| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV lung cancer condition |
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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 | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous non-small cell lung cancer |
| 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 maintenance pemetrexed with respect to progression-free survival (PFS) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent central review (BICR) in participants with stage IV nonsquamous non-small-cell lung cancer (NSCLC) with stable disease (SD), partial response (PR), or complete response (CR) following induction treatment with pembrolizumab combined with pemetrexed and platinum (carboplatin or cisplatin).
2. To compare pembrolizumab plus maintenance olaparib with pembrolizumab plus maintenance pemetrexed with respect to overall survival (OS) in participants with stage IV NSCLC with SD, PR, or CR following induction treatment with pembrolizumab combined with pemetrexed and platinum (carboplatin or cisplatin).
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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 maintenance pemetrexed in participants with stage IV NSCLC with SD, PR, or CR following induction treatment with pembrolizumab combined with pemetrexed and platinum (carboplatin or cisplatin).
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 with pembrolizumab plus pemetrexed in participants with stage IV NSCLC with SD, PR, or CR following induction treatment with pembrolizumab combined with pemetrexed and platinum (carboplatin or cisplatin).
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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 and 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 histologically confirmed or cytologically confirmed diagnosis of nonsquamous NSCLC.
2. Have Stage IV (T any, N any, M1a, M1b, or M1c - American Joint Committee on Cancer (AJCC) 8th Edition) nonsquamous NSCLC.
3. Have confirmation that EGFR, ALK, or ROS1-directed therapy is not indicated (documentation of absence of tumor-activating EGFR mutations AND absence of ALK and ROS1 gene rearrangements, OR presence of a K-Ras mutation).
4. Have measurable disease, based on RECIST 1.1, as determined by the local site investigator/radiology assessment. Lesions that appear measurable, but are situated in a previously irradiated area, can be considered measurable (eligible for selection as target lesions) if they have shown documented growth since the completion of radiation.
5. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance score of 0 or 1 assessed within 7 days prior to the administration of study intervention.
8. Have not received prior systemic treatment for their advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
9. Have adequate organ function. All screening laboratory tests should be performed within 10 days prior to the first dose of study intervention.
10. Be at least 18 years of age at the time of signing the informed consent.
11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention:
- Refrain from donating sperm
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
- Agree to use contraception, unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
a) Is not a WOCBP
OR
b) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
13. Have (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.
14. Have a CR/PR or SD of their NSCLC after completion of the study-specified Induction Phase, as determined by central imaging review.
15. Have an ECOG performance status score at randomization of 0 or 1.
16. 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.
17. Have adequate organ function, as indicated by the laboratory values in Table 3 above.
18. Are not taking medications or vaccinations specifically prohibited in the Exclusion Criteria
19. 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.
20. Have not withdrawn consent to continue treatment.
21. Continue to derive clinical benefit from study participation according to investigator’s discretion.
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| E.4 | Principal exclusion criteria |
1. Has predominantly squamous cell histology NSCLC.
2. Has a known additional malignancy that is progressing or has progressed within the past 3 years requiring active treatment.
3. Has known active central nervous system metastases and/or carcinomatous meningitis.
4. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
5. Participant has a known hypersensitivity to any components or excipients of cisplatin, carboplatin, pemetrexed, or olaparib.
6. Has active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
7. 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.
8. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required, unless mandated by local health authority.
11. Has a known history of hepatitis B or known active hepatitis C virus infection.
12. Has a known history of active tuberculosis.
13. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
14. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary.
15. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
16. Before the first dose of study intervention:
a. Has received prior systemic cytotoxic chemotherapy for metastatic disease.
b. Has received antineoplastic biological therapy (eg, erlotinib, crizotinib, cetuximab) for metastatic disease.
c. Had major surgery (<3 weeks prior to study intervention) or has not recovered from any effects of any major surgery.
17. Has received prior therapy with olaparib or with any other PARP inhibitor.
18. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study intervention.
19. Is expected to require any other form of antineoplastic therapy while on study.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
21. Has received a live vaccine within 30 days prior to the first dose of study drug.
22. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs, other than an aspirin dose ≤1.3 g per day, for a 5-day period (an 8-day period for long-acting agents, such as piroxicam).
23. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
24. 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.
25. Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study.
26. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.
27. 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 treatment.
28. Has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.), or participant has congenital long QT syndrome.
29. Is considered a poor medical risk, in the opinion of the treating investigator, due to a serious, uncontrolled medical disorder or nonmalignant systemic disease.
30. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
31. 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.
32. Is unable to swallow orally administered medication, or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, or malabsorption).
33. Has had an allogeneic-tissue/solid-organ transplant.
34. Completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
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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)
2. Overall Survival (OS)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~3 years
2. Up to ~5 years
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| E.5.2 | Secondary end point(s) |
1. Number of Participants Experiencing an Adverse Event (AE)
2. Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)
3. Change from Baseline 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
4. Change from Baseline in EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score
5. Change from Baseline in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score
6. Change from Baseline in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
7. Change from Baseline in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
8. Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health Status / Quality of Life (Items 29 & 30) Scale Score
9. Time to True Deterioration (TTD) in EORTC QLQ-LC13 Cough (Item 1) Scale Score
10. Time to True Deterioration (TTD) in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score
11. Time to True Deterioration (TTD) in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
12. Time to True Deterioration (TTD) in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~5 years
2. Up to ~5 years
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 ~5 years
9. Up to ~5 years
10. Up to ~5 years
11. Up to ~5 years
12. Up to ~5 years
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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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 94 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Canada |
| Colombia |
| France |
| Germany |
| Japan |
| Korea, Republic of |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| 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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| LPLV- Last Participant Last Visit |
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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 | 11 |
| E.8.9.1 | In the Member State concerned days | 27 |
| 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 | 4 |
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