| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SQUAMOUS NON−SMALL CELL LUNG CANCER |
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| E.1.1.1 | Medical condition in easily understood language |
| SQUAMOUS NON−SMALL CELL LUNG CANCER |
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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 | 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.1.3 | 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 as measured by investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the tumor gene expression (tGE) population and the intent-to-treat (ITT) population
•To evaluate the efficacy of atezolizumab as measured by overall survival (OS) in the ITT population
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of atezolizumab as measured by:
oOS in the tGE population
oInvestigator-assessed PFS according to RECIST v1.1 and OS in the TC2/3 or IC2/3 population and the TC1/2/3 or IC1/2/3 population
oInvestigator-assessed ORR and DOR according to RECIST v1.1 in the tGE population and the ITT population
•To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE and the ITT population
•To determine the impact of atezolizumab as measured by time to deterioration (TTD) and change from baseline in patient-reported lung cancer symptoms
•To evaluate the efficacy of the treatment regimen of atezolizumab+carboplatin+paclitaxel versus atezolizumab+carboplatin+nab-paclitaxel as measured by investigator-assessed PFS according to RECIST v1.1 and OS in the tGE population and the ITT population
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Eastern Cooperative Oncology Group performance status of 0 or 1
• Histologically or cytologically confirmed Stage IV squamous NSCLC
Patients with tumors of mixed histology (squamous and non-squamous) are eligible if the major histological component appears to be squamous.
• No prior treatment for Stage IV squamous NSCLC
Patients known to have a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more EGFR tyrosine kinase inhibitor (TKIs), such as erlotinib, gefitinib, or another EGFR TKI appropriate for the treatment of EGFR-mutant NSCLC.
Patients with unknown EGFR mutation status do not require testing.
Patients known to have an anaplastic lymphoma kinase (ALK) fusion oncogene must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more ALK inhibitors (i.e., crizotinib) appropriate for the treatment of NSCLC in patients having an ALK fusion oncogene.
Patients with unknown ALK mutation status do not require testing.
• 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.
• Measurable disease, as defined by RECIST v1.1
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| E.4 | Principal exclusion criteria |
• Active or untreated CNS metastases as determined by CT or 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 > 2 weeks prior to randomization
• Leptomeningeal disease
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Positive test for HIV
All patients will be tested for HIV prior to inclusion into the study; patients who test positive for HIV will be excluded from the clinical.
• Uncontrolled tumor-related pain
• 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 treated with expected curative outcome
• Known tumor PD-L1 expression status from other clinical trials
• Women who are pregnant, lactating, or intending to become pregnant during the study
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• 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
• Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
• Active tuberculosis
• Severe infections within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
• 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
• 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
• 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 from treatment complications
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1.PFS, defined as the time from randomization to the first occurrence of the disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first, in the tGE population and ITT population
2.OS, defined as the time from randomization to death from any cause, in the ITT population
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first
2.Time from randomization to death from any cause
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| E.5.2 | Secondary end point(s) |
1.OS in the tGE population
2.PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 or IC2/3 population and the TC1/2/3 or IC1/2/3 population
3.Objective response, defined as partial response (PR) or complete response (CR) as determined by the investigator according to RECIST v1.1 in the tGE population and ITT population
4. DOR, defined as the time 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 occurs first, in the tGE population and ITT population
5.PFS, as determined by the investigator according to RECIST v1.1, and OS in the two atezolizumab-containing arms in the tGE population and the ITT population
6.OS rate at 1 and 2 years in each treatment arm for the tGE population and the ITT population
7.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], dyspnea, chest pain, and arm/shoulder pain) in the tGE population and ITT population
8.Change from baseline in patient-reported lung cancer symptoms (cough, dyspnea, and chest pain) on the symptom severity score of the SILC scale in the tGE population and ITT population
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time from randomization to death from any cause
2 and 5. Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first
3. To be analysed at the time of the primary analysis
4. Time interval from the date of the first occurrence of a complete or partial response until the first date that progressive disease or death is documented, whichever occurs first
6. At 1 and 2 years
7. Time from randomization to deterioration
8. Baseline and survival follow-up (every 3 months after disease progression or loss of clinical benefit)
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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) | 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 | 3 |
| 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 | 60 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Peru |
| Portugal |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Ukraine |
| 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 is defined as the date of the last follow-up visit of the last patient or when all patients have been enrolled into an extension study. The Sponsor may decide to terminate the study at any time. If the Sponsor decides to end the study, patients who are still receiving study treatment or are in survival follow-up may be offered enrollment in an extension study or a non-interventional study. |
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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 | 4 |
| 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 | 4 |
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