| 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 progression free survival (PFS) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
|
|
| E.2.2 | Secondary objectives of the trial |
1.Compare OS
2.Compare the PFS as assessed by blinded independent central review according to RECIST 1.1
3.Compare the PFS after second-line treatment as determined by the investigator according to the local standard of clinical practice following discontinuation of study treatment administration
4.Evaluate the safety and tolerability of pembrolizumab administered with chemotherapy and olaparib maintenance
5.Compare the mean change from baseline of GHS/QoL score using the EORTC, QLQC30 and abdominal/GI symptoms using the EORTC QLQOV28
abdominal/GI symptom scale
6.Compare TTD of GHS/QoL score using EORTC QLQ-C30 and abdominal/GI symptoms using EORTC QLQ-OV28
7.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
8.Compare the rate of locally determined pCR of pembrolizumab+carboplatin/paclitaxel vs carboplatin/paclitaxel alone when administered as neoadjuvant therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant has histologically confirmed FIGO Stage III or Stage IV EOC (high-grade predominantly serous, endometrioid, (any grade), 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 debulking surgery or is a potential candidate for interval 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 or equal to 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 3 days prior to Day 1 of Cycle 1.
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
•Is not a woman of childbearing potential (WOCBP)
OR
•Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the Treatment Period and for at least 120 days following the last dose of pembrolizumab (or pembrolizumab placebo) and bevacizumab (if administered), at least 180 days following the last dose of olaparib (or olaparib placebo), and at least 210 days following the last dose of chemotherapy and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study treatment.
•A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within either 24 hours (urine) or 72 hours (serum) before the first dose of study treatment.
•If a urine test cannot be confirmed as negative (eg, 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.
•The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
•Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
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 prior to starting chemotherapy in the lead-in period. |
|
| 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
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 4 weeks (28 days) prior to receiving chemotherapy during the Lead-in Period.
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 <6 months prior to screening to treat borderline tumors, early stage EOC, or early stage fallopian tube cancer.
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 or known active hepatitis C virus infection.
19. Participant is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption
20. Participant has uncontrolled hypertension.
21. Participant has current, clinically relevant bowel obstruction, abdominal fistula or gastrointestinal perforation, related to underlying EOC
22. Participant has a history of hemorrhage, hemoptysis or active gastrointestinal bleeding within 6 months prior to randomization
23. 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 Day 1 of cycle 1, is pregnant or breastfeeding, or is expecting to conceive children within the projected duration of the study.
24. Participant has received prior treatment for any stage of OC
25. 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
26. Participant has received prior therapy with either olaparib or any other PARP inhibitor
27. Is a participant for whom intraperitoneal chemotherapy is planned or has been administered as first-line therapy
28. Participant has received a live vaccine within 30 days prior to the first dose of study treatment on Day 1 of Cycle 1
29. Participant has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients
30. Participant is currently receiving either strong or moderate inhibitors or inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued prior to starting
31. Participant is currently participating / has participated in a study of an investigational agent or has used an investigational device within 4 weeks (28 days) of starting chemotherapy in the Lead-in Period
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 is unlikely to comply with requirements of the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Progression-free survival (PFS) based on RECIST 1.1 as assessed by investigator in participants with PD-L1 positive tumors (CPS ≥10).
• PFS per RECIST 1.1 assessed by investigator in all participants. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• IA1: PFS and OS analysis around 42 months after the first participant is randomized, when ~257 PFS events are observed in participants with CPS ≥10, and ~ 516 PFS events have been observed in all participants for Arm 1 versus Arm 3 comparison.
• IA2: PFS and OS analysis around 55 months after the first participant is randomized, when ~306 PFS events are observed in participants with CPS ≥10, and ~ 615 PFS events have been observed in all participants for Arm 1 versus Arm 3 comparison. |
|
| E.5.2 | Secondary end point(s) |
• Overall survival (OS) in participants with PD-L1 positive tumors (CPS = 10)
• Overall survival (OS) in all participants |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• IA1: PFS and OS analysis around 42 months after the first participant is randomized, when ~257 PFS events are observed in participants with CPS ≥10, and ~ 516 PFS events have been observed in all participants for Arm 1 versus Arm 3 comparison.
• IA2: PFS and OS analysis around 55 months after the first participant is randomized, when ~306 PFS events are observed in participants with CPS ≥10, and ~ 615 PFS events have been observed in all participants for Arm 1 versus Arm 3 comparison.
• FA: OS analysis around 70 months after the first participant is randomized, when ~217 OS events are observed in participants with CPS
=10 for Arm 2 versus Arm 3 comparison, and ~445 OS events are observed in all participants for Arm 1 versus Arm 3 comparison |
|
| 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) | 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| South Africa |
| Taiwan |
| United States |
| France |
| Poland |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Hungary |
| Ireland |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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
|
The overall study ends when the last participant completes the last
study-related telephone call or visit, withdraws consent or is lost to
follow-up. For the purposes of analysis and reporting, the overall study
ends when the Sponsor receives the last laboratory test result or at the
time of final contact with the participant, whichever comes last. |
|
| 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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