| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
A:platinum-resistant or partially platinum-sensitive recurrent ovarian cancer (OC) who received 1 but no more than 3 prior lines of anticancer regimens/local standard following primary or interval debulking surgery with a platinum free interval or treatment-free interval of 3-12 months based on last regimen received
B:recurrent OC who received 3-5 prior lines of anticancer regimens/local standard with a platinum-free interval or treatment-free interval >or=3months based on last regimen received |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 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) |
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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 evaluate clinical anti-tumor activity of pembrolizumab monotherapy based on overall response rate (ORR) as assessed by BICR per RECIST 1.1 in Cohort A-All Comer group
(2) To evaluate clinical anti-tumor activity of pembrolizumab monotherapy based on ORR as assessed by BICR per RECIST 1.1 in Cohort A- PD-L1 High (PD-L1H) subgroup using a PD-L1 expression cutpoint established in the training set.
(3) To evaluate clinical anti-tumor activity of pembrolizumab monotherapy based on ORR as assessed by BICR per RECIST 1.1 in Cohort B-All Comer group
(4) To evaluate clinical anti-tumor activity of pembrolizumab monotherapy based on ORR as assessed by BICR per RECIST 1.1 in Cohort B PD-L1H subgroup using a PD-L1 expression cutpoint established in the training set from Cohort A
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| E.2.2 | Secondary objectives of the trial |
1 Evaluate duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) as assessed by BICR per RECIST1.1 in Cohort A-All Comer group, Cohort A-PD-L1H subgroup, Cohort B-All Comer group, Cohort B-PD-L1H subgroup. PFS rate at 6,12,18 months
2 Evaluate ORR, DOR, DCR, and PFS as assessed by investigator per RECIST1.1 in Cohort A-All Comer group, Cohort A-PD-L1H subgroup, Cohort B-All Comer group, Cohort B-PD-L1H subgroup
3 Evaluate ORR, DOR, DCR and PFS as assessed by BICR and by investigator per RECIST1.1, in Cohort A-All Comer subgroup with PFI/TFI>or=3-6 months and the subgroup with PFI/TFI>6-12 months
4 Evaluate OS in Cohort A-All Comer group, Cohort A-PD-L1H subgroup,Cohort A-All Comer subgroup with PFI/TFI>or=3-6 months and the subgroup with PFI/TFI >6-12 months, Cohort B-All Comer group,Cohort B-PD-L1H subgroup
5 Evaluate and characterize tolerability and safety profile of entire study population, cohorts and subgroups 6 Assess pharmacokinetics
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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. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be > or = 18 years of age on day of signing informed consent.
3. Have histologically confirmed epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer
4. Have received a front line platinum-based regimen (administered via either IV or IP route) per local standard of care or treatment guideline following the primary or interval debulking surgery with documented disease recurrence.
Note: Maintenance treatment following the front line treatment is permitted and counted together as part of the front line treatment.
5. Have fulfilled the following additional requirements regarding prior treatments for recurrent ovarian cancer (ROC) depending on the cohort subject is to be enrolled. Each subject must have documented evidence of clinical response or disease stabilization to the last regimen received.
Cohort A: Have received 0 to 2 additional prior lines for treating ROC (or 1 to 3 total prior lines counting the front line) and must have a platinum-free interval (PFI) of > or = 3 to 12 months if the last regimen received is a platinum-based, or a treatment-free interval (TFI) of > or = 3 to 12 months if the last regimen received is a non-platinum-based.
Cohort B: Have received 3 to 5 additional prior lines for treating ROC (or 4 to 6 total prior lines counting the front line) and must have a PFI of > or =3 months if the last regimen received is a platinum-based, or a TFI of > or = 3 months if the last regimen received is a non-platinum-based.
Note: PFI is defined as the time elapsed between the last dose of platinum and the documented evidence of disease progression per RECIST 1.1. Treatment-free interval is defined as the time elapsed between the last dose of the regimen received and the documented evidence of disease progression per RECIST 1.1.
6. Have measurable disease at baseline based on RECIST 1.1 as determined by the central imaging vendor.
Note: Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8. Have a life expectancy of > or =16 weeks.
9. Have provided a tumor tissue sample either collected from prior cytoreductive surgery or fresh newly obtained tumor tissue at screening. Formalin-fixed paraffin-embedded (FFPE) block specimens are preferred to slides. Additional samples may be requested if tumor tissue provided is not adequate for quality and/or quantity as assessed by the central laboratory.
Note 1: Tumor tissue samples from recent biopsy are much preferred as it represents the current disease status and is much more informative for understanding the correlation between clinical activity and tumor microenvironment.
If available, paired tumor tissue samples from prior cytoreductive surgery and recent biopsy are strongly encouraged in order to understand the changes in tumor microenvironment during the course of the treatments.
Note 2: For archival tumor tissue samples, block specimens are much preferred than slides. If submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from when the slides are cut. See Section 4.2.3.3 in protocol for an explanation.
10. Have demonstrated adequate organ function as defined in Table 1 of the protocol. All screening labs should be performed within 10 days of treatment initiation.
11. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.7.1 – Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
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| E.4 | Principal exclusion criteria |
1. Is currently participating in or has participated in a clinical study and received an investigational agent or used an investigational device within 4 weeks prior to the first dose of study treatment.
Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the planned first dose of the study. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
4. Has had prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to the planned first dose of the study
5. Has not recovered from adverse events to < or = Grade 1 or prior treatment level due to a previously administered agent.
Note: Subjects with < or = Grade 2 neuropathy or alopecia of any grade are an exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
6. Has EOC with mucinous histology subtype. Or has a known additional malignancy that progressed or required active treatment within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
7. Has a known additional malignancy that progressed or required active treatment within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has
undergone potentially curative therapy or in situ cervical cancer.
8. Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases.
9. Has known history of, or any evidence of active, non-infectious pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has symptoms of bowel obstruction in the past three months
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137) or has participated in prior pembrolizumab trials.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of the planned first dose of the study.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) based on the disease assessment by BICR per RECIST 1.1 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At least 8 months after the last subject for each cohort is enrolled. |
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| E.5.2 | Secondary end point(s) |
| 1) Duration of Response (DOR), Disease Control Rate (DCR) , Progression-Free Survival (PFS) , per RECIST 1.1 as assessed by BICR; 2) ORR, DOR, DCR, PFS per RECIST 1.1 as assessed by investigator; 3) Overall survival; 4) Proportions of PFS at 6, 12 and 18 months and proportions of survival at 6, 12, 18, and 24 months |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final clinical cutoff for the study (i.e., study completion) will be 3 years after the last subject is enrolled for final OS analysis |
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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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Canada |
| Israel |
| Japan |
| Russian Federation |
| South Africa |
| United States |
| Belgium |
| Finland |
| France |
| Germany |
| Italy |
| Lithuania |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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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