PDR001 in Combination With Platinum-doublet Chemotherapy and Other Immunology Agents in PD-L1 Unselected, Metastatic NSCLC Patients

Study Overview
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Brief Summary
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The primary purpose of this study is to establish the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of PDR001 when administered in combination with platinum-doublet chemotherapy and other immunooncology agent(s) in treatment naive patients with PD-L1 unselected, advanced NSCLC, and to estimate the preliminary anti-tumor activity in this patient population.

Official Title
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Phase Ib, Multicenter, Open Label Study of PDR001 in Combination With Platinum Doublet Chemotherapy and Other Immunooncology Agents in PD-L1 Unselected, Metastatic NSCLS Patients (ElevatION:NSCLC-101 Trial)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: PDR001
* Drug: Cisplatin
* Drug: Gemcitabine
* Drug: Pemetrexed
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Canakinumab


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Patient has stage IIIB (and is not a candidate for definitive multimodality therapy) or has stage IV NSCLC or relapsed locally advanced or metastatic NSCLC as follows: Group A, group B and group C only: Patients not previously treated with any systemic anti-cancer therapy (e.g. cytotoxic drugs, targeted therapy, monoclonal antibody therapy including immunotherapy (e.g. PD-1/PD-L1 inhibitors) or targeted therapies, either experimental or not), with exception of neo-adjuvant or adjuvant therapy as depicted in inclusion criterion 4. Group D only: Patients who have received only one prior systemic therapy treatment consisting of a PD-1 and/or PD-L1 inhibitor with or without a CTLA4 inhibitor for NSCLC, with exception of neo-adjuvant or adjuvant therapy as depicted in inclusion criterion 4. The last dose of prior immunotherapy must have been administered at least 6 weeks prior to the start of study treatment (cycle 1 day 1). Histologically or cytologically confirmed diagnosis of NSCLC that is EGFR Wild-type, ALK-negative rearrangement and ROS1-negative rearrangement Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Patients with at least 1 measurable tumor lesion as assessed by Computed Tomography (CT) Scan or Magnetic Resonance Imaging (MRI) according to RECIST 1.1. Main Exclusion Criteria: Patient with a history of severe hypersensitivity reaction to the planned study treatment including gemcitabine, paclitaxel, cisplatin, carboplatin, pemetrexed or any known excipients of these drugs History of severe hypersensitivity reactions to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction. Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention). History of leptomeningeal metastases Active, known or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease (Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll). Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: squamous, gem/cis+PDR001<br> | Drug: PDR001<br>* Powder for solution for infusion<br>Drug: Cisplatin<br>* Intravenous infusion<br>Drug: Gemcitabine<br>* Intravenous infusion<br>|
| Experimental: Group B: non-squamous, pem/cis+PDR001<br> | Drug: PDR001<br>* Powder for solution for infusion<br>Drug: Cisplatin<br>* Intravenous infusion<br>Drug: Pemetrexed<br>* Intravenous infusion<br>|
| Experimental: Group C: paclitaxel/carbo+PDR001<br> | Drug: PDR001<br>* Powder for solution for infusion<br>Drug: Carboplatin<br>* Intravenous infusion<br>Drug: Paclitaxel<br>* Intravenous infusion<br>|
| Experimental: Group E: non-squamous, pem/cis (or carbo)+PDR001+canakinumab<br> | Drug: PDR001<br>* Powder for solution for infusion<br>Drug: Cisplatin<br>* Intravenous infusion<br>Drug: Pemetrexed<br>* Intravenous infusion<br>Drug: Carboplatin<br>* Intravenous infusion<br>Drug: Canakinumab<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) during the first 6 weeks of therapy | A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 42 days | 42 days | 
| Overall response rate (ORR) per local investigator assessment for groups A, B and C | ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 and local investigator assessment for groups A, B and C | From baseline up to approximately 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) per local investigator assessment for group E | ORR is defined as the proportion of patients with BOR of CR or PR, as per RECIST 1.1 and local investigator assessment for group E | Up to approximately 28 months | 
| Progression Free Survival (PFS) per Investigator | PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, as per RECIST 1.1 and local investigator assessment | From start of treatment to the date of the first documented progression or death due to any cause, whichever comes first, assessed up to approximately 28 months | 
| Disease Control Rate (DCR) per Investigator | DCR is the proportion of patients with a BOR of CR or PR or stable disease (SD), as per RECIST 1.1 and local investigator assessment. | Up to approximately 28 months | 
| Duration of Response (DOR) per Investigator | DOR is defined by responders as the time between the date of first documented response (CR or PR) and the date of first documented progression (RECIST 1.1 and local investigator assessment) or death due any cause | From date of first documented response to the first documented progression or death due to any cause, whichever comes first, assessed up to approximately 28 months | 
| Time to Response (TTR) per Investigator | TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR as per RECIST 1.1 and local investigator assessment | From start of treatment to the date of the first documented reponse (CR or PR), assessed up to approximately 28 months | 
| Overall survival (OS) | OS is defined as the time from date of start of treatment to date of death due to any cause. | from date of start of treatment to date of death due to any cause (assessed up to approximately 3.5 years) | 
| Trough plasma Concentration (Ctrough) of PDR001 | Blood samples will be collected at indicated time points for pharmacokinetic analysis. | Pre-infusion on Day 1 of Cycle 1 to 4 of induction phase; pre-infusion on Day 1 of Cycle 1 to 4, 6, 8 and every 6 cycle afterwards of maintenance phase; Cycle = 21 Days | 
| Trough plasma Concentration (Ctrough) of chemotherapy | Blood samples will be collected at indicated time points for pharmacokinetic analysis. Ctrough will be assessed for all chemotherapy agents: cysplatin, pemetrexed, carboplatin and gemcitabine | Pre-infusion on Day 1 of Cycle 1, 3 and 4 of induction phase; Cycle = 21 Days | 
| Trough plasma Concentration (Ctrough) of canakinumab | Blood samples will be collected at indicated time points for pharmacokinetic analysis. | Pre-infusion on Day 1 of Cycle 1, 3 and 4 of induction phase; Cycle = 21 Days | 
| PDR001 Antidrug antibodies (ADA) prevalence at baseline | Blood samples will be collected at indicated time points for immunogenicity analysis. | Baseline | 
| Canakinumab ADA prevalence at baseline | Blood samples will be collected at indicated time points for immunogenicity analysis. | Baseline | 
| PDR001 ADA incidence during treatment | Blood samples will be collected at indicated time points for immunogenicity analysis. | Pre-infusion on Day 1 of Cycle 1 to 4 of induction phase, pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 6, 8 and every 6 cycle afterwards of maintenance phase, end of treatment and 30 and 150-day post-treatment | 
| Canakinumab ADA incidence during treatment | Blood samples will be collected at indicated time points for immunogenicity analysis. | Pre-infusion on Day 1 of Cycle 1 and 4 of induction phase, pre-infusion on Day 1 of Cycle 6, 14 and 20 of maintenance phase, end of treatment and 30 and 150-day post-treatment | 
| Incidence of Adverse Events (AEs) | Incidence of AEs (CTCAE v4.03) | through study completion, up to approximately 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDR001, immunotherapy, Non-small cell lung cancer, lung, NSCLC