| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced epithelial ovarian cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| First line treatment of advanced ovarian cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 the progressionfree survival (PFS) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
2. To compare overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
1.Compare the PFS as assessed by blinded independent central review according to RECIST 1.1
2.Compare the PFS after next-line treatment (PFS2) following discontinuation of study treatment administration as determined by the investigator according to the local standard of clinical practice
3.Evaluate the safety and tolerability of pembrolizumab administered with chemotherapy and olaparib maintenance
4.Compare the GHS/QoL score using the EORTC, QLQC30 and abdominal/GI symptoms using the EORTC QLQOV28 abdominal/GI symptom scale
5.Compare the time to first subsequent anti-cancer treatment , the time to second subsequent anti-cancer treatment, and the time to discontinuation of study treatment or death
6.Compare the rate of locally determined pathological complete response (pCR) of pembrolizumab plus carboplatin/paclitaxel versus carboplatin/paclitaxel alone when administered as neoadjuvant therapy
7.Compare the time without symptoms of disease progression or toxicity of treatment |
|
| 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 |
|
| E.3 | Principal inclusion criteria |
1. Participant has histologically confirmed FIGO Stage III or Stage IV EOC (high-grade predominantly serous, endometrioid, carcinosarcoma, mixed mullerian with highgrade serous component, clear cell, or low-grade serous OC), primary peritoneal cancer, or fallopian tube cancer
2. Participant has just completed primary debulking surgery or is eligible for primary or interval debulking surgery. Participant must be randomized within 56 days of primary debulking surgery
3. Participant is a candidate for carboplatin and paclitaxel chemotherapy, to be administered in the adjuvant or neoadjuvant setting
4. Participant that is a candidate for neoadjuvant chemotherapy has a CA-125 (kilounits/L):carcinoembryonic antigen (CEA; ng/mL) ratio greater than 25
5. Participant is able to provide a newly obtained core or excisional biopsy of a tumor lesion for prospective testing of BRCA1/2 and PD-L1 status prior to randomization
6. Participant is female and at least 18 years of age on the day of signing informed consent
7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to initiating chemotherapy in the lead-in period and within 7 days prior to randomization
8. A female participant is eligible to participate if she is not pregnant , not breastfeeding, and at least 1 of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP)
OR
b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days following the last dose of pembrolizumab (or pembrolizumab placebo) and olaparib (or olaparib placebo) and at least 210 days following the last dose of chemotherapy or bevacizumab (if administered)
9. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research; however, the participant may participate in the main study without participating in future biomedical research
10. Participant has adequate organ function; all screening laboratory tests should be performed within 7 days of initiating chemotherapy in the lead-in period. Hematological parameters must be reassessed and adequate after the lead-in period and within 7 days prior to randomization
|
|
| E.4 | Principal exclusion criteria |
1. Participant has mucinous, germ cell, or borderline tumor of the ovary
2. Participant has a known or suspected deleterious mutation (germline or somatic) in either BRCA1 or BRCA2
3. Participant has a history of non-infectious pneumonitis that required treatment with steroids or currently has pneumonitis
4. Participant either has myelodysplastic syndrome (MSD)/acute myeloid leukemia (AML)or has features suggestive of MDS/AML
5. Participant has a known additional malignancy that is progressing or has required active treatment in the last 3 years
6. Participant has ongoing Grade 3 or Grade 4 toxicity, excluding alopecia, following chemotherapy administered during the lead-in period
7. Participant has known active central nervous system metastases and/or carcinomatous meningitis.
8. Participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization
9. Participant has an active autoimmune disease that has required systemic treatment in the past 2 years
10. Participant has a known history of active tuberculosis (TB; Bacillus Tuberculosis)
11. Participant has an active infection requiring systemic therapy
12. Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator
13. Participant has received colony-stimulating factors within 2 weeks prior to randomization
14. Participant is considered to be of poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection
15. Participant has had surgery to treat borderline tumors, early stage EOC, or fallopian tube cancer <6 months prior to screening
16. Participant has a known psychiatric or substance abuse disorder that would interfere with the ability to cooperate with the requirements of the study
17. Participant has a known history of human immunodeficiency virus (HIV) infection.
18. Participant has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
19. Participant is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption
20. Participant has current, clinically relevant bowel obstruction (including sub-occlusive disease), abdominal fistula or gastrointestinal perforation, related to underlying EOC
21. Participant has a history of hemorrhage, hemoptysis or active gastrointestinal bleeding within 6 months prior to randomization
22. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of chemotherapy in the lead-in period and within 72 hours prior to randomization, is pregnant or breastfeeding, or is expecting to conceive children within the projected duration of the study.
23. Participant has received prior treatment for advanced or metastatic OC, including radiation or systemic anti-cancer therapy
24. Participant 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
25. Participant has received prior therapy with either olaparib or any other PARP inhibitor
26. Is a participant for whom intraperitoneal chemotherapy is planned as first-line therapy
27. Participant has received a live vaccine within 30 days prior to the first dose of study treatment
28. Participant has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients
29. Participant is currently receiving either strong or moderate inhibitors or inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
30. Participant has received whole blood transfusions in the last 120 days prior to randomization
31. Participant is currently participating or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of the first dose of study treatment
32. Participant has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator, or participant has congenital long QT syndrome
33. Participant has had an allogenic tissue/solid organ transplant, has received previous allogenic bone-marrow transplant, or has received double umbilical cord transplantation
34. Participant either had major surgery within 2 weeks of randomization or has not recovered from any effects of any major surgery
35. Participant, in the judgement of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Progression-free survival (PFS) based on RECIST 1.1 as assessed by investigator
2) Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) PFS and OS analysis around 30 months after the first participant is randomized, when at least 362 PFS events are observed for both comparisons
2) PFS and OS analysis around 36 months after the first participant is randomized, when at least 452 PFS events are observed for both comparisons
3) OS analysis around 52 months after the first participant is randomized, when at least 289 OS events are observed for both comparisons
4) Final Analysis: OS analysis around 66 months after the first participant is randomized, when at least 361 OS events are observed for both comparisons
|
|
| E.5.2 | Secondary end point(s) |
1) PFS based on RECIST 1.1 as assessed by BICR
2) PFS after next-line treatment (PFS2)
3) Safety and tolerability of the 3 treatment groups |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 66 months after first particpanct is randomized |
|
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 140 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| New Zealand |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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 |
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