Study of Efficacy and Safety of Pembrolizumab Plus Platinum-based Doublet Chemotherapy With or Without Canakinumab in Previously Untreated Locally Advanced or Metastatic Non-squamous and Squamous NSCLC Subjects

Study Overview
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Brief Summary
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This is a phase III study of pembrolizumab plus platinum-based doublet chemotherapy with or without canakinumab in previously untreated locally advanced or metastatic non-squamous and squamous NSCLC subjects. The study will assess primarily the safety and tolerability (safety run-in part) of pembrolizumab plus platinum-based doublet chemotherapy with canakinumab and then the efficacy (double-blind, randomized, placebo controlled part) of pembrolizumab plus platinum-based doublet chemotherapy with or without canakinumab.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Pembrolizumab Plus Platinum-based Doublet Chemotherapy With or Without Canakinumab as First Line Therapy for Locally Advanced or Metastatic Non-squamous and Squamous Non-small Cell Lung Cancer Subjects (CANOPY-1)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: canakinumab
* Drug: canakinumab matching placebo
* Drug: pembrolizumab
* Drug: carboplatin
* Drug: cisplatin
* Drug: paclitaxel
* Drug: nab-paclitaxel
* Drug: pemetrexed


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Histologically confirmed locally advanced stage IIIB or stage IV NSCLC for treatment in the first-line setting Known PD-L1 status determined by a Novartis designated central laboratory. A newly obtained tissue biopsy or an archival biopsy (block or slides) is required for PD-L1 determination (PD-L1 IHC 22C3 pharmDx assay), prior to study randomization. Note: For the safety run-in part, known PD-L1 status is not required. Eastern Cooperative oncology group (ECOG) performance status of 0 or 1. At least 1 measurable lesion by RECIST 1.1 Key exclusion criteria: Previous immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways). Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1β inhibitor). Subjects with epidermal growth factor receptor (EGFR) sensitizing mutations (identified in exons 19, 20, or 21), and/or ALK rearrangement by locally approved laboratory testing. Previously untreated or symptomatic central nervous system (CNS) metastases or lepto-meningeal disease. Subject with suspected or proven immune-compromised state or infections. Subject has prior to starting study drug: received live vaccination ≤3 months, had major surgery ≤4 weeks prior to starting study drug, has thoracic radiotherapy: lung fields ≤ 4 weeks, other anatomic sites ≤ 2 weeks, palliative radiotherapy for bone lesions ≤ 2 weeks. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: canakinumab<br>canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy | Drug: canakinumab<br>* canakinumab every 3 weeks (squamous and non-squamous)<br>* Other names: ACZ885;Drug: pembrolizumab<br>* 200 mg every 3 weeks (squamous and non-squamous)<br>Drug: carboplatin<br>* Area Under the Curve (AUC) 5 mg/mL*min every 3 weeks (non-squamous) or AUC 6 mg/mL*min (squamous)<br>Drug: cisplatin<br>* 75 mg/m2 every 3 weeks (non-squamous)<br>Drug: paclitaxel<br>* 200 mg/m2 every 3 weeks (squamous)<br>Drug: nab-paclitaxel<br>* 100 mg/m2 every 3 weeks (squamous)<br>Drug: pemetrexed<br>* 500 mg/m2 every 3 weeks (non-squamous)<br>|
| Other: canakinumab matching-placebo<br>canakinumab matching-placebo in combination with pembrolizumab and platinum-based doublet chemotherapy | Drug: canakinumab matching placebo<br>* canakinumab placebo every 3 weeks (squamous and non-squamous)<br>Drug: pembrolizumab<br>* 200 mg every 3 weeks (squamous and non-squamous)<br>Drug: carboplatin<br>* Area Under the Curve (AUC) 5 mg/mL*min every 3 weeks (non-squamous) or AUC 6 mg/mL*min (squamous)<br>Drug: cisplatin<br>* 75 mg/m2 every 3 weeks (non-squamous)<br>Drug: paclitaxel<br>* 200 mg/m2 every 3 weeks (squamous)<br>Drug: nab-paclitaxel<br>* 100 mg/m2 every 3 weeks (squamous)<br>Drug: pemetrexed<br>* 500 mg/m2 every 3 weeks (non-squamous)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in part: Incidence of dose limiting toxicities (DLTs) | Incidence of DLTs assessed among at least 6 evaluable subjects during the first 42 days of study treatment | 6 months from start of safety run-in part | 
| Double-blind, randomized, placebo-controlled part: Progression free survival (PFS) per investigator assessment using RECIST v1.1 | Progression free survival is defined as the time from randomization to the date of the first documented radiological progression using RECIST 1.1(Response evaluation criteria in solid tumor) or death due to any cause | 18 months from start of randomization part | 
| Double-blind, randomized, placebo-controlled part: Overall survival (OS) per investigator assessment using RECIST v1.1 | Overall survival is defined as the time from date of randomization to date of death due to any cause | 38 months from start of randomization part | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in part: Overall response rate (ORR) per investigator assessment using RECIST v1.1 | ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1 | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 6 months | 
| Double-blind, randomized, placebo-controlled part : Overall response rate (ORR) per investigator assessment using RECIST v1.1 | ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1 | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 18 months | 
| Safety run-in part: Disease control rate (DCR) per investigator assessment using RECIST v1.1 | Disease control rate is defined as the proportion of patients with complete response (CR) or partial response (PR) or subjects with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 6 months | 
| Double-blind, randomized, placebo-controlled part : Disease control rate (DCR) per investigator assessment using RECIST v1.1 | Disease control rate is defined as the proportion of patients with complete response (CR) or partial response (PR) or subjects with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 18 months | 
| Safety run-in part: Duration of response (DOR) per investigator assessment using RECIST v1.1 | Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 6 months | 
| Double-blind, randomized, placebo-controlled part : Duration of response (DOR) per investigator assessment using RECIST v1.1 | Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 18 months | 
| Double-blind, randomized, placebo-controlled part only: Time to response (TTR) per investigator assessment using RECIST v1.1 | Time to response (TTR) is defined as duration of time between the date of randomization and the date of first documented response of either CR or PR, according to RECIST 1.1 criteria | Baseline, every 6 weeks (for the first 12 weeks), then every 9 weeks (for the next 21 weeks) and every 12 weeks thereafter until progression per investigator assessment and up to 18 months | 
| Safety run-in part: Antidrug antibodies (ADA) of canakinumab |  | Predose (0 hours (h)) on Day 1 of Cycles 1, 4, 8, 12, 16 (Cycle length =21 days), at end of treatment & then at 26, 78 and 130 days after last dose | 
| Double-blind, randomized, placebo-controlled part : Antidrug antibodies (ADA) of canakinumab |  | Predose (0 h) on Day 1 of Cycles 1, 4, 8, 12, 16 (Cycle length =21 days), at end of treatment & then at 26, 78 and 130 days after last dose | 
| Safety run-in part: Antidrug antibodies (ADA) of pembrolizumab |  | Predose (0 h) on Day 1 of Cycles 1, 2, 4, 8, 12, 16 (Cycle length =21 days), at end of treatment & then at 26 days after last dose | 
| Double-blind, randomized, placebo-controlled part : Antidrug antibodies (ADA) of pembrolizumab |  | Predose (0 h) on Day 1 of Cycles 1, 2, 4, 8, 12, 16 (Cycle length =21 days), at end of treatment & then at 26 days after last dose | 
| Safety run-in part: Serum canakinumab concentration |  | Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, Post dose on Cycle 5 day 8, at end of treatment & then at 26, 78 and 130 days after last dose (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part : Serum canakinumab concentration |  | Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, Post dose on Cycle 5 day 8, at end of treatment & then at 26, 78 and 130 days after last dose (Cycle length =21 days) | 
| Safety run-in part: Serum pembrolizumab concentration |  | Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, at end of treatment & then at 26 days after last dose (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part : Serum pembrolizumab concentration |  | Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, at end of treatment & then at 26 days after last dose (Cycle length =21 days) | 
| Safety run-in part: Plasma pemetrexed concentration |  | Predose (0 h) and end of infusion on Cycle 1 and 2; 1, 4, 8 h post infusion on Cycle 1; 1, 2, 4, 8h post infusion on Cycle 2 (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part : : Plasma pemetrexed concentration |  | Predose (0 h) and end of infusion on Cycle 1 and 2; 1, 4, 8 h post infusion on Cycle 1; 1, 2, 4, 8h post infusion on Cycle 2 (Cycle length =21 days) | 
| Safety run-in part: Plasma cisplatin concentration |  | Predose (0 h) and end of infusion on Cycle 1 and 2; 2, 4, 8 h post infusion on Cycle 1; 1.5, 2, 4, 8 h post infusion on Cycle 2 (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part: Plasma cisplatin concentration |  | Predose (0 h) and end of infusion on Cycle 1 and 2; 2, 4, 8 h post infusion on Cycle 1; 1.5, 2, 4, 8 h post infusion on Cycle 2 (Cycle length = 21 days) | 
| Safety run-in part: Plasma carboplatin concentration |  | Predose (0 h), end of infusion, 1, 2, 4, 8 h post infusion on Cycles 1 and 2 (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part: Plasma carboplatin concentration |  | Predose (0 h), end of infusion, 1, 2, 4, 8 h post infusion on Cycles 1 and 2 (Cycle length =21 days) | 
| Safety run-in part: Plasma paclitaxel concentration |  | Predose (0 h) and end of infusion on Cycle 1 and 2; 4, 8, 12 h post infusion on Cycle 1; 4, 6, 8, 12 h post infusion on Cycle 2 (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part: Plasma paclitaxel concentration |  | Predose (0 h) and end of infusion on Cycle 1 and 2; 4, 8, 12 h post infusion on Cycle 1; 4, 6, 8, 12 h post infusion on Cycle 2 (Cycle length =21 days) | 
| Double-blind, randomized, placebo-controlled part: Plasma nab-paclitaxel concentration |  | Predose (0 h) and end of infusion on Cy 1 and 2, 4, 8, 12 h post infusion on Cy 1, 4, 6, 8, 12 h post infusion on Cy 2 (Cy length =21 days) | 
| Double-blind, randomized, placebo-controlled part only :Time to definitive 10 point deterioration symptom scores of pain, cough and dyspnea per EORTC QLQ-LC13 questionnaire | To assess the effect of canakinumab vs placebo on time to onset or deterioration of lung cancer specific symptoms using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) | Baseline and at day 1 of every visit (with dosing or not) until end of treatment, before each tumor assessments and 2 times (7 days and 28 days) after disease progression and up to 18 months | 
| Double-blind, randomized, placebo-controlled part only: Time to definitive deterioration in global health status/quality of life, shortness of breath and pain per EORTC QLQ-C30 questionnaire | To assess the effect of canakinumab vs placebo on time to onset or deterioration of lung cancer specific symptoms using the European Organization for Research and Treatment Quality of Life Questionnaire core 30 (EORTC QLQ-C30) | Baseline and at day 1 of every visit (with dosing or not) until end of treatment, before each tumor assessments and 2 times (7 days and 28 days) after disease progression and up to 18 months | 
| Double-blind, randomized, placebo-controlled part only: change from baseline in score as per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire | To assess the effect of canakinumab versus placebo on patient reported outcomes ((PROs) - patient's health related quality of life) | Baseline and at day 1 of every visit (with dosing or not) until end of treatment, before each tumor assessments and 2 times (7 days and 28 days) after disease progression and up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACZ885, canakinumab, pembrolizumab, carboplatin, cisplatin, paclitaxel, nab-paclitaxel, pemetrexed, NSCLC, non-small cell lung cancer, non small cell lung cancer, squamous, non-squamous, hsCRP, IL-1β, PD-L1, CANOPY, CANOPY-1, platinum-based doublet chemotherapy, first line therapy, locally advanced, metastatic