| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| STAGE IV NON-SQUAMOUS NON−SMALL CELL LUNG CANCER |
|
| 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) |
|
| 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 + carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel 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 + carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel as measured by overall survival (OS) in the ITT-WT population |
|
| 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 population and the TC1/2/3 or IC1/2/3 WT population oInvestigator-assessed PFS according to RECIST v1.1 and OS in the tGE population and the ITT population oInvestigator-assessed ORR and DOR according to RECIST v1.1 in the tGE-WT population and the ITT-WT population
• To evaluate the OS rate at 1 and 2 years in each treatment arm in the tGE-WT population and the ITT-WT population
• To determine the impact of atezolizumab as measured by time to deterioration (TTD) and change from baseline in patient-reported lung cancer symptoms |
|
| 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 (e.g., crizotinib) appropriate for the treatment of NSCLC in patients with ALK fusion oncogene. Patients with unknown EGFR and ALK status require test results at screening. ALK and/or EGFR may be assessed locally or at a central laboratory.
• 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 cycle.
• Measurable disease, as defined by RECIST v1.1
• Known PD-L1 tumor status as determined by an IHC assay performed by a centrallaboratory on previously obtained archival tumor tissue or tissue obtained from a biopsy at screening. |
|
| E.4 | Principal exclusion criteria |
•Active or untreated CNS metastases as determined by CT or MRI evaluation duringscreening and prior radiographic assessments
•Spinal cord compression not definitively treated with surgery and/or radiation orpreviously diagnosed and treated spinal cord compression without evidence thatdisease has been clinically stable for > 2 weeks prior to randomization
•Leptomeningeal disease
•Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to randomization. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for locoregional therapy, if appropriate, prior to randomization.
•Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently)
•Malignancies other than NSCLC within 5 years prior to randomization, with theexception of those with a negligible risk of metastasis or death (e.g., expected5-year OS> 90%) treated with expected curative outcome (such as adequatelytreated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localizedprostate cancer treated surgically with curative intent, ductal carcinoma in situtreated surgically with curative intent)
•Known tumor PD-L1 expression status from other clinical trials (e.g., patients whosePD-L1 expression status was determined during screening for entry into a trial withanti-programmed death-1 [PD-1] or anti-PD-L1 antibodies but were not eligible areexcluded)
•History of severe allergic, anaphylactic, or other hypersensitivity reactionsto chimeric or humanized antibodies or fusion proteins
•Positive test for HIV |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. 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
2.OS, defined as the time from randomization to death from any cause, in the ITT-WT population |
|
| 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 |
|
| 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 for 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 occurs first for the tGE-WT population and the ITT-WT population
6. OS rates at 1 and 2 years for the tGE-WT population and the ITT-WT 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 [multi-item subscale], chest pain, and arm/shoulder pain) in the tGE-WT population and the ITT-WT population
8. Change from baseline in patient-reported lung cancer symptoms (chest pain, dyspnea, and cough) on the symptom severity score of the SILC scale in the tGE-WT population and the ITT-WT population |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time from randomization to death from any cause
2-3. Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first
4. To be analyzed at the time of the primary analysis
5. 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) |
|
| 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 | Yes |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| Spain |
| 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 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. |
|
| 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 | 0 |
| 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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