Placebo-controlled, Study of Concurrent Chemoradiation Therapy With Pembrolizumab Followed by Pembrolizumab and Olaparib in Newly Diagnosed Treatment-Naïve Limited-Stage Small Cell Lung Cancer (LS-SCLC) (MK 7339-013/KEYLYNK-013)

Study Overview
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Brief Summary
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The purpose of this study is to compare overall survival (OS) and 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). Hypothesis (H1): Concurrent chemoradiation therapy with pembrolizumab followed by pembrolizumab plus olaparib is superior to concurrent chemoradiation therapy alone with respect to PFS per RECIST 1.1 by BICR. Hypothesis (H2): Concurrent chemoradiation therapy with pembrolizumab followed by pembrolizumab is superior to concurrent chemoradiation therapy alone with respect to PFS per RECIST 1.1 by BICR. Hypothesis (H3): Concurrent chemoradiation therapy with pembrolizumab followed by pembrolizumab plus olaparib is superior to concurrent chemoradiation therapy alone with respect to OS. Hypothesis (H4): Concurrent chemoradiation therapy with pembrolizumab followed by pembrolizumab is superior to concurrent chemoradiation therapy alone with respect to OS.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase 3 Study of Pembrolizumab (MK-3475) in Combination With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib (MK-7339), Compared to Concurrent Chemoradiation Therapy Alone in Participants With Newly Diagnosed Treatment-Naïve Limited-Stage Small Cell Lung Cancer (LS-SCLC)

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Biological: Pembrolizumab 200 mg
* Biological: Pembrolizumab 400 mg
* Drug: Pembrolizumab placebo (saline)
* Drug: Pembrolizumab placebo (saline)
* Drug: Olaparib 300 mg BID
* Drug: Olaparib matching placebo
* Drug: Etoposide 100 mg/m^2
* Drug: Platinum, investigator's choice
* Radiation: Standard Thoracic Radiotherapy
* Radiation: Prophylactic Cranial Irradiation (PCI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has pathologically (histologically or cytologically) confirmed Small Cell Lung Cancer (SCLC). Note: Note: Participants with histology showing a mixed tumor with small cell and non-small cell elements are not eligible. Has Limited-Stage SCLC (Stage I-III, by AJCC 8th Edition Cancer Staging), and can be safely treated with definitive radiation doses. Has no evidence of metastatic disease by whole body positron emission tomography /computed tomography (PET/CT scan), CT or magnetic resonance imaging (MRI) scans Has at least 1 lesion that meets the criteria for being measurable, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) Has not received prior treatment (chemotherapy or radiotherapy or surgery resection) of LS-SCLC. Is not expected to require tumor resection during the course of the study. Must submit a pre-treatment tumor tissue sample (formalin-fixed, paraffin embedded blocks are preferred to slides) including cytologic sample, if tissue sample unavailable. Has Eastern Cooperative Oncology Group (ECOG) Performance score 0 or 1 assessed within 7 days prior to the first administration of study intervention. Has a life expectancy of at least 6 months. Has adequate organ function. Male and female participants who are not pregnant and of childbearing potential must follow contraceptive guidance during the treatment period and for the time needed to eliminate each study intervention. Male and female participants who are at least 18 years of age at the time of signing the information consent. Male participants must refrain from donating sperm during the treatment period and for the time needed to eliminate each study intervention. Abstains from breastfeeding during the study intervention period and for at least the following period after the last study intervention: Pembrolizumab: 120 days Olaparib: 7 days Exclusion Criteria: Has history, current diagnosis, or features suggestive of myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML). Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PDL1), or anti- programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor Has received prior therapy with olaparib or with any other polyadenosine 5'diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor. Had major surgery <4 weeks prior to the first dose of study intervention (except for placement of vascular access). Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Has severe hypersensitivity (≥ Grade 3) to study intervention and/or any of its excipients. Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (non-infectious) pneumonitis/interstitial lung disease that requires steroids Has an active infection requiring systemic therapy. Has a known history of human immunodeficiency virus (HIV) infection or Hepatitis B or known active Hepatitis C virus infection.

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: Group A - Pembrolizumab 200 mg<br>Participants will receive 4 cycles of standard-of-care chemotherapy (etoposide/platinum) plus pembrolizumab 200 mg every 3 weeks (Q3W) concurrently with standard thoracic radiotherapy, followed by 9 cycles of pembrolizumab 400 mg every 6 weeks (Q6W) plus olaparib matching placebo twice daily (BID) for 12 months or until specific discontinuation criteria are met. | Biological: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg Q3W<br>* Other names: KEYTRUDA®;Biological: Pembrolizumab 400 mg<br>* Pembrolizumab 400 mg Q6W<br>* Other names: KEYTRUDA®;Drug: Olaparib matching placebo<br>* Olaparib matching placebo BID<br>Drug: Etoposide 100 mg/m^2<br>* Etoposide 100 mg/m^2 intravenous (IV) Q3W, Day 1-3<br>Drug: Platinum, investigator's choice<br>* Carboplatin titrated to an area under the plasma drug concentration time curve (AUC) of 5 mg/mL/min IV Q3W OR Cisplatin 75 mg/m^2 IV Q3W on Day 1 of each cycle<br>Radiation: Standard Thoracic Radiotherapy<br>* Standard Thoracic Radiotherapy<br>Radiation: Prophylactic Cranial Irradiation (PCI)<br>* PCI will be strongly recommended for participants who achieve CR or PR after completion of chemoradiation treatment.<br>|
| Experimental: Group B - Pembrolizumab 200 mg plus Olaparib 300 mg BID<br>Participants will receive 4 cycles of standard-of-care chemotherapy (etoposide/platinum) plus pembrolizumab 200 mg Q3W concurrently with standard thoracic radiotherapy, followed by 9 cycles of pembrolizumab 400 mg Q6W plus olaparib 300 mg BID for 12 months or until specific discontinuation criteria are met. | Biological: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg Q3W<br>* Other names: KEYTRUDA®;Biological: Pembrolizumab 400 mg<br>* Pembrolizumab 400 mg Q6W<br>* Other names: KEYTRUDA®;Drug: Olaparib 300 mg BID<br>* Olaparib 300 mg twice daily (BID)<br>* Other names: LYNPARZA®;Drug: Etoposide 100 mg/m^2<br>* Etoposide 100 mg/m^2 intravenous (IV) Q3W, Day 1-3<br>Drug: Platinum, investigator's choice<br>* Carboplatin titrated to an area under the plasma drug concentration time curve (AUC) of 5 mg/mL/min IV Q3W OR Cisplatin 75 mg/m^2 IV Q3W on Day 1 of each cycle<br>Radiation: Standard Thoracic Radiotherapy<br>* Standard Thoracic Radiotherapy<br>Radiation: Prophylactic Cranial Irradiation (PCI)<br>* PCI will be strongly recommended for participants who achieve CR or PR after completion of chemoradiation treatment.<br>|
| Placebo Comparator: Group C (Pembrolizumab and Olaparib Matching Placebos)<br>Participants will receive 4 cycles of standard-of-care chemotherapy (etoposide/platinum) plus pembrolizumab placebo (saline) Q3W concurrently with standard thoracic radiotherapy, followed by 9 cycles of pembrolizumab placebo (saline) Q6W plus olaparib matching placebo for 12 months or until specific discontinuation criteria are met. | Drug: Pembrolizumab placebo (saline)<br>* Pembrolizumab placebo (saline) Q3W<br>Drug: Pembrolizumab placebo (saline)<br>* Pembrolizumab placebo (saline) Q6W<br>Drug: Olaparib matching placebo<br>* Olaparib matching placebo BID<br>Drug: Etoposide 100 mg/m^2<br>* Etoposide 100 mg/m^2 intravenous (IV) Q3W, Day 1-3<br>Drug: Platinum, investigator's choice<br>* Carboplatin titrated to an area under the plasma drug concentration time curve (AUC) of 5 mg/mL/min IV Q3W OR Cisplatin 75 mg/m^2 IV Q3W on Day 1 of each cycle<br>Radiation: Standard Thoracic Radiotherapy<br>* Standard Thoracic Radiotherapy<br>Radiation: Prophylactic Cranial Irradiation (PCI)<br>* PCI will be strongly recommended for participants who achieve CR or PR after completion of chemoradiation treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); the time from randomization to progression or death due to any cause, whichever occurs first | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) is the time from randomization to progression or death due to any cause, whichever occurs first. | Up to approximately 59 months | 
| Overall Survival: the time from randomization to death due to any cause | Overall Survival (OS) is the time from randomization to death due to any cause. | Up to approximately 82 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing an Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to approximately 82 months | 
| Number of Participants Discontinuing Study Treatment Due to Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to approximately 82 months | 
| Objective Response (OR): Complete Response (CR) or Partial Response (PR) | Percentage of participants in the analysis population who have a best overall response of either confirmed CR or a PR per RECIST 1.1. | Up to approximately 82 months | 
| Duration of Response (DOR): the time from the earliest date of first documented evidence of confirmed CR or PR until the earliest date of disease progression or death from any cause, whichever comes first | DOR is the time from the earliest date of first documented evidence of confirmed CR or PR until the earliest date of disease progression or death from any cause, whichever comes first. | Up to approximately 82 months | 
| Change from Baseline at Cycle 1 in European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status / Quality of Life (Items 29 & 30) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question How would you rate your overall health during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 scores will be presented. | Baseline and 82 months post randomization | 
| Change from Baseline at Cycle 1 in EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score | The EORTC QLQ-LC13 is a lung cancer specific supplemental questionnaire used in combination with the EORTC QLQC30 questionnaire. Participant responses to the question How much did you cough? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in EORTC QLQ-LC13 cough (Item 1) score will be presented. | Baseline and 82 months post randomization | 
| Change from Baseline at Cycle 1 in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQC30 questionnaire. Participant responses to the question How was your chest pain? are scored on a 4 point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in EORTC QLQ-LC13 chest pain (Item 10) score will be presented. | Baseline and 82 months post randomization | 
| Change from Baseline at Cycle 1 in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question Were you short of breath? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in EORTC QLQ-LC13 dyspnea (Item 8) score will be presented. | Baseline and 82 months post randomization | 
| Change from Baseline at Cycle 1 in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score will be presented. | Baseline and 82 months post randomization | 
| Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health Status / Quality of Life (Items 29 & 30) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question How would you rate your overall health during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in EORTC QLQ-C30 Items 29 and 30 scale scores. | Up to approximately 82 months post randomization | 
| Time to True Deterioration (TTD) in Cough (LC13/Item 1) Scale Score | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQC30 questionnaire. Participant responses to the question How much did you cough? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in cough EORTC QLQLC13 cough (Item 1) scale score. | Up to approximately 82 months post randomization | 
| Time to True Deterioration (TTD) in Chest Pain (LC13/Item 10) Scale Score | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQC30 questionnaire. Participant responses to the question How was your chest pain? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in EORTC QLQ-LC13 chest pain (Item 10) scale score. | Up to approximately 82 months post randomization | 
| Time to True Deterioration (TTD) in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question Were you short of breath? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in EORTC QLQ-C30 dyspnea (Item 8) scale score. | Up to approximately 82 months post randomization | 
| Time to True Deterioration (TTD) in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in EORTC QLQ-C30 physical functioning (Items 1 to 5) scale scores. | Up to approximately 82 months post randomization | 
| Objective Response (OR, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels | Percentage of participants in the analysis population who have a best overall response of either confirmed CR or a PR per RECIST 1.1, analyzed by programmed cell death ligand 1 (PD-L1) expression levels. | Up to approximately 82 months | 
| Duration of Response (DOR, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels | DOR is the time from the earliest date of first documented evidence of confirmed CR or PR until the earliest date of disease progression or death from any cause, whichever comes first, analyzed by programmed cell death ligand 1 (PD-L1) expression levels. | Up to approximately 82 months | 
| Progression-free Survival (PFS, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels | Progression-free Survival Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); the time from randomization to progression or death due to any cause, whichever occurs first, analyzed by programmed cell death ligand 1 (PD-L1) expression levels. | Up to approximately 59 months | 
| Overall Survival (OS) assessed by programmed cell death ligand 1 (PD-L1) expression levels | Overall Survival: the time from randomization to death due to any cause, analyzed by programmed cell death ligand 1 (PD-L1) expression levels. | Up to approximately 82 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Pembrolizumab, Olaparib