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) - MK7339-013 (KEYLYNK-013)

Studio Clinico

Patologia: Neoplasie del polmone

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: III

Richiesta mandatoria di tessuto: Sì

Linee di trattamento: Prima linea

Criteri di inclusione: 

1. 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. 
2. Has Limited-Stage SCLC (Stage I-III, by AJCC 8th Edition Cancer Staging), and can be safely treated with definitive radiation doses.
3. Has no evidence of metastatic disease by whole body positron emission tomography /computed tomography (PET/CT scan), CT or magnetic resonance imaging (MRI) scans
4. 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)
5. Has not received prior treatment (chemotherapy or radiotherapy or surgery resection) of LS-SCLC.
6. Is not expected to require tumor resection during the course of the study.
7. Must submit a pre-treatment tumor tissue sample (formalin-fixed, paraffin embedded blocks are preferred to slides) including cytologic sample, if tissue sample unavailable.
8. Has Eastern Cooperative Oncology Group (ECOG) Performance score 0 or 1 assessed within 7 days prior to the first administration of study intervention.
9. Has a life expectancy of at least 6 months.
10. Has adequate organ function.
11. 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.
12. Male and female participants who are at least 18 years of age at the time of signing the information consent.
13. Male participants must refrain from donating sperm during the treatment period and for the time needed to eliminate each study intervention.               
14. 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.

Criteri di esclusione: 

1. Has history, current diagnosis, or features suggestive of myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML).
2. 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
3. Has received prior therapy with olaparib or with any other polyadenosine 5'diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor.
4. Had major surgery <4 weeks prior to the first dose of study intervention (except for placement of vascular access).
5. 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.
6. 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.
7. 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.
8. Has severe hypersensitivity (≥ Grade 3) to study intervention and/or any of its excipients.
9. Has an active autoimmune disease that has required systemic treatment in past 2 years
10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that requires steroids
11. Has an active infection requiring systemic therapy.
12. Has a known history of human immunodeficiency virus (HIV) infection or Hepatitis B or known active Hepatitis C virus infection.

Schema di trattamento: 

- Experimental: Group A - Pembrolizumab 200 mg
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.
- Experimental: Group B - Pembrolizumab 200 mg plus Olaparib 300 mg BID
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.
- Placebo Comparator: Group C (Pembrolizumab and Olaparib Matching Placebos)
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.

Trattamento sperimentale: 

- Group A - Pembrolizumab 200 mg
- Group B - Pembrolizumab 200 mg plus Olaparib 300 mg BID

Trattamento di controllo: 

Group C (Pembrolizumab and Olaparib Matching Placebos)

Obiettivi primari dello studio: 

- 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 [ Time Frame: Up to approximately 59 months ]
- 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.
- Overall Survival: the time from randomization to death due to any cause [ Time Frame: Up to approximately 82 months ]
Overall Survival (OS) is the time from randomization to death due to any cause.

Obiettivi secondari dello studio: 

1) Number of Participants Experiencing an Adverse Events (AEs)
2) Number of Participants Discontinuing Study Treatment Due to Adverse Events (AEs)
3) Objective Response (OR): Complete Response (CR) or Partial Response (PR)
4) 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
5) 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
6) Change from Baseline at Cycle 1 in EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score
7) Change from Baseline at Cycle 1 in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score
8) Change from Baseline at Cycle 1 in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
9) Change from Baseline at Cycle 1 in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
10) Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health Status / Quality of Life (Items 29 & 30) Scale Score
11) Time to True Deterioration (TTD) in Cough (LC13/Item 1) Scale Score
12) Time to True Deterioration (TTD) in Chest Pain (LC13/Item 10) Scale Score
13) Time to True Deterioration (TTD) in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
14) Time to True Deterioration (TTD) in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
15) Objective Response (OR, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels
16) Duration of Response (DOR, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels
17) Progression-free Survival (PFS, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels
18) Overall Survival (OS) assessed by programmed cell death ligand 1 (PD-L1) expression levels.

Data di inizio dell'arruolamento: 20.01.2021

Data di fine dell'arruolamento: 09.12.2023

Centri partecipanti

Nord Italia

Centro Italia

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2019-003616-31

Data di inserimento: 21.05.2021

Data di aggiornamento: 23.11.2023

Promotore

Merck Sharp & Dohme Corp.

Principal Investigator ITALIA

Istituto Europeo di Oncologia, Milano

Riferimento: Prof. Filippo De Marinis

Telefono: 0257489773

Email: filippo.demarinis@ieo.it

Localita: Milano