E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Extensive Stage Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Stage IV lung cancer condition |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041068 |
E.1.2 | Term | Small cell lung cancer extensive stage |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To compare pembrolizumab (MK-3475) plus maintenance olaparib (MK-7339) with pembrolizumab plus placebo with respect to progression-free survival (PFS) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR) in participants with extensive stage small cell lung cancer (ES-SCLC) with stable disease (SD), partial response (PR), or complete response (CR) following induction treatment with pembrolizumab combined with etoposide and carboplatin or cisplatin 2. To compare pembrolizumab plus maintenance olaparib with pembrolizumab plus placebo with respect to overall survival (OS) |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of pembrolizumab plus maintenance olaparib compared to pembrolizumab plus placebo 2. To evaluate the change from Baseline (at randomization) and the time to true deterioration (TTD) in global health status/quality of life (QoL), cough, chest pain, dyspnea and physical functioning following treatment with pembrolizumab plus maintenance olaparib compared to pembrolizumab plus placebo |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (Blood, tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time |
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E.3 | Principal inclusion criteria |
1. Have 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 incisional biopsy, or resections) will need to undergo a new biopsy to provide a tissue sample 2. Have extensive stage disease defined as Stage IV (T any, N any, M 1a/b/c) by the American Joint Committee on Cancer, Eighth Edition 3. Have at least 1 lesion that meets the criteria for being measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology review. Lesions that appear measurable, but have undergone palliative irradiation, cannot be target lesions 4. Have provided archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue 5. Have an ECOG Performance Status of 0 to 1 assessed within 7 days prior to the administration of study intervention 6. Have a life expectancy of at least 3 months 7. Have adequate organ function; all screening laboratory tests should be performed within 10 days prior to initiation of study intervention 8. Be at least 18 years of age at the time of signing the informed consent 9. A male participant must agree to use contraception during the treatment period and for at least 180 days following the last dose of pembrolizumab and olaparib or at least 180 days following the last dose of cytotoxic chemotherapy 10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: - Not a woman of childbearing potential (WOCBP) OR - A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 180 days following the last dose of pembrolizumab and olaparib or at least 180 days following the last dose of cytotoxic chemotherapy 11. Has (or legally acceptable representative if applicable) provided written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research
Additional Criteria Applicable to Maintenance Phase Only – Prior to Randomization 12. Have a CR/PR or stable disease of their SCLC after completion of the study-specified Induction Phase, as determined by central imaging review 13. Have an ECOG score of 0 or 1 14. All AEs (except alopecia, Grade 2 fatigue, and endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement) resolved to Grade ≤1 or baseline following Induction Phase treatment 15. Have adequate organ function 16. Are not taking medications or vaccinations specifically prohibited in the Exclusion Criteria 17. Are not pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting from the pre-randomization visit through 180 days after the last dose of study intervention 18. Have not withdrawn consent to continue treatment 19. Continue to derive clinical benefit from study participation according to investigator’s discretion |
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E.4 | Principal exclusion criteria |
1. Has received prior systemic therapy for the treatment of SCLC 2. Is expected to require any other form of antineoplastic therapy for SCLC, including radiation therapy, while on study 3. Has a known history of interstitial lung disease. Lymphangitic spread of the SCLC is not exclusionary 4. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis 5. Has a known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis 6. Has had major surgery within 3 weeks of starting study intervention or has not recovered from any effects of any major surgery 7. Has a known additional malignancy that is progressing or requires active treatment 8. Has a known hypersensitivity to the components or excipients of cisplatin, carboplatin, etoposide, or olaparib 9. 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 10. Has active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 11. Has a known history of, or active, neurologic paraneoplastic syndrome 12. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients 13. Has active infection requiring systemic therapy 14. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority 15. Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive) or known active hepatitis C virus (defined as hepatitis C virus RNA [qualitative] is detected) infection 16. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis) 17. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible 18. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 180 days after the last dose of study intervention 19. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study 20. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML 21. Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor or recombinant erythropoietin) within 28 days prior to the first dose of study intervention 22. Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome 23. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption) 24. Has received a live vaccine within 30 days prior to the first dose of study intervention 25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, CD137) 26. Has received prior therapy with olaparib or with any other PARP inhibitor 27. Is currently receiving either strong or moderate inhibitors of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. 28. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents. 29. 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 30. Has resting electrocardiogram indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator or participant has congenital long QT syndrome 31. Has had an allogeneic tissue/solid organ transplant |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) 2. Overall Survival (OS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 33 months 2. Up to approximately 42 months |
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E.5.2 | Secondary end point(s) |
1. Number of Participants Who Experience an Adverse Event (AE) 2. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) 3. Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score 4. Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Cough (Item 1) Score 5. Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Chest Pain (Item 10) Score 6. Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Dyspnea (Item 8) Score 7. Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Combined Score 8. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score 9. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Cough (Item 1) Score 10. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Chest Pain (Item 10) Score 11. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Dyspnea (Item 8) Score 12. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Combined Score 13. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Cough (Item 1); Chest Pain (Item 10) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Dyspnea (Item 8) Combined Score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 42 months 2. Up to approximately 24 months 3. Baseline (at randomization) and Week 18 post-randomization 4. Baseline (at randomization) and Week 18 post-randomization 5. Baseline (at randomization) and Week 18 post-randomization 6. Baseline (at randomization) and Week 18 post-randomization 7. Baseline (at randomization) and Week 18 post-randomization 8. Up to approximately 42 months 9. Up to approximately 42 months 10. Up to approximately 42 months 11. Up to approximately 42 months 12. Up to approximately 42 months 13. Up to approximately 42 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Brazil |
Canada |
China |
Colombia |
Czech Republic |
France |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
New Zealand |
Poland |
Romania |
Spain |
Switzerland |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |