| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer (mCRPC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Prostate Cancer |
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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 | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
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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 estimate the objective response rate (ORR) by RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4.
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| E.2.2 | Secondary objectives of the trial |
1)To determine the safety and tolerability of pembrolizumab for all cohorts combined(Cohorts 1, 2, 3, 4, and 5) and by each cohort
2)To estimate disease control rate(DCR) and radiographic progression-free survival(rPFS) by PCWG3-modified RECIST 1.1 assessed by central imaging vendor and PSA response rate, time to PSA progression, and OS for Cohorts 1 and 2 combined, Cohorts 1, 2, and 3 combined, Cohorts 4 and 5 combined, and by each cohort
3)To estimate the duration of response(DOR) by PCWG3-modified RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4
4)To estimate the DOR by RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4
5)To estimate duration of PSA response, time to initiation of cytotoxic chemotherapy, time to new-anticancer therapy, and time to first skeletal-related event in Cohorts 4 and 5 |
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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 ≥18 years of age on day of signing informed consent.
3. Have histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the Investigator.
4. Have RECIST 1.1-measurable prostate cancer on computed tomography (CT) or magnetic resonance imaging (MRI) scans (Cohorts 1 ,2 and 4) or detectable bone metastases by whole body bone scintigraphy and no RECIST 1.1-measurable tumors (Cohorts 3 and 5), as determined by central review. Disease must be either metastatic or locally confined inoperable disease that cannot be treated with definitive intent.
5. Have supplied tumor tissue from a newly obtained biopsy or provided a tumor tissue specimen ≤12 months prior to the screening date and an archival specimen, if available, from a site not previously irradiated (tumors progressing in a prior site of radiation are allowed for PD-L1 characterization; other exceptions may be considered after Sponsor consultation). Adequacy of these specimens for PD-L1 biomarker analysis will be required by a central laboratory prior to enrollment. Subjects in Cohorts 1, 2, and 4 with visceral/measurable lesions must provide a newly obtained biopsy performed after the last line of systemic therapy where safely available or a specimen obtained ≤12 months prior to the screening date and an archival specimen, if available. Subjects in Cohort 3 and 5 must at least provide an archival specimen.
For Cohorts 1, 2, and 3 only:
6. Have been treated with:
a. At least one targeted endocrine therapy (defined as second generation antiandrogen therapies that include but are not limited to abiraterone acetate with prednisone, enzalutamide, and next generation targeted agents such as ARN-509).
b. At least one regimen/line of chemotherapy that contained docetaxel.
c. No more than two chemotherapy regimens.
d. No more than three regimens/lines of the aforementioned treatments (having failed/progressed on hemotherapy and targeted endocrine therapy).
For Cohorts 4 and 5 only:
7. For chemotherapy-naïve subjects with mCRPC either having failed or showing early signs of failing on enzalutamide treatment as defined by PCWG3 guidelines (eg, signs of clinical progression, increased alkaline phosphatase, PSA increase, or positive imaging assessments). Subjects can have failed prior abiraterone treatment before current enzalutamide treatment. Subjects must have had a clinically meaningful response to enzalutamide treatment. Enzalutamide must have been initiated no less than 4 weeks prior to the first dose of trial treatment and be continued throughout the study.
All Cohorts:
8. Have documented prostate cancer progression within 6 months prior to screening, as determined by the Investigator, by means of one of the following:
a. PSA progression as defined by a minimum of 3 rising PSA levels with an interval of ≥ 1 week between each assessment where the PSA value at screening should be ≥ 2 ng/mL.
b. Radiographic disease progression in soft tissue or bone with or without PSA progression
9. Have ongoing androgen deprivation with total serum testosterone < 50 ng/dL (< 2.0 nM). If the subject is currently being treated with LHRH agonists (subjects who have not undergone an orchiectomy), this therapy must have been initiated at least 4 weeks prior to first dose of trial treatment. This treatment must be continued throughout the study.
10. Subjects receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have been on stable doses for ≥ 4 weeks prior to first dose of trial treatment.
11. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
12. Male subjects of reproductive potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
13. Demonstrate adequate organ function as defined in protocol
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| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of trial treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor (replacement therapy for adrenal insufficiency is permitted).
3. Has had a prior anti-cancer mAb within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to mAbs administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or external beam radiation therapy within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered agent. Treatment with Radium-223 is allowed as long as the last dose has been administered no less than 4 weeks prior to the first dose.
5. Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin, and squamous cell carcinoma of the skin that has undergone potentially curative therapy.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to the first dose of trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with 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, etc.) is not considered a form of systemic treatment.
8. Has evidence of interstitial lung disease and/or a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
9. Has an active infection requiring systemic therapy.
10. 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.
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
12. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
15. Has received a live vaccine within 30 days of planned start of study therapy.
Additionally, the following apply to Cohorts 4 and 5 only:
16. Has received prior chemotherapy (e.g., docetaxel) for mCPRC.
17. Has any condition (cardiac, neurologic, absorption) other than clinically failing or showing early signs of failing on enzalutamide treatment that would require imminent discontinuation of enzalutamide treatment. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohorts 1, 2, and 4 - Objective response rate (ORR) per RECIST 1.1 assessed by central imaging vendor: Proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) where responses are determined by RECIST 1.1 assessed by central imaging vendor.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis: To be performed about 27 weeks after the first 100 subjects with RECIST 1.1-measurable disease (Cohorts 1 and 2) and all subjects in Cohort 3 have been enrolled. Scope of analyses: ORR
Final Analysis: The final analysis of ORR in the population with measurable disease by RECIST 1.1 will be performed after all subjects have been enrolled and all subjects have accumulated mature data and had adequate follow -up. |
|
| E.5.2 | Secondary end point(s) |
1.Duration of Response (DOR ) per PCWG3-modified RECIST 1.1 assessed by central imaging vendor.
For subjects who demonstrated CR or PR, DOR is defined as the time from first documented evidence of CR or PR until disease progression assessed by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using RECIST 1.1/PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1 or death due to any cause, whichever occurs first
2. Duration of Response (DOR) – per RECIST 1.1 assessed by central imaging vendor.
For subjects who demonstrated CR or PR, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) assessed by central imaging using RECIST 1.1 or death due to any cause, whichever occurs first.
3.Disease Control Rate (DCR) - assessed by central imaging vendor
Proportion of subjects in the analysis population who have CR or PR or stable disease (SD) for at least 6 months, by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1
4. PSA Response Rate
Proportion of subjects in the analysis population who have PSA response defined as more than 50% decline from baseline measured twice at least 3 weeks apart.
5. Time to PSA Progression, defined as the time from first day of study treatment to the date of PSA progression. Subjects without PSA progression will be censored at the last PSA assessment date. PSA progression is defined as the date that an increase of 25% or more and an absolute increase of 2 ng/mL or more from the nadir are documented. For subjects who had an initial PSA decline during treatment, this must be confirmed by a second value 3 or more weeks later.
6. Radiographic progression-free survival (rPFS) -per PCWG3-modified RECIST 1.1 assessed by central imaging vendor. It is defined as the time from first day of study treatment to the documented disease progression by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1 or death due to any cause, whichever occurs first.
7. Overall Survival (OS)
Overall survival (OS) is defined as the time from first day of study treatment to the time of death.
8.Duration of PSA response (Cohorts 4 and 5 only)
Duration of PSA response is defined as the time from PSA response, when the PSA value first declines by at least 50% of the baseline (must be confirmed by a second value), to the date of PSA progression at which there is an increase of 25% or more from the nadir PSA, provided the absolute increase from the nadir PDA is at least 2 ng/mL .
9.Time to initiation of cytotoxic chemotherapy (Cohorts 4 and 5 only)
Time to initiation of cytotoxic chemotherapy is defined as the time from first day of study treatment to the time of initiation of cytotoxic chemotherapy for prostate cancer.
10.Time to new-anticancer therapy (Cohorts 4 and 5 only) Time to new-anticancer therapy is defined as the time from first day of study treatment to the time of new-anticancer therapy for prostate cancer
11.Time to first skeletal-related event (Cohorts 4 and 5 only)
Time to initiation of first skeletal-related event is defined as the time from first day of study treatment to the first skeletal-related event, which is defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change or antineoplastic therapy to treat bone pain. See Section 8.6.1 for censoring rules.
12. Safety endpoints: Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab, including serious adverse events (SAEs) and events of clinical interest (ECIs). Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim analysis: To be performed about 27 weeks after the first 100 subjects with RECIST 1.1-measurable disease (Cohorts 1 and 2) and all subjects in Cohort 3 have been enrolled. Scope of analyses: DOR and safety will be evaluated
Final Analysis: All analyses, including safety, DOR, DCR, PSA response, time to PSA progression, rPFS , and OS will be performed after all subjects have been enrolled and all subjects have accumulated mature data and had adequate follow -up. |
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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 | Yes |
| 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 | Yes |
| 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 | 53 |
| 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 |
| Hong Kong |
| Turkey |
| Estonia |
| Brazil |
| Canada |
| Finland |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
| France |
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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
|
| The overall trial ends when the last subject completes the last study-related phone-call or trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
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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 | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
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