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: Completed
• First Posted: May 5, 2016
• Results First Posted: June 13, 2019
• Last Update Posted: July 28, 2023
• 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: July 28, 2023
• 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: July 10, 2023)

• 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.

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: July 10, 2023)

• Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population [ Time Frame: Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 23 months) ]
  Objective response (OR) is defined as complete response (CR) or partial response (PR) as determined by the investigator according to RECIST v1.1.
• Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population [ Time Frame: First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 23 months) ]
  DOR is defined as the time interval from first occurrence of a documented objective response to the time of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever comes first.
• PFS Rate at 6 Months and at 1 Year in Global Population [ Time Frame: 6 months, 1 year ]
  PFS rates at 6 months and at 1 year is defined as the proportion of participants who are alive without disease progression 6 months and 1 year after randomization, respectively.
• OS Rate at 1 Year and 2 Years in the Global Population [ Time Frame: 1 year, 2 years ]
  OS rates at 1 and 2 years is defined as the proportion of participants who are alive 1 year and 2 years after randomization, respectively.
• 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 [ Time Frame: Baseline until deterioration per symptom subscale (up to approximately 23 months) ]
  TTD according to the EORTC QLQ-C30 and EORTC QLQ-LC13 measures were evaluated in each of the following linearly transformed symptom scores: cough, dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain. The linear transformation gives each individual symptom subscale a possible score of 0 to 100. For the symptom to be considered "deteriorated," a score increase of ≥10 points above baseline must be held for at least two consecutive assessments or an initial score increase of ≥10 points is followed by death within 3 weeks from the last assessment. A ≥ 10-point change in the symptoms subscale score is perceived by participants as clinically significant.
• Percentage of Participants With at Least One Adverse Event in the Global Population [ Time Frame: Baseline until up to 90 days after end of treatment (up to approximately 49 months) ]
  The percentage of participants with at least one adverse event in the global population.
• Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population [ 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 23 months) and 120 days after last dose (up to approximately 23 months overall) ]
  The baseline prevalence and post-baseline incidence of ADAs against atezolizumab.
• Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population [ Time Frame: Post-dose Day 1 of Cycle 1 (cycle length = 21 days) ]
  Atezolizumab maximum observed plasma concentration (Cmax; 30 minutes following the end of the atezolizumab infusion) for each respective day.
• Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population [ Time Frame: Predose on Day 1 of Cycles 1, 3, 4, 8, 16 and 24 (cycle length = 21 days) ]
  Atezolizumab pre-dose plasma concentration (Cmin) for each respective day.
• Plasma Concentration of Carboplatin in the Global Population [ Time Frame: Predose, before end of infusion, and after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days) ]
  Plasma concentration of carboplatin in the Global population.
• Plasma Concentration of Etoposide in the Global Population [ Time Frame: 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) ]
  Plasma concentration of etoposide in the Global Population.

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, Kazarnowicz A, Karaseva N, Sanchez 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, Szczesna 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: Completed
• Actual Enrollment (submitted: July 10, 2023): 503
• Original Estimated Enrollment (submitted: May 4, 2016): 400
• Actual Study Completion Date: July 7, 2022
• 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
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: July 2023