A Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy or Immunotherapy in Participants With Non-small Cell Lung Cancer (MK-3475-021/KEYNOTE-021)

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic non-small cell lung cancer (NSCLC).

Official Title
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A Phase I/II Study of MK-3475 (SCH900475) in Combination With Chemotherapy or Immunotherapy in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Carcinoma

Conditions
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Non-small Cell Lung Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Paclitaxel
* Drug: Carboplatin
* Biological: Bevacizumab
* Drug: Pemetrexed
* Biological: Ipilimumab
* Drug: Erlotinib
* Drug: Gefitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage IIIb/IV NSCLC Disease progression >1 year after completing adjuvant therapy for Stage I-IIIA disease and no systemic therapy for the recurrent disease Resolution of any toxic effects (excepting alopecia) of the most recent therapy At least one radiographically measurable lesion Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale Female participants of reproductive potential must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start) Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 120 days after the last dose of study therapy and for up to 180 days after the last dose of chemotherapeutic agents or tyrosine kinase inhibitors Exclusion Criteria: Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of pembrolizumab Expected to require any other form of antineoplastic therapy while on study Is on chronic systemic steroid therapy or on any other form of immunosuppressive medication Has received a live-virus vaccination within 30 days of planned treatment start Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation) History of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the participant has undergone potentially curative therapy with no evidence of that disease for 5 years Active central nervous system (CNS) metastases and/or carcinomatous meningitis Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb) Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed) Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first dose of study medication Radiation therapy to lung >30 Gy within 6 months of first dose of study medication Prior tyrosine kinase inhibitor therapy or palliative radiation within 7 days of first dose of study medication Active infection requiring therapy History of Human Immunodeficiency Virus (HIV) Active Hepatitis B or C Symptomatic ascites or pleural effusion Interstitial lung disease or pneumonitis requiring oral or IV glucocorticoids Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study Psychiatric disorders and substance (drug/alcohol) abuse

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C])<br>Cohort A participants receive pembrolizumab (2 mg/kg) via intravenous (IV) infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (Aare Under the Curve [AUC] 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Paclitaxel<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: ABRAXANE®;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;|
| Experimental: Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])<br>Cohort B2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Paclitaxel<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: ABRAXANE®;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;Biological: Bevacizumab<br>* IV on Day 1 of each 3-week cycle<br>* Other names: AVASTIN®;|
| Experimental: Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C)<br>Cohort C2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV on Day 1 of each 3-week cycle<br>* Other names: ALIMTA®;|
| Experimental: Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I])<br>Cohort D1 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Biological: Ipilimumab<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: YERVOY®;|
| Experimental: Part 1 Cohort E (Pembro 2mg/kg+Erlotinib)<br>Cohort E participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS erlotinib (150 mg) via oral tablet once a day on every day of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Erlotinib<br>* Orally tablet once daily<br>* Other names: TARCEVA®;|
| Experimental: Part 1 Cohort F (Pembro 2mg/kg+Gefitinib)<br>Cohort F participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS gefitinib (250 mg) via oral tablet once a day on every day of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Gefitinib<br>* Oral tablet once daily<br>* Other names: IRESSA®;|
| Experimental: Part 2 Cohort G+ (Pembro 200mg+C+Pe)<br>Cohort G+ participants receive pembrolizumab (200 mg) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV on Day 1 of each 3-week cycle<br>* Other names: ALIMTA®;|
| Experimental: Part 2 Cohort H (Pembro+I)<br>Cohort H participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle (at the recommended Phase II dose determined in Cohort D). | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Biological: Ipilimumab<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: YERVOY®;|
| Experimental: Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C])<br>Cohort A10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Paclitaxel<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: ABRAXANE®;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;|
| Experimental: Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B])<br>Cohort B10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Paclitaxel<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: ABRAXANE®;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;Biological: Bevacizumab<br>* IV on Day 1 of each 3-week cycle<br>* Other names: AVASTIN®;|
| Experimental: Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C)<br>Cohort C10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV on Day 1 of each 3-week cycle<br>* Other names: ALIMTA®;|
| Experimental: Part 2 Cohort G- (Placebo+C+Pe)<br>Cohort G- participants receive placebo (normal saline solution) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS. | Drug: Carboplatin<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV on Day 1 of each 3-week cycle<br>* Other names: ALIMTA®;|
| Experimental: Part 1 Cohort D2 (Pembro 10mg/kg+Ipilimumab [I])<br>Cohort D2 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (3 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Biological: Ipilimumab<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: YERVOY®;|
| Experimental: Part 1 Cohort D4 (Pembro 2mg/kg+Ipilimumab [I])<br>Cohort D1 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | Biological: Pembrolizumab<br>* IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy<br>* Other names: SCH 900475;Biological: Ipilimumab<br>* IV on Day 1 of each 3-week cycle for a maximum of 4 administrations<br>* Other names: YERVOY®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR). | Up to approximately 2 years | 
| Part 2 Cohorts D4 and H: Objective Response Rate (ORR) | For participants who demonstrated a confirmed response (Complete Response [CR]: Disappearance of all target lesions or Partial Response [PR]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR. | Up to approximately 2 years | 
| All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. A DLT was defined as any of the following events: Grade 4 non-hematologic toxicity (not laboratory); Grade 4 hematologic toxicity lasting ≥7 days; Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and diarrhea) lasting >3 days despite optimal supportive care; Any Grade 3 or Grade 4 non-hematologic laboratory value requiring treatment or hospitalization, or persisting for >1 week; Febrile neutropenia Grade 3 or Grade 4; Qualifying thrombocytopenia <25,000/mm^3; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Missing >10% of erlotinib or gefitinib doses as a result of adverse events (AEs) during the DLT window of observation; or Grade 5 toxicity. | Cycle 1 (Up to 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) | PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. PFS was assessed by BICR. | Up to approximately 2 years | 
| Part 2 Cohorts G+ and G-: Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. | Up to approximately 2 years | 
| Part 2 Cohorts G+ and G-: Duration of Response (DOR) | For participants who demonstrated a confirmed response (Complete Response [CR]: Disappearance of all target lesions or Partial Response [PR]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR. | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-1, PD1, Programmed Cell Death-1, Programmed Cell Death 1, Chemotherapy, Pemetrexed, Paclitaxel, Bevacizumab, Erlotinib, Gefitinib, Ipilimumab, Carboplatin