A Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With First Line Metastatic Squamous Non-small Cell Lung Cancer (MK-3475-407/KEYNOTE-407)

Study Overview
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Brief Summary
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This is a study of carboplatin and paclitaxel or nano particle albumin-bound paclitaxel (nab-paclitaxel) with or without pembrolizumab (MK-3475, KEYTRUDA®) in adults with first line metastatic squamous non-small cell lung cancer (NSCLC). The primary hypotheses are that treatment with pembrolizumab prolongs: 1) Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor compared to placebo, and 2) Overall Survival (OS). After analysis of interim results was conducted, the protocol was amended (Amendment 5) to allow participants the option to discontinue placebo in the control arm and to switch to pembrolizumab in the event of documented progressive disease as assessed by central review.

Official Title
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A Randomized, Double-Blind, Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Paclitaxel
* Drug: Nab-paclitaxel
* Drug: Carboplatin
* Drug: Saline placebo for pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b-American Joint Committee on Cancer [AJCC] 7th edition) squamous NSCLC. Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Has not received prior systemic treatment for metastatic NSCLC. Has provided tumor tissue from locations not radiated prior to biopsy. Has a life expectancy of at least 3 months. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status. Has adequate organ function. If female of childbearing potential, is willing to use an adequate method of contraception for the course of the study through 180 days after the last dose of study drug. If male with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception starting with the first dose of study drug through 95 days after the last dose of study drug. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Exclusion Criteria: Has non-squamous histology NSCLC. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab. Before the first dose of study drug: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease; b) Has received other targeted or biological antineoplastic therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease; c) Has had major surgery (<3 weeks prior to first dose). Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study drug. Completed palliative radiotherapy within 7 days of the first dose of study drug. Is expected to require any other form of antineoplastic therapy while on study. Has received a live-virus vaccination within 30 days of planned treatment start. Has a known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria. Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody. Has a known sensitivity to any component of carboplatin or paclitaxel or nab-paclitaxel. Has active autoimmune disease that has required systemic treatment in past 2 years. Is on chronic systemic steroids. Had prior treatment with any other anti-programmed cell death 1 (anti-PD-1), or programmed cell death ligand 1 (PD-L1) or PD-L2 agent or an antibody or a small molecule targeting other immuno-regulatory receptors or mechanisms. Has participated in any other pembrolizumab trial and has been treated with pembrolizumab. Has an active infection requiring therapy. Has known history of Human Immunodeficiency Virus (HIV). Has known active Hepatitis B or C. Active Hepatitis B. Is, at the time of providing documented informed consent, a regular user (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol). Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Chemotherapy<br>Participants receive pembrolizumab 200 mg by intravenous (IV) infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS Investigator's choice of paclitaxel (200 mg/m^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Nab-paclitaxel<br>* IV infusion<br>* Other names: ABRAXANE®;Drug: Carboplatin<br>* IV infusion Carboplatin dose should not to exceed 900 mg.<br>* Other names: PARAPLATIN®;|
| Active Comparator: Chemotherapy<br>Participants receive normal saline by IV infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS Investigator's choice of paclitaxel (200 mg/m^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. | Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Nab-paclitaxel<br>* IV infusion<br>* Other names: ABRAXANE®;Drug: Carboplatin<br>* IV infusion Carboplatin dose should not to exceed 900 mg.<br>* Other names: PARAPLATIN®;Drug: Saline placebo for pembrolizumab<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 is presented. | Up to approximately 19 months (Database cutoff date of 03-Apr-2018) | 
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. OS is presented. | Up to approximately 19 months (Database cutoff date of 03-Apr-2018) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | ORR was defined as the percentage of participants 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) as assessed by RECIST 1.1. ORR as assessed by blinded independent central review per RECIST 1.1 is presented. | Up to approximately 19 months (Database cutoff date of 03-Apr-2018) | 
| Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 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, DOR was defined as the time from first documented evidence of CR or PR until disease progression as assessed by RECIST 1.1 or death. DOR as assessed by blinded independent central review per RECIST 1.1 is presented. | Up to approximately 19 months (Database cutoff date of 03-Apr-2018) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. | Up to approximately 19 months (Database cutoff date of 03-Apr-2018) | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | The number of participants who discontinued study treatment due to an AE is presented. | Up to approximately 19 months (Database cutoff date of 03-Apr-2018) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD1, PD-1, PDL1, PD-L1