| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV non-squamous non small cell lung cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Stage IV non-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 | 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) |
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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 RECIST v1.1 in the tumor gene expression (tGE)-wild type (WT) population and the ITT-WT population
•To evaluate the efficacy of atezolizumab as measured by overall survival (OS) in the ITT-WT 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-WT population
oInvestigator-assessed PFS according to RECIST v1.1 and OS in the TC2/3 or IC2/3 WT and TC1/2/3 or IC1/2/3 WT population
oInvestigator-assessed PFS according to RECIST v1.1 and OS in the tGE and ITT population
oInvestigator-assessed objective response rate (ORR) and duration of response (DOR) according to RECIST v1.1 in the tGE-WT and ITT-WT population
oIndependent Review Facility assessment of PFS according to RECIST v1.1 in the tGE-WT and ITT-WT population
•To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE-WT and ITT-WT population
•To compare the efficacy of the two atezolizumab-containing arms, Arm A versus Arm B, as measured by investigator-assessed PFS according to RECIST v1.1 and by OS in the tGE-WT and ITT-WT population
•To determine the impact of atezolizumab as measured by time to deterioration & change from baseline in patient-reported lung cancer symptoms
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| 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 NSCLC
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible if the major histological component appears to be non-squamous.
•No prior treatment for Stage IV non-squamous NSCLC
Patients with a sensitizing mutation in the EGFR gene must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more EGFR TKIs, such as erlotinib, gefitinib, or another EGFR TKI appropriate for the treatment of EGFR-mutant NSCLC.
Patients with an 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)
•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.
•Patients with a history of treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria:
Measurable disease outside CNS
Only supratentorial metastases allowed (i.e., no metastases to midbrain, pons, medulla or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization
No evidence of interim progression between the completion of CNS - directed therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be eligible without the need for an additional brain scan prior to enrollment, if all other criteria are met.
•Known PD-L1 tumor status as determined by an IHC assay performed by a central laboratory on previously obtained archival tumor tissue or tissue obtained from a biopsy at screening
•Measurable disease, as defined by RECIST v1.1
•Adequate hematologic and end organ function,
•For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 5 months after the last dose of atezolizumab (and/or 6 months after the last dose of bevacizumab or paclitaxel, whichever is later). Women must refrain from donating eggs during this same period
•Women who are not postmenopausal or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
•For male patients with female partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 1% per year] when used consistently and correctly, and to continue its use for 6 months after the last dose of bevacizumab, carboplatin, or paclitaxel.
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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 tumor-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 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
•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 MPDL3280A 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
•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.
•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) |
•PFS, defined as the time from randomization to the first occurrence of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first in the tGE-WT population and the ITT-WT population
•OS, defined as the time from randomization to death from any cause in the ITT-WT 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-WT population
2. PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 or IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population
3. PFS, as determined by the investigator according to RECIST v1.1, and OS in the tGE population and the ITT population
4. Objective response, defined as partial response (PR) or complete response (CR) as determined by the investigator according to RECIST v1.1 in the tGE-WT population and the ITT-WT population
5. DOR, defined as the time interval 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 comes first in the tGE-WT population and the ITT-WT population
6. PFS, defined as the time from randomization to the first occurrence of disease progression as determined by the IRF using RECIST v1.1 or death from any cause, whichever occurs first in the tGE-WT population and the ITT-WT population
7. PFS, as determined by the investigator according to RECIST v1.1, and OS in the two atezolizumab-containing arms in the tGE-WT population and the ITT-WT population
8. OS rates at 1 and 2 years for the tGE-WT population and the ITT-WT population
9. Time to deterioration 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 in the tGE-WT population and the ITT-WT population
10. Change from baseline in patient reported lung cancer symptoms (chest pain, dyspnea, and cough) on the symptom severity score of the SILC scale for the tGE-WT population and the ITT-WT 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
2-3. and 6-7. Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first
4. To be analysed at the time of the primary analysis5. 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
8. At 1 and 2 years
9. Time from randomization to deterioration
10. 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 | 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 | 2 |
| 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 |
| France |
| Germany |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Peru |
| Portugal |
| Russian Federation |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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