Study of Pembrolizumab With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib in Stage III Non-Small Cell Lung Cancer (NSCLC) (MK-7339-012/KEYLYNK-012)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of pembrolizumab in combination with concurrent chemoradiation therapy followed by either pembrolizumab with olaparib placebo (Arm 1) or with olaparib (Arm 2) compared to concurrent chemoradiation therapy followed by durvalumab (Arm 3) in participants with unresectable, locally advanced NSCLC. Arms 1 and 2 will be studied in a double-blind design and Arm 3 will be open-label. The primary hypotheses are: Pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with olaparib is superior to concurrent chemoradiation therapy followed by durvalumab with respect to progression-free survival (PFS) and overall survival (OS) Pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab is superior to concurrent chemoradiation therapy followed by durvalumab with respect to PFS and OS

Official Title
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A Phase 3 Study of Pembrolizumab (MK-3475) in Combination With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib vs Concurrent Chemoradiation Therapy Followed by Durvalumab in Participants With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Lung Neoplasms, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Olaparib
* Drug: Placebo for olaparib
* Drug: Etoposide
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Paclitaxel
* Drug: Pemetrexed
* Radiation: Thoracic Radiotherapy
* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has pathologically (histologically or cytologically) confirmed diagnosis of NSCLC Has Stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8 Is unable to undergo surgery with curative intent for Stage III NSCLC Has no evidence of metastatic disease indicating Stage IV NSCLC Has measurable disease as defined by RECIST 1.1 Has not received prior treatment (chemotherapy, targeted therapy or radiotherapy) for Stage III NSCLC; participants who have received neoadjuvant and/or adjuvant therapy for early stage disease are not eligible Has provided a tumor tissue sample (tissue biopsy [core, incisional, or excisional]) Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 assessed within 7 days prior to the first administration of study intervention Has a life expectancy of at least 6 months A male participant must agree to use contraception and refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention unless confirmed to be azoospermic (vasectomized or secondary to medical cause). The length of time required to continue contraception for each study intervention is as follows: Olaparib, platinum doublet, and radiotherapy: 90 days A female participant is eligible to participate if she is not pregnant, not breastfeeding, and agrees to use contraception and refrain from donating eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during the treatment period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees to abstain from breastfeeding during the study intervention period and for at least 120 days after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: Pembrolizumab: 120 days; Olaparib, platinum doublet, and radiotherapy: 180 days Has a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Has had her medical history, menstrual history, and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. Has adequate pulmonary function tests Has adequate organ function Has provided written informed consent Exclusion Criteria: Has small cell lung cancer or a mixed tumor with presence of small cell elements Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML Has had documented weight loss >10% (from baseline) in the preceding 3 months Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer Has received prior therapy with an anti-programmed cell death 1 (ant-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 stimulatory or co-inhibitory T-cell receptor Has received prior therapy with olaparib or with any other polyadenosine 5'diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor Has had major surgery <4 weeks prior to the first dose of study treatment (except for placement of vascular access) Is expected to require any other form of antineoplastic therapy, while on study Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines is allowed Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study treatment Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days before, during, and for at least 2 days after administration of pemetrexed Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone during administration of pemetrexed Has received an investigational agent or has used an investigational device within 4 weeks prior to study treatment The presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator or has congenital long QT syndrome Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 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 with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (excluding carcinoma-in situ-of the bladder) that have undergone potentially curative therapy 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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease 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 active tuberculosis (TB; Mycobacterium tuberculosis) and is receiving treatment Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease in the opinion of the treating investigator Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption Has had an allogenic tissue/solid organ transplant

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+chemoradiation→pembrolizumab+olaparib placebo<br>Participants will receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) in combination with 3 cycles of the investigator's choice of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gray (Gy) over 6 weeks) followed by pembrolizumab plus olaparib placebo twice a day (BID) for approximately 1 year. | Biological: Pembrolizumab<br>* intravenous (IV) infusion<br>* Other names: MK-3475;Drug: Placebo for olaparib<br>* oral tablets<br>Drug: Etoposide<br>* IV infusion<br>* Other names: VEPESID®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Cisplatin<br>* IV infusion<br>* Other names: PLATINOL®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Pemetrexed<br>* IV infusion<br>* Other names: ALIMTA®;Radiation: Thoracic Radiotherapy<br>* external beam radiation<br>|
| Experimental: pembrolizumab+chemoradiation→pembrolizumab+olaparib<br>Participants will receive pembrolizumab 200 mg IV Q3W in combination with 3 cycles of the investigator's choice of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gy over 6 weeks) followed by pembrolizumab plus olaparib 300 mg BID for approximately 1 year. | Biological: Pembrolizumab<br>* intravenous (IV) infusion<br>* Other names: MK-3475;Drug: Olaparib<br>* oral tablets<br>* Other names: KU-0059436;Drug: Etoposide<br>* IV infusion<br>* Other names: VEPESID®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Cisplatin<br>* IV infusion<br>* Other names: PLATINOL®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Pemetrexed<br>* IV infusion<br>* Other names: ALIMTA®;Radiation: Thoracic Radiotherapy<br>* external beam radiation<br>|
| Active Comparator: chemoradiation→durvalumab<br>Participants will receive 3 cycles of the investigator's choice of platinum doublet chemotherapy with concurrent standard thoracic radiotherapy (60 Gy over 6 weeks) followed by durvalumab 10 mg/kg every 2 weeks (Q2W) for approximately 1 year. | Drug: Etoposide<br>* IV infusion<br>* Other names: VEPESID®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Cisplatin<br>* IV infusion<br>* Other names: PLATINOL®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Pemetrexed<br>* IV infusion<br>* Other names: ALIMTA®;Radiation: Thoracic Radiotherapy<br>* external beam radiation<br>Drug: Durvalumab<br>* IV infusion<br>* Other names: IMFINZI®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. | Up to approximately 48 months | 
| Overall Survival (OS) | OS is the time from randomization to death due to any cause. | Up to approximately 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AE) | An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to approximately 72 months | 
| Discontinuation Rate of Study Intervention Due to an Adverse Event (AE) | An AE is defined as as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to approximately 72 months | 
| 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 is defined as the percentage of participants who have achieved a Complete Response (CR) or a Partial Response (PR). | Up to approximately 72 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 is defined as the time from first documented evidence of Complete Response (CR) or a Partial Response (PR) until disease progression or death due to any cause, whichever occurs first. | Up to approximately 72 months | 
| Change from Baseline in EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Scale Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life 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 scale scores will be presented. | Baseline (at randomization) and at the end of study (approximately 72 months post randomization) | 
| Change From Baseline in Cough Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module 13 (EORTC QLQ-LC13) Item 1 Score | The EORTC QLQ-LC13 is a supplemental lung cancer-specific questionnaire that includes a single-item scale score for cough (Item 1). For this item, individual responses to the question How much did you cough? are given on a 4-point scale (1=Not at all; 4=Very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100, with a lower score indicating a better outcome. The change from baseline in the EORTC QLQ-LC13 cough scale score will be presented. | Baseline (at randomization) and at the end of study (approximately 72 months post randomization) | 
| Change From Baseline in Chest Pain Using the EORTC QLQ-LC13 Item 10 Score | The EORTC QLQ-LC13 is a supplemental lung cancer-specific questionnaire that includes a single-item scale score for chest pain (Item 10). For this item, individual responses to the question Have you had pain in your chest? are given on a 4-point scale (1=Not at all; 4=Very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100, with a lower score indicating a better outcome. The change from baseline in the EORTC QLQ-LC13 chest pain scale score will be presented. | Baseline (at randomization) and at the end of study (approximately 72 months post randomization) | 
| Change From Baseline in Dyspnea Using the EORTC QLQ-C30 Item 8 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients and includes a single-item scale score for dyspnea (Item 8). 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, with a lower score indicating a better outcome. The change from baseline in the EORTC QLQ-C30 dyspnea scale score will be presented. | Baseline (at randomization) and at the end of study (approximately 72 months post randomization) | 
| Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The physical functioning scale consists of participant responses to 5 questions regarding performance of daily activities [1) strenuous activities; 2) long walks; 3) short walks; 4) bed/chair rest; and 5) needing help with eating, dressing, washing themselves or using the toilet]. Participant responses 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, with a higher score indicating a better quality of life. The change from baseline in the EORTC QLQ-C30 physical functioning scale score will be presented. | Baseline (at randomization) and at the end of study (approximately 72 months post randomization) | 
| Change from Baseline in Role Functioning Using the EORTC QLQ-C30 Items 6-7 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The role functioning scale consists of participant responses to 2 questions regarding limitations in doing work or other activities and pursuing hobbies or leisure activities. Participant responses 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, with a higher score indicating a better quality of life. The change from baseline in the EORTC QLQ-C30 role functioning scale score will be presented. | Baseline (at randomization) and at the end of study (approximately 72 months post randomization) | 
| Time to Deterioration (TTD) in HRQoL Using the EORTC QLQ-C30 Items 29 and 30 Score | TTD is defined as the time to first onset of a ≥10-point decrease from baseline for EORTC QLQ-C30 Items 29 and 30 scale scores. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life 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. | Up to approximately 72 months post randomization | 
| TTD in Cough Using the EORTC QLQ-LC13 Item 1 Score | TTD is defined as the time to first onset of a ≥10-point decrease from baseline for EORTC QLQ-LC13 Item 1 scale score. The EORTC QLQ-LC13 is a supplemental lung cancer-specific questionnaire that includes a single-item scale score for cough (Item 1). For this item, individual responses to the question How much did you cough? are given on a 4-point scale (1=Not at all; 4=Very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100, with a lower score indicating a better outcome. | Up to approximately 72 months post randomization | 
| TTD in Chest Pain Using the EORTC QLQ-LC13 Item 10 Score | TTD is defined as the time to first onset of a ≥10-point decrease from baseline for EORTC QLQ-LC13 Item 10 scale score. The EORTC QLQ-LC13 is a supplemental lung cancer-specific questionnaire that includes a single-item scale score for chest pain (Item 10). For this item, individual responses to the question Have you had pain in your chest? are given on a 4-point scale (1=Not at all; 4=Very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100, with a lower score indicating a better outcome. | Up to approximately 72 months post randomization | 
| TTD in Dyspnea Using the EORTC QLQ-C30 Item 8 Score | TTD is defined as the time to first onset of a ≥10-point decrease from baseline for EORTC QLQ-C30 Item 8 scale score. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients and includes a single-item scale score for dyspnea (Item 8). 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, with a lower score indicating a better outcome. | Up to approximately 72 months post randomization | 
| TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score | TTD is defined as the time to first onset of a ≥10-point decrease from baseline for EORTC QLQ-C30 Items 1-5 scale scores. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The physical functioning scale consists of participant responses to 5 questions regarding performance of daily activities [1) strenuous activities; 2) long walks; 3) short walks; 4) bed/chair rest; and 5) needing help with eating, dressing, washing themselves or using the toilet]. Participant responses 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, with a higher score indicating a better quality of life. | Up to approximately 72 months post randomization | 
| TTD in Role Functioning Using the EORTC QLQ-C30 Items 6-7 Score | TTD is defined as the time to first onset of a ≥10-point decrease from baseline for EORTC QLQ-C30 Items 6-7 scale scores. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The role functioning scale consists of participant responses to 2 questions regarding limitations in doing work or other activities and pursuing hobbies or leisure activities. Participant responses 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, with a higher score indicating a better quality of life. | Up to approximately 72 months post randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death Receptor 1 (PD-1, PD1), Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1), Programmed Cell Death Receptor Ligand 2 (PD-L2, PDL2), polyadenosine 5'diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor