A Study of Pembrolizumab (MK-3475) in Combination With Etoposide/Platinum (Cisplatin or Carboplatin) for Participants With Extensive Stage Small Cell Lung Cancer (MK-3475-604/KEYNOTE-604)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of pembrolizumab plus standard of care (SOC) chemotherapy (etoposide/platinum [EP]) in participants with newly diagnosed extensive stage small cell lung cancer (ES-SCLC) who have not previously received systemic therapy for this malignancy. The primary study hypotheses are that pembrolizumab+EP prolongs Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review (BICR) and Overall Survival (OS) compared with placebo+EP in adult participants with ES-SCLC. In this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. With protocol Amendment 07 (03-Oct-2018), the outcome measure of Change from Baseline at Weeks 12 and 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale was replaced with a single time point analysis at Week 18.

Official Title
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A Phase 3 Randomized, Double-Blind, Placebo-controlled Trial of Pembrolizumab (MK-3475/SCH900475) in Combination With Etoposide/Platinum (Cisplatin or Carboplatin) for the First-line Treatment of Subjects With Extensive Stage Small Cell Lung Cancer (KEYNOTE-604)

Conditions
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Small Cell Lung Cancer (SCLC)

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Normal saline solution
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a documented new diagnosis of SCLC by histology or cytology from brushing, washing, or needle aspiration of a defined lesion. Participants who do not have histology samples (defined as core or excisional biopsy, or resections) will need to undergo a new biopsy to provide a tissue sample. Has extensive-stage disease defined as Stage IV (T any, N any, M 1a/b) by the American Joint Committee on Cancer (AJCC), Seventh Edition Has ≥1 lesion that meets the criteria for measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology assessment Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Has a life expectancy of ≥3 months Has adequate organ function Female and male participants of childbearing potential must be willing to use an adequate method of contraception, starting with the first dose of study treatment through 120 days after the last dose of study treatment and up to 180 days after last dose of chemotherapeutic agents Exclusion Criteria: Has received prior systemic therapy for the treatment of SCLC Is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment for another health-related problem Is expected to require any other form of antineoplastic therapy for SCLC, including radiation therapy, while on study. (Prophylactic cranial irradiation will be possible for those participants with stable disease or better at the completion of the 4 cycles of chemotherapy with or without pembrolizumab.) Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Participants with brain metastases may participate only if they satisfy all of the following: Has completed treatment (eg, whole brain radiation treatment [WBRT], stereotactic radiosurgery, or equivalent) ≥14 days prior to the first dose of study treatment, Has no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed ≥3 weeks after pre-treatment brain imaging, and Is neurologically stable without the need for steroids for ≥7 days before first dose of study treatment. Has had major surgery within 3 weeks prior to receiving the first dose of study treatment or has not recovered adequately from toxicity and/or complications from an intervention prior to receiving the first dose of study treatment. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis Has a known history of interstitial lung disease Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy. Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment. Has a known history of, or active, neurologic paraneoplastic syndrome Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis Has a history of a severe hypersensitivity reaction to treatment with another monoclonal antibody Is taking chronic systemic steroids (in doses exceeding 10 mg daily of prednisone equivalent) within 7 days prior to the first dose of study treatment Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of study treatment Has received a live vaccine within 30 days prior to the first dose of study treatment Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor (i.e., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], tumor necrosis factor receptor superfamily member 9 [TNFRSF9, OX-40, CD137]) or has previously participated in a Merck pembrolizumab (MK-3475) clinical trial Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known history of Hepatitis B or known active Hepatitis C virus infection Has a known history of active TB (Bacillus Tuberculosis) Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of study treatment through and up to 180 days after last dose of chemotherapeutic agents

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: Pembrolizumab+EP<br>During each 21-day cycle, participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stop pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stop after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, are eligible for up to an additional 1 year of treatment after progressive disease if they meet the criteria for retreatment. | Biological: Pembrolizumab<br>* IV infusion on Day 1 of each cycle prior to chemotherapy<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion on Day 1 of each cycle<br>* Other names: PARAPLATIN®;Drug: Cisplatin<br>* IV infusion on Day 1 of each cycle<br>* Other names: PLATINOL®;Drug: Etoposide<br>* IV infusion on Days 1, 2 and 3 of each cycle<br>* Other names: TOPOSAR™;|
| Active Comparator: Placebo+EP<br>During each 21-day cycle, participants receive placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). | Drug: Normal saline solution<br>* IV infusion on Day 1 of each cycle prior to chemotherapy<br>Drug: Carboplatin<br>* IV infusion on Day 1 of each cycle<br>* Other names: PARAPLATIN®;Drug: Cisplatin<br>* IV infusion on Day 1 of each cycle<br>* Other names: PLATINOL®;Drug: Etoposide<br>* IV infusion on Days 1, 2 and 3 of each cycle<br>* Other names: TOPOSAR™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD, as determined by RECIST 1.1, was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The PFS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol. | Up to approximately 30.5 months | 
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow up. The OS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol. | Up to approximately 30.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | ORR was defined as the percentage of participants who achieve a best objective response of complete response (CR) or partial response (PR) per RECIST 1.1. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was calculated using the Miettinen & Nurminen method stratified by type of platinum therapy (carboplatin or cisplatin), baseline ECOG performance status (0 or 1), and baseline LDH (≤ or > upper limit of normal) and presented for the first course of study treatment per protocol. | Up to approximately 30.5 months | 
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | DOR was defined as the time from first documented evidence of a Complete Response (CR) or Partial Response (PR) per RECIST 1.1 until progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurred first. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data and is presented for the first course of study treatment per protocol. | Up to approximately 30.5 months | 
| Number of Participants Who Experienced an Adverse Event (AE) | An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol. | Up to approximately 30.5 months | 
| Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE) | An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who discontinued due to an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol. | Up to approximately 26 months | 
| Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03) | The CTCAE uses Grades 1 through 5 correlating to AE severity criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2=moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. The number of participants who experienced any Grade 3 to 5 AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol. | Up to approximately 30.5 months | 
| Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. Change from baseline scores were calculated using a constrained longitudinal data analysis (cLDA) model. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Data are presented for the first course of study treatment per protocol. | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 18 | 
| Change From Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment. | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 12 | 
| Change From Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment. | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 24 | 
| Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13) | TTD in patient-reported lung cancer symptoms of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), and dyspnea (QLQ-C30 Item 8) was a composite endpoint defined as the time to first onset of ≥10 point deterioration from baseline in an item confirmed by a second adjacent ≥10 point deterioration. The QLQ-LC13 consists of 13 measures of lung cancer symptoms and side effects from chemotherapy and radiation. It is scored on a 4-point scale (1=none, 2=a little, 3=quite a bit, 4=very much). Scores were transformed to a range of 0 to 100 using a standard algorithm. Higher scores represented increasing symptom severity. TTD was calculated using the product-limit Kaplan-Meier method for censored data and is presented for the first course of study treatment per protocol. | Day 1 of Cycles 1-9, Day 1 of every other cycle for Cycles 10-17 and 30 days after last dose of study treatment (Up to approximately 27 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extensive stage small cell lung cancer (ES-SCLC), Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death Ligand 1 (PDL1, PD-L1), Programmed Cell Death Ligand 2 (PDL2, PD-L2)