E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer (NSCLC) 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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
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 compared with single agent chemotherapy in patients with treatment-naïve locally advanced or metastatic NSCLC who are deemed unsuitable for any platinum doublet chemotherapy, as measured by overall survival (OS). |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of atezolizumab compared with single agent chemotherapy as measured by OS rates at 6, 12, 18 and 24 months -To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with respect to antitumor effects as measured by investigator assessed ORR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 -To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with respect to antitumor effects as measured by investigator assessed progression-free survival (PFS) using RECIST v1.1 -To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with respect to antitumor effects as measured by investigator assessed duration of response (DOR) using RECIST v1.1 -To evaluate the safety and tolerability of atezolizumab compared with single agent chemotherapy -To evaluate and compare PROs of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female, age >= 18 years - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition - No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected - No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC NSCLC as per the AJCC 7th edition - Life expectancy >= 8 weeks - Deemed unsuitable for any platinum-doublet chemotherapy by the investigator due to poor performance status (ECOG PS of 2-3) However, if patients do not meet this criterion, they may be included due to: a) substantial comorbidities b) contraindication(s) for platinum doublet chemotherapy. - Representative formalin-fixed paraffin-embedded (FPPE) tumor tissue block obtained during course of disease (archival tissue) or at screening (tumor blocks are highly preferred for central analysis of PD-L1 expression and exploratory biomarkers) - Patients with treated, asymptomatic central nervous system (CNS) metastases - Measurable disease (by RECIST v1.1) - Adequate hematologic and end organ function - Female patients of childbearing potential and male patients with partners of childbearing potential agree to use protocol defined methods of contraception |
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E.4 | Principal exclusion criteria |
Cancer-Specific Exclusion Criteria: - Patients younger than 70 years and with an ECOG PS of 0 or 1 - Active or untreated central nervous system metastases - Uncontrolled tumor-related pain - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX®) are allowed. - Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab - History of other malignancy within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome - Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from randomization since the last chemotherapy, radiotherapy, or chemoradiotherapy
General Medical Exclusion Criteria: - Women who are pregnant or lactating, or intending to become pregnant during the study. Women of childbearing potential including women who have had a tubal ligation, must have a negative serum pregnancy test result within 14 days prior to initiation of study drug. - History of autoimmune disease - Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) - History of idiopathic pulmonary fibrosis (IPF), organizing pneumonia (e.g., bronchiolitis obliterans), 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. - Known positivity for human immunodeficiency virus (HIV) - Known active hepatitis B or known active hepatitis C - Active tuberculosis - Severe infections within 4 weeks prior to randomization - Significant cardiovascular disease - Major surgical procedure other than for diagnosis within 4 weeks 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 serious medical condition (including metabolic dysfunction, physical examination finding) or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study or that may affect the interpretation of the results or render the patient at high risk for treatment complications - Patients with an illness or condition that may interfere with capacity or compliance with the study protocol, as per investigator's judgment - Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to randomization
Exclusion Criteria Related to Atezolizumab: - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation - Oral or IV antibiotic treatment. Patients will thus need to have recovered from any infection requiring antibiotics. Patients receiving prophylactic antibiotics are eligible. - 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 immunostimulatory agents (including but not limited to interferons, interleukin-2 [IL-2]) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to randomization - Treatment with systemic corticosteroids or other immunosuppressive medications - Patients not willing to stop treatment with traditional herbal medicines - Ongoing treatment with denosumab
Exclusion Criteria Related to Chemotherapy: - Known sensitivity and contraindications to the 2 comparative chemotherapy agents (i.e. vinorelbine, oral or intravenous, and gemcitabine) |
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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 |
1. Time from randomization to death from any cause |
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E.5.2 | Secondary end point(s) |
1. Overall Survival rates at 6, 12, 18 and 24 months 2. Objective Response Rate 3. Progression Free Survival 4. Duration of Response 5. Incidence, nature, and severity of adverse events 6. Changes in vital signs, physical findings, and clinical laboratory results 7. Change from baseline in PROs of lung cancer symptoms, patient functioning, HRQoL as assessed by European Organisation for Research and treatment of Cancer (EORTC) Quality-of-life Questionnaire Core 30 (QLQ-C30) and its supplementary Lung Cancer module (LC13) 8. Time to deterioration (TTD) in patient-reported lung cancer symptoms of cough, dyspnea (single-item and multi-item subscales), chest pain, arm/shoulder pain, or fatigue using EORTC QLQ-C30 and Quality-of-Life Questionnaire Lung Cancer Module (QLQ-LC13) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Months 6, 12, 18, and 24 2. Time from initial response (partial or complete response) until documented disease progression, or death from any cause, whichever occurs first 3. Time from randomization to the first occurrence of disease progression, or death from any cause, whichever occurs first 4. Time from the first occurrence of a documented objective response to the time of disease progression, or death from any cause, whichever occurs first 5-8. Screening (Days-28 to -1), baseline, Day 1 of all cycles, ≤ 1 Week after Last Dose, ≤30 days after the last dose of study drug
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Yes |
E.8.2.2 | Placebo | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 69 |
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 |
Argentina |
Brazil |
Canada |
China |
Colombia |
India |
Mexico |
Peru |
Viet Nam |
Luxembourg |
Poland |
Bulgaria |
Romania |
Spain |
Switzerland |
Czechia |
Germany |
Italy |
Belgium |
Denmark |
Ireland |
Kazakhstan |
Portugal |
Slovakia |
United Kingdom |
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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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This study is event-driven, with a recruitment period of approximately 24 months. The required number of events for the final analysis of the primary endpoint of OS is expected to occur approximately 40 months after the first patient has been enrolled. |
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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 | |
E.8.9.1 | In the Member State concerned months | 40 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 40 |