E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041068 |
E.1.2 | Term | Small cell lung cancer extensive stage |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the efficacy of atezolizumab (Atezo) + carboplatin (Carb) + etoposide (Etop) compared with placebo + Carb + Etop in the intent-to-treat (ITT) population as measured by investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) • To evaluate the efficacy of Atezo + Carb + Etop compared with placebo + Carb + Etop in the ITT population as measured by overall survival (OS)
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of Atezo + Carb + Etop compared with placebo+Carb+Etop in the ITT population as measured by investigator-assessed objective response rate (ORR) and duration of response (DOR) according to RECIST v1.1 • To evaluate PFS rate at 6 months and at 1 year and OS rate at 1 and 2 years in each treatment arm for the ITT population • To determine the impact of Atezo as measured by time to deterioration (TTD) in patient-reported lung cancer symptoms in each treatment arm for the ITT population •To evaluate safety and tolerability of Atezo+Carb+Etop compared with Carb and Etop •To evaluate incidence and titers of anti-therapeutic antibodies (ATAs) against Atezo and to explore the potential relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy •To characterize pharmacokinetics of Atezo, Carb, and Etop in chemotherapy-naive patients with extensive-stage small cell lung cancer |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female, 18 years of age or older - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung Study Group (VALG) staging system - No prior systemic treatment for ES-SCLC - Patients who have received prior chemoradiotherapy for limited stage SCLC must have been treated with curative intent and experienced a treatment-free interval of at least 6 months since last chemotherapy, radiotherapy, or chemoradiotherapy cycle from diagnosis of extensive stage SCLC - Patients with treated asymptomatic CNS metastases are eligible (only supratentorial and cerebellar metastases allowed) - Measurable disease, as defined by RECIST v1.1 - Adequate haematologic and end organ function - Patients must submit a pre-treatment tumour tissue sample during the study. Any available tumour tissue sample can be submitted. The tissue sample should be submitted before or within 4 weeks after randomization; however, patients may be enrolled into the study before the pre-treatment tumor tissue sample is submitted - For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study treatment - Men with female partners of childbearing potential or pregnant female partners must remain abstinent or use a condom during treatment with chemotherapy (i.e., carboplatin and etoposide) and for at least 6 months after the last dose of chemotherapy to avoid exposing the embryo - For patients enrolled in the extended China enrollment phase: current resident of mainland China, Hong Kong, or Taiwan and of Chinese ancestry |
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E.4 | Principal exclusion criteria |
- Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments - Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >=1 week prior to randomization - Leptomeningeal disease - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) - Uncontrolled or symptomatic hypercalcaemia - Malignancies other than SCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome - Women who are pregnant, lactating, or intending to become pregnant during the study - History of autoimmune disease - History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan - Positive test for HIV - Active hepatitis B or hepatitis C - Active tuberculosis - Severe infections at the time of randomization, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia - Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina - Major surgical procedure other than for diagnosis within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study - Prior allogeneic bone marrow transplantation or solid organ transplant - Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk for treatment complications - Patients with illnesses or conditions that interfere with their capacity to understand, follow, and/or comply with study procedures - Treatment with any other investigational agent with therapeutic intent within 28 days prior to randomization - Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study - Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, and anti−PD-L1 therapeutic antibodies - Treatment with systemic immunosuppressive medications within 1 weeks prior to randomization - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation - History of allergic reactions to carboplatin or etoposide |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Objective response 2. DOR 3. PFS rates at 6 months and at 1 year 4. OS rates at 1 and 2 years 5. TTD on each of the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and EORTC Quality-of-Life Questionnaire Lung Cancer Module (QLQ-LC13) symptom subscales 6. Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 7. Changes in vital signs, physical findings, and clinical laboratory results 8. Incidence of ATA response to Atezo and potential correlation with PK, pharmacodynamic, safety, and efficacy parameters 9. Maximum observed serum Atezo concentration (Cmax) 10. Minimum observed serum Atezo concentration (Cmin) 11. Plasma concentrations for Carb 12. Plasma concentrations for Etop |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Up to 31 months 6-7. Until 90 days after the last dose of study drug 8. Cycle (C) 1 Day (D) 1, C2D1, C3D1, C4D1, C8D1, C16D1, after Cycle 16, Day 1 of every eighth cycle, at treatment discontinuation, 120 (+/- 30) days after last dose of Atezo 9. C1D1, C2D1, C3D1, C4D1, C8D1, C16D1, after Cycle 16, Day 1 of every eighth cycle, at treatment discontinuation, 120 (+/- 30) days after last dose of Atezo 10. C1D1, C2D1, C3D1, C4D1, C8D1, C16D1, after Cycle 16, Day 1 of every eighth cycle, at treatment discontinuation, 120 (+/- 30) days after last dose of Atezo 11-12. C1D1, C3D1 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Efficacy data of the combination Atezo+Carboplatin+Etoposide for SLCC condition |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Bosnia and Herzegovina |
Chile |
China |
Czech Republic |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Italy |
Korea, Republic of |
Mexico |
Poland |
Russian Federation |
Serbia |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study will occur when all of the following criteria have been met: *The LPLV has occurred (i.e., last patient in the global and extended China enrollment phases combined). *Approximately 306 deaths have been observed among the randomized patients in the global enrollment phase. *There are sufficient OS events in the ITT population enrolled in the China enrollment phase (see Section 6.1.1). Additionally, the Sponsor may decide to terminate the study at any time. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 1 |