| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV Non-Squamous or Squamous Non−Small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer that has spread to areas near the lungs or other organs and has not yet been treated by chemotherapy |
|
| 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 | 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) |
|
| 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 |
| •The primary objective for this study is to evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy consisting of a platinum agent (cisplatin or carboplatin) in combination with either pemetrexed (non-squamous disease) or gemcitabine (squamous disease) in chemotherapy-naive patients with Stage IV NSCLC as measured by OS. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as measured by investigator-assessed PFS according to RECIST v1.1
•To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as measured by ORR according to RECIST v1.1 assessed by investigator
•To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of response (DOR) according to RECIST v1.1
•To determine the impact of atezolizumab compared with platinum-based chemotherapy as measured by time to deterioration (TTD) and change from baseline (i.e., improvement or deterioration based on presenting symptomatology) in patient reported lung cancer symptom (cough, dyspnoea, chest pain) score
•To evaluate the OS rate at 1- and 2- year landmark timepoints in each treatment arm
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- ECOG performance status of 0 or 1
- Histologically or cytologically confirmed, Stage IV non-squamous or squamous NSCLC
- No prior treatment for Stage IV non-squamous or squamous NSCLC, Patients known to have a sensitizing mutation in the EGFR gene or an ALK fusion oncogene are excluded from the study.
• Patients with non-squamous NSCLC who have an unknown EGFR or ALK status will be required to be tested at prescreening/screening. Patients with squamous NSCLC who have an unknown EGFR or ALK status will not be required to be tested at prescreening/screening.
- Tumour PD-L1 expression as determined by an IHC assay performed by a central laboratory on previously obtained archival tumour tissue or tissue obtained from a biopsy at screening
- Measurable disease, as defined by RECIST v1.1
- Adequate hematologic and end-organ function
- Women who are not postmenopausal (>= 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
- For patients enrolled in the China extension phase: residence in the People's Republic of China
|
|
| E.4 | Principal exclusion criteria |
- Active or untreated CNS metastases as determined by CT or MRI evaluation during screening
- Leptomeningeal disease
- Uncontrolled tumour-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
- Uncontrolled or symptomatic hypercalcemia
- Malignancies other than NSCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death
- History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
- 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
- Patients with active hepatitis B or hepatitis C
- Active tuberculosis
- Severe infections within 4 weeks prior to 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
- Treatment with any other investigational agent with therapeutic intent within 28 days prior to randomization
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Administration of a live, attenuated vaccine within 4 weeks before randomization, during treatment, or within 90 days following last dose of atezolizumab (for patients randomized to atezolizumab)
- Treatment with systemic immunostimulatory agents (including but not limited to interferons, IL-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to randomization
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization
- 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
- History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome measure for this study is OS, defined as the time from randomization to death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first
- OS at 1- and 2-year landmark time-points
- TTD and change from baseline (i.e., improvement or deterioration based on presenting symptomatology) in patient-reported lung cancer symptoms (cough, dyspnea, or chest pain, whichever occurs first) with use of the SILC scale symptom score
- TTD in patient-reported lung cancer symptoms, defined as time from randomization to deterioration (10-point change) on each of the EORTC QLQ-C30 and EORTC QLQ-LC13 symptom subscales (cough, dyspnea [single-item and multi-item subscales], chest pain, or arm/shoulder pain)
- OS and investigator-assessed PFS according to RECIST v1.1 in the tGE subpopulation
- OS at 3-year landmark time-point
- OS and investigator-assessed PFS according to RECIST v1.1 in subgroups based on demographic and baseline characteristics |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
· The required number of deaths for the final analysis of OS has been observed among patients enrolled during the global enrollment phase (see Section 6.10.1)
· The required number of deaths for the final analysis of OS in the China subpopulation has been observed (see Section 6.11)
· The last patient has been enrolled in the study (i.e., global enrollment phase plus China extension phase)
Protocol section 3.2 for further details |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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