E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic non-squamous non-small cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer 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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029514 |
E.1.2 | Term | Non-small cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 in the programmed death−ligand 1 (PD-L1)−selected population as measured by investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in atezolizumab + carboplatin + pemetrexed versus carboplatin + pemetrexed
•To evaluate the efficacy of atezolizumab in the intent-to-treat (ITT) population as measured by investigator-assessed PFS according to RECIST v1.1 in atezolizumab + carboplatin + pemetrexed versus carboplatin + pemetrexed
•To evaluate the efficacy of atezolizumab in the PD-L1−selected population as measured by investigator-assessed PFS according to RECIST v1.1 in atezolizumab + carboplatin or cisplatin + pemetrexed versus carboplatin or cisplatin (pooled) + pemetrexed
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of atezolizumab as measured by progression-free survival, objective response rate, overall survival, duration of response, time to response, and time to deterioration
• To evaluate the safety and tolerability of atezolizumab
• To characterize the pharmacokinetics of atezolizumab, carboplatin, cisplatin, and pemetrexed
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female, 18 years of age or older
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Histologically or cytologically confirmed, Stage IV non-squamous NSCLC
- No prior treatment for Stage IV non-squamous NSCLC
- Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 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 or completion of chemoradiotherapy
- Known PD-L1 tumor status as determined by an immunohistochemistry (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 women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of study treatment
- For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm
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E.4 | Principal exclusion criteria |
Cancer-Specific Exclusions
- Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging (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 or symptomatic hypercalcemia (> 1.5 millimole/Liter ionized calcium or calcium > 12 milligram/deciliter or corrected serum calcium > upper limit of normal)
- Malignancies other than non−small cell lung cancer (NSCLC) within 5 years prior to randomization
- Known tumor PD-L1 expression status from other clinical studies (e.g., patients whose PD-L1 expression status was determined during screening for entry into a study with anti-PD-1 or anti−PD L1 antibodies but were not eligible are excluded)
General Medical Exclusions:
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- History of certain autoimmune disease
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
- Severe infections within 4 weeks prior to randomization
- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina
Exclusion Criteria Related to Medications and Chemotherapy:
- Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, and anti−PD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents within 4 weeks prior to randomization
- Treatment with systemic immunosuppressive medications
Exclusion Criteria Related to Chemotherapy:
- History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds
- Patients with hearing impairment (cisplatin)
- Grade >= 2 peripheral neuropathy as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 criteria (cisplatin)
- Creatinine clearance (CRCL) =< 60 milliliter (mL)/minute (min) for cisplatin or < 45 mL/min for carboplatin
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival as assessed by the investigator |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Overall Survival
2. Objective Response Rate
3. Duration of Response
4. Time to Response
5. Progression free survival as determined by the Independent Review Facility
6. Landmark analysis on Overall Survival
7. Time to deterioration in patient-reported lung cancer symptoms using each of the EORTC QLQ-C30 and EORTC QLQ-LC13 symptom subscales
8. Time to deterioration in patient-reported lung cancer symptoms (cough, dyspnea, or chest pain, whichever occurs first) with use of the SILC scale symptom score
9. Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v4.0
10. Maximum observed serum atezolizumab concentration (Cmax) after infusion (Arm A)
11. Minimum observed serum atezolizumab concentration (Cmin) prior to infusion (Arm A)
12. Plasma concentrations for carboplatin or cisplatin (Arm A)
13. Plasma concentrations for pemetrexed (Arm A)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Up to 44 months
6. 1, 2, and 3 years
7-9. Up to 44 months
10-11. C1D1, C2D1, C3D1, C4D1, C8D1, C16D1, after C16 every eighth cycle D1, at treatment discontinuation, 120 (+/-30) days after last dose of atezolizumab
12-13. C1D1, C3D1
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 138 |
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 |
Bulgaria |
Canada |
Chile |
France |
Hong Kong |
Hungary |
Israel |
Italy |
Latvia |
Lithuania |
Malaysia |
Netherlands |
New Zealand |
Peru |
Poland |
Portugal |
Romania |
Russian Federation |
Singapore |
Slovakia |
Spain |
Taiwan |
Ukraine |
United Kingdom |
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 this study is defined as the date when the last patient, last visit (LPLV) occurs
or the date at which the last data point required for statistical analysis (i.e., final OS
analysis) or safety follow-up is received from the last patient, whichever occurs later. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 15 |