per symptom subscale (up to approximately 46 months) ]
• Percentage of Participants With Adverse Events [ Time Frame: Baseline until up to 90 days after end of treatment (up to approximately 46 months) ]
• Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) [ Time Frame: 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 46 months) and 120 days after last dose (up to approximately 46 months overall) ]
• Maximum Observed Serum Concentration (Cmax) of Atezolizumab [ Time Frame: Predose (0 H) and postdose (0.5 H) on D1 of C1; predose (0 H) on D1 of C2, 3, 4, 8, 16, and Q8C thereafter (cycle = 21 days) until treatment discontinuation (up to 46 months) and 120 days after last dose (up to approximately 46 months overall) ]
  Atezolizumab infusion duration is 60 minutes for the first infusion and 30 minutes for subsequent infusions.
• Minimum Observed Serum Concentration (Cmin) of Atezolizumab [ Time Frame: Predose (0 H) on D1 of C1, 2, 3, 4, 8, 16, and Q8C thereafter (cycle = 21 days) until treatment discontinuation (up to 46 months) and 120 days after last dose (up to approximately 46 months overall) ]
  Atezolizumab infusion duration is 60 minutes for the first infusion and 30 minutes for subsequent infusions.
• Plasma Concentration of Carboplatin [ Time Frame: Predose (0 H) and 5-10 minutes before end/1 H after end of carboplatin infusion (infusion duration = 1 H) on D1 of C1 and C3 (cycle = 21 days)(up to approximately 46 months) ]
• Plasma Concentration of Etoposide [ Time Frame: Predose (0 H) and 5-10 minutes before end/1 H and 4H after end of etoposide infusion (infusion duration = 1 H) on D1 of C1 and C3 (cycle = 21 days)(up to approximately 46 months) ]

Original Secondary Outcome Measures (submitted: May 4, 2016)

• Number of Participants With Objective Response as Assessed by the Investigator Using RECIST v1.1 [ Time Frame: Baseline until partial response (PR) or complete response (CR) (up to approximately 37 months) ]
• Duration of Response as Assessed by the Investigator Using RECIST v1.1 [ Time Frame: First occurrence of PR or CR until disease progression or death, whichever occurred first (up to approximately 37 months) ]
• Time in Response as Assessed by the Investigator Using RECIST v1.1 [ Time Frame: Baseline until disease progression or death, whichever occurred first (up to approximately 37 months) ]
• Progression-Free Survival at 6 Month and 1 Year, as Assessed by Investigator Using RECIST v1.1 [ Time Frame: 6 Month and 1 Year ]
• Overall Survival at 6 Month and 1 Year [ Time Frame: 6 Month and 1 Year ]
• Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score [ Time Frame: Baseline, up to approximately 37 months ]
• Change From Baseline in EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) Score [ Time Frame: Baseline, up to approximately 37 months ]
• Number of Participants with Adverse Events [ Time Frame: up to 90 days after end of treatment (approximately up to 37 months) ]
• Number of Participants With Anti-Therapeutic Antibodies (ATA) [ Time Frame: Pre-dose (PrD) on Day (D) 1 of each treatment cycle (C (C length=21 days) until treatment discontinuations (up to approximately 37 months [Mo]), 120 days after last dose (up to approximately 37 Mo overall) ]
• Maximum Observed Serum Atezolizumab Concentration (Cmax) [ Time Frame: PrD) 0.5 hours post-dose on C1D1, PrD on D1 of C2, 3, 4, 8, 16, then PrD on D1 of every eighth cycle until treatment discontinuation (up to approximately 37 Mo), 120 days after last dose (up to approximately 37 Mo overall) (each C length=21 days) ]
• Minimum Observed Serum Atezolizumab Concentration (Cmin) [ Time Frame: PrD on D1 of C1, 2, 3, 4, 8, 16, then every eighth cycle until treatment discontinuation (up to approximately 37 Mo), 120 days after last dose (up to approximately 37 Mo overall) (each C length=21 days) ]
• Maximum Observed Plasma Carboplatin Concentration [ Time Frame: PrD, 5-10 minutes before the end of carboplatin infusion (infusion duration=1 hour), and 1 hour after the end of carboplatin infusion (infusion duration=1 hour) on C1D1 and C3D1 (each cycle length=21 days) ]
• Maximum Observed Plasma Etoposide Concentration\n [ Time Frame: PrD, 5-10 minutes before the end of etoposide infusion (infusion duration=1 hour), and 1, 4 hour after the end of etoposide infusion (infusion duration=1 hour) on C1D1 and C3D1 (each cycle length=21 days) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Carboplatin Plus Etoposide With or Without Atezolizumab in Participants With Untreated Extensive-Stage (ES) Small Cell Lung Cancer (SCLC)
• Official Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Small Cell Lung Carcinoma

Intervention

• Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
  Atezolizumab intravenous infusion was administered at a dose of 1200 mg on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).
  Other Name: MPDL3280A, RO5541267, Tecentriq
• Drug: Carboplatin
  Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).
• Drug: Etoposide
  Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).
• Drug: Placebo
  Placebo intravenous infusion was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

Study Arms

• Experimental: 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.
  Interventions:

  • Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
  • Drug: Carboplatin
  • Drug: Etoposide
• Active Comparator: 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.
  Interventions:

  • Drug: Carboplatin
  • Drug: Etoposide
  • Drug: Placebo

Publications *

• Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, Garassino MC, De Castro Carpeno J, Califano R, Nishio M, Orlandi F, Alatorre-Alexander J, Leal T, Cheng Y, Lee JS, Lam S, McCleland M, Deng Y, Phan S, Horn L. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021 Feb 20;39(6):619-630. doi: 10.1200/JCO.20.01055. Epub 2021 Jan 13.
• Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z, Reck M, Atagi S, Lee JS, Garassino M, Liu SV, Horn L, Wen X, Quach C, Yu W, Kabbinavar F, Lam S, Morris S, Califano R. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020 Feb;31(2):310-317. doi: 10.1016/j.annonc.2019.10.021. Epub 2019 Dec 9.
• Nishio M, Sugawara S, Atagi S, Akamatsu H, Sakai H, Okamoto I, Takayama K, Hayashi H, Nakagawa Y, Kawakami T. Subgroup Analysis of Japanese Patients in a Phase III Study of Atezolizumab in Extensive-stage Small-cell Lung Cancer (IMpower133). Clin Lung Cancer. 2019 Nov;20(6):469-476.e1. doi: 10.1016/j.cllc.2019.07.005. Epub 2019 Jul 31.
• Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.1056/NEJMoa1809064. Epub 2018 Sep 25.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 21, 2019): 403
• Original Estimated Enrollment (submitted: May 4, 2016): 400
• Estimated Study Completion Date: March 31, 2021
• Actual Primary Completion Date: April 24, 2018 (Final data collection date for primary outcome measure)

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
• History of severe (or known) hypersensitivity to chimeric or humanized antibodies or fusion proteins or any component of atezolizumab formulation.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Brazil, Chile, China, Czechia, France, Germany, Greece, Hungary, Italy, Japan, Korea, Republic of, Mexico, Poland, Russian Federation, Serbia, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Czech Republic, Hong Kong

Administrative Information

• NCT Number: NCT02763579
• Other Study ID Numbers: GO30081; 2015-004861-97 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Hoffmann-La Roche
• Study Sponsor: Hoffmann-La Roche
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: January 2021