A Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab in Patients With Untreated Extensive-Stage Small Cell Lung Cancer
- Conditions
- Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT04256421
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This study will evaluate the efficacy of tiragolumab plus atezolizumab and carboplatin and etoposide (CE) compared with placebo plus atezolizumab and CE in participants with chemotherapy-naive extensive-stage small cell lung cancer (ES-SCLC). Eligible participants will be stratified by Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), LDH (\</= upper limit of normal \[ULN\] vs. \> ULN), and presence or history of brain metastasis (yes vs. no) and randomly assigned in a 1:1 ratio to receive one of the following treatment regimens during induction phase:
* Arm A: Tiragolumab plus atezolizumab plus CE
* Arm B: Placebo plus atezolizumab plus CE
Following the induction phase, participants will continue maintenance therapy with either atezolizumab plus tiragolumab (Arm A) or atezolizumab plus placebo (Arm B).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 490
- Histologically or cytologically confirmed extensive-stage small cell lung cancer (ES-SCLC)
- No prior systemic treatment for ES-SCLC
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (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
- Symptomatic or actively progressing central nervous system (CNS) metastases
- Malignancies other than small cell lung cancer (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
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- Positive test result for human immunodeficiency virus (HIV)
- Active hepatitis B or hepatitis C
- Severe infection at the time of randomization
- Treatment with any other investigational agent within 28 days prior to initiation of study treatment
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4), anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug elimination half-lives prior to randomization
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Atezolizumab + CE Placebo Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by placebo on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Tiragolumab + Atezolizumab + CE Atezolizumab Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by tiragolumab on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Placebo + Atezolizumab + CE Atezolizumab Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by placebo on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Placebo + Atezolizumab + CE Etoposide Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by placebo on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Placebo + Atezolizumab + CE Carboplatin Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by placebo on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Tiragolumab + Atezolizumab + CE Tiragolumab Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by tiragolumab on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Tiragolumab + Atezolizumab + CE Carboplatin Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by tiragolumab on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3. Tiragolumab + Atezolizumab + CE Etoposide Participants will receive atezolizumab on Day 1 of each 21-day cycle followed by tiragolumab on Day 1 of each 21-day cycle. Carboplatin will be administered followed by etoposide on Day 1 for 4 cycles. Participants will also receive etoposide on Days 2 and 3.
- Primary Outcome Measures
Name Time Method Investigator-Assessed Progression Free Survival (PFS) in the Primary Analysis Set (PAS) From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 24 months) PFS was defined as the time from randomization to the first documented disease progression (PD) as determined by the investigator with the use of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first. PD: at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Overall Survival (OS) in the PAS From randomization to death from any cause (up to approximately 24 months) OS was defined as the time from randomization to death from any cause.
- Secondary Outcome Measures
Name Time Method PFS in the FAS From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 24 months) PFS was defined as the time from randomization to the first documented PD as determined by the investigator with the use of RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of \>/= 5 mm.
OS in the FAS From randomization to death from any cause (up to approximately 24 months) OS was defined as the time from randomization to death from any cause.
Investigator-Assessed Confirmed Objective Response Rate (ORR) in the PAS From randomization up to approximately 24 months ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the investigator with the use of RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR.
Investigator-Assessed Confirmed ORR in the FAS From randomization up to approximately 24 months ORR was defined as the percentage of participants with CR or PR as determined by the investigator with the use of RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR.
Investigator-Assessed Duration of Response (DOR) in the PAS From the first occurrence of a documented confirmed objective response to disease progression or death from any cause, whichever occurs first (up to approximately 24 months) DOR was defined as the time from the first occurrence of a documented objective response (OR) to PD or death from any cause, whichever occurred first, as determined by the investigator with the use of RECIST v1.1. CR: was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to \< 10 mm PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD= at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of \>/= 5 mm.
Investigator-Assessed DOR in the FAS From the first occurrence of a documented confirmed objective response to disease progression or death from any cause, whichever occurs first (up to approximately 24 months) DOR was defined as the time from the first occurrence of a documented OR to PD or death from any cause, whichever occurred first, as determined by the investigator with the use of RECIST v1.1. CR: was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to \< 10 mm PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD= at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of \>/= 5 mm.
Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS Month 6, Month 12 PFS rate at 6 months and 12 months was defined as the percentage of participants who were event free at these specific time points. Percentages have been rounded off to the nearest decimal point. A point estimate of the event-free rate is a single, numerical value used to approximate the true event-free rate of the entire population at a specific point in time. This value is calculated from ordered data (Event, Censoring) of each patient, using the Kaplan-Meier method, and accounts for censored observations( so Event free rates may not directly be calculated based only on patients remaining at risk).
Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS Month 6, Month 12 PFS rate at 6 months and 12 months was defined as the percentage of participants who were event free at these specific time points. Percentages have been rounded off to the nearest decimal point. A point estimate of the event-free rate is a single, numerical value used to approximate the true event-free rate of the entire population at a specific point in time. This value is calculated from ordered data (Event, Censoring) of each patient, using the Kaplan-Meier method, and accounts for censored observations( so Event free rates may not directly be calculated based only on patients remaining at risk).
Overall Survival Rates at 12 Months and 24 Months in the PAS Month 12, Month 24 Overall survival rate at 12 months and 24 months was defined as the percentage of participants who were alive at these specific time points. Percentages have been rounded off to the nearest decimal point. A point estimate of the event-free rate is a single, numerical value used to approximate the true event-free rate of the entire population at a specific point in time. This value is calculated from ordered data (Event, Censoring) of each patient, using the Kaplan-Meier method, and accounts for censored observations( so Event free rates may not directly be calculated based only on patients remaining at risk).
Overall Survival Rates at 12 Months and 24 Months in the FAS Month 12, Month 24 Overall survival rate at 12 months and 24 months was defined as the percentage of participants who were alive at these specific time points. Percentages have been rounded off to the nearest decimal point. A point estimate of the event-free rate is a single, numerical value used to approximate the true event-free rate of the entire population at a specific point in time. This value is calculated from ordered data (Event, Censoring) of each patient, using the Kaplan-Meier method, and accounts for censored observations( so Event free rates may not directly be calculated based only on patients remaining at risk).
Time to Confirmed Deterioration (TTCD) of European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core (QLQ-C30) Physical Functioning in the PAS From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months TTCD was the time from randomization until the first confirmed clinically meaningful deterioration in physical functioning. TTCD was determined based on patient-reported physical functioning (items 1-5) as collected and measured by the EORTC QLQ-C30. The PF is measured on 4-point scale (1='Not at all' to 4='Very much'). A high score for the physical function subscale represented a high/healthy level of functioning. The scale was linearly transformed so that each score ranged from 0 to 100. A score change of at least 10-point in physical functioning subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration was defined as a clinically meaningful decrease from baseline that was held for at least two consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks.
TTCD of EORTC QLQ-C30 Physical Functioning in the FAS From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months TTCD was the time from randomization until the first confirmed clinically meaningful deterioration in physical functioning. TTCD was determined based on patient-reported physical functioning (items 1-5) as collected and measured by the EORTC QLQ-C30. The PF is measured on 4-point scale (1='Not at all' to 4='Very much'). A high score for the physical function subscale represented a high/healthy level of functioning. The scale was linearly transformed so that each score ranged from 0 to 100. A score change of at least 10-point in physical functioning subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration was defined as a clinically meaningful decrease from baseline that was held for at least two consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks.
TTCD of EORTC QLQ-C30 Global Health Status (GHS)/Quality of Life (QoL) in the PAS From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months TTCD was the time from randomization until the first confirmed clinically meaningful deterioration in patient-reported global health status (GHS)/ quality of life (QoL). TTCD was determined based on patient-reported GHS/QoL (items 29-30) as collected and measured by the EORTC QLQ-C30. HS/QoL items are scored on a 7-point scale that ranges from "very poor" to "excellent". A high score for the GHS/QoL subscale represented a high health related quality of life. The scale was linearly transformed so that each score ranged from 0 to 100. A score change of at least 10-point in GHS/QoL subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration was defined as a clinically meaningful decrease from baseline that was held for at least two consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks.
TTCD of EORTC QLQ-C30 GHS/QoL in the FAS From randomization until the first confirmed clinically meaningful deterioration up to 24 months TTCD was the time from randomization until the first confirmed clinically meaningful deterioration in patient-reported global health status (GHS)/ quality of life (QoL). TTCD was determined based on patient-reported GHS/QoL (items 29-30) as collected and measured by the EORTC QLQ-C30. HS/ QoL items are scored on a 7-point scale that ranges from "very poor" to "excellent". A high score for the GHS/QoL subscale represented a high health related quality of life. The scale was linearly transformed so that each score ranged from 0 to 100. A score change of at least 10-point in GHS/QoL subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration was defined as a clinically meaningful decrease from baseline that was held for at least two consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks.
Percentage of Participants With Adverse Events Up to 65 months An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Minimum Serum Concentration (Cmin) of Tiragolumab At the end of each cycle (each cycle is 21 days) of Cycles 1, 2, 3, 7, 11 and 15 (approximately 11 months) Cmin of Atezolizumab At the end of each cycle (each cycle is 21 days) of Cycles 1, 2, 3, 7, 11 and 15 (approximately 11 months) Maximum Serum Concentration (Cmax) of Tiragolumab Predose and 30 minutes post end of infusion (EOI) on Day 1 of Cycle 1 (each cycle is 21 days) Cmax of Atezolizumab Predose and 30 minutes post EOI on Day 1 of Cycle 1 (each cycle is 21 days) Number of Participants With Anti-Drug Antibodies (ADAs) to Tiragolumab Predose on Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4, 8,12 and 16 and at treatment discontinuation (TD) visit (up to 24 months) Reported here is the number of participants who had a positive ADA assay result at baseline and the number of participants positive for treatment emergent ADAs. The participants positive for treatment emergent ADAs include treatment-induced and treatment-enhanced ADA positive participants. Treatment-induced ADAs are participants with negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result. Treatment-enhanced ADAs are participants with a positive ADA result at baseline who had one or more post-baseline titer results that were at least 0.60 t.u. greater than the baseline titer result. The total number of participants who developed ADAs to tiragolumab was determined by summing the ADA-positive participants across all timepoints.
Number of Participants With ADAs to Atezolizumab Predose on Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4, 8,12 and 16 and at TD visit (up to 24 months) Reported here is the number of participants who had a positive ADA assay result at baseline and the number of participants positive for treatment emergent ADAs. The number of participants positive for treatment emergent ADAs includes treatment-induced and treatment-enhanced ADA positive participants. Treatment-induced ADAs are participants with negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result. Treatment-enhanced ADAs are participants with a positive ADA result at baseline who had one or more post-baseline titer results that were at least 0.60 t.u. greater than the baseline titer result. The total number of participants who developed ADAs to atezolizumab was determined by summing the ADA-positive participants across all timepoints.
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Index-based and Visual Analog Scale Scores From baseline up to 65 months The EQ-5D-5L is a validated self-report health status questionnaire that was used to calculate a health status utility score for use in health economic analyses. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a visual analog scale (VAS) that measured health state. The EQ VAS records the participant's self-rated health on a vertical visual analogue scale ranging from 0 to 100 A single composite score was calculated based on the responses as an indicator of the participant's health status. The scale ranges 0-100, 0=worst health and 100=best health.
Trial Locations
- Locations (121)
Asklepios Klinik Gauting
🇩🇪München-Gauting, Germany
Seoul National University Bundang Hospital
🇰🇷Gyeonggi-do, South Korea
Vall d?Hebron Institute of Oncology (VHIO), Barcelona
🇪🇸Barcelona, Spain
Rocky Mountain Cancer Centers - Lone Tree
🇺🇸Lone Tree, Colorado, United States
MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)
🇺🇸Washington D.C., District of Columbia, United States
Florida Cancer Specialists
🇺🇸Fort Myers, Florida, United States
SCRI Florida Cancer Specialists North
🇺🇸Sarasota, Florida, United States
Northwest Georgia Oncology Centers PC - Marietta
🇺🇸Marietta, Georgia, United States
Illinois Cancer Care
🇺🇸Peoria, Illinois, United States
New England Cancer Specialists
🇺🇸Scarborough, Maine, United States
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