| 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 |
|
| 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 |
|
| 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 the safety and tolerability of the pembrolizumab combination therapy.
2. To estimate PSA response rate of the pembrolizumab combination
therapy. PSA response is defined as a reduction in the PSA level of 50% or more from baseline measured twice at least 3 weeks apart.
3. To estimate the objective response rate (ORR) based on RECIST 1.1 assessed by BICR. |
|
| E.2.2 | Secondary objectives of the trial |
1. To estimate time to PSA progression, defined as the time from the first day of study treatment to the date of PSA progression.
2. To estimate ORR based on PCWG3-modified RECIST 1.1 criteria assessed by BICR
3. To estimate radiographic progression-free survival (rPFS) based on PCWG3-modified RECIST 1.1 assessed by BICR.
4. To estimate OS.
5. To estimate DOR based on a) RECIST 1.1 and b) PCWG3-modified RECIST 1.1 assessed by BICR
6. To estimate DCR based on RECIST 1.1 and PCWG3-modified RECIST 1.1 assessed by BICR.
7. For Cohort A only, to estimate the composite response rate defined as any one of the following:
-Response according to RECIST 1.1 assessed by BICR
-PSA response rate (reduction in the PSA level of 50% or more from baseline measured twice at least 3 weeks apart)
-Conversion in the circulating tumor-cell (CTC) count, defined as a reduction in the number of CTCs from 5 cells or more per 7.5 mL of blood at baseline to less than 5 cells per 7.5 mL during 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 (Tumor Tissue collection, genetic analysis, RNA analysis, plasma biomarker analysis, serum biomarker analysis, ctDNA analysis, AR-V7) 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/assent for the trial. The subject may also provide consent/assent 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 (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the investigator.
4. For all Cohorts: Have provided tumor tissue from a site not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed; other exceptions may be considered after Sponsor consultation). Adequacy of these for biomarker analysis will be evaluated by a central laboratory prior to enrollment.
Cohort A: A core or excisional biopsy from soft tissue or a bone biopsy is required. A biopsy from soft tissue is preferred. In lieu of a soft tissue biopsy, a fresh bone biopsy is permitted. This biopsy must be performed within 1 year of screening and after developing mCRPC. A recent prior archival specimen should also be provided for these subjects, if available.
Cohort B: An archival tumor tissue sample or tumor tissue from a fresh core or excisional biopsy from soft tissue is required.
Cohorts C & D: Subjects with soft tissue disease must provide a core or excisional biopsy from a soft tissue lesion if clinically accessible. In addition to the biopsy an archival specimen should also be provided if one is available. The biopsy must be performed within 1 year of screening and after developing mCRPC. If soft tissue disease cannot be biopsied then an archival specimen is required. For subjects with bone metastasis only, an archival tumor tissue specimen must be provided.
5. Have prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following:
a. PSA progression using local laboratory values as defined by a minimum of 2 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 based on RECIST 1.1 criteria with or without PSA progression.
c. Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.
6. Have progression under the following conditions if the subject received anti-androgen therapy prior to enrollment:
a. Evidence of progression >4 weeks since last flutamide treatment.
b. Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment.
7. Have ongoing androgen deprivation with serum testosterone <50 ng/dL (< 2.0 nM).
If the subject is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists (subjects who have not undergone an orchiectomy) for cohorts A, B, C, and D this therapy must have been initiated at least 4 weeks prior to first dose of trial treatment and treatment must be continued throughout the study.
8. Subjects receiving bone resorptive therapy (including, but not limited to, bisphosphonate or receptor activator of nuclear factor kappa-β ligand inhibitor) must have been on stable doses for ≥4 weeks prior to first dose of trial treatment.
9. Agree to use an adequate method of contraception, if the subject is of reproductive potential, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
10. Demonstrate adequate organ function in the protocol; all screening labs should be performed within 10 days of the first dose of trial treatment
Cohort Specific inclusion Criteria are to be found in the protocol |
|
| E.4 | Principal exclusion criteria |
1. Has had a prior anticancer mAb within 4 weeks prior to first dose of trial treatment or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due to mAbs administered more than 4 weeks prior to first dose of trial treatment.
2. Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the treatment allocation.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to treatment allocation. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor (replacement therapy for adrenal insufficiency is permitted).
4. If a subject has undergone major surgery, they must have recovered adequately from the toxicities and/or complications from the intervention prior to starting therapy.
5. Has had a prior radium treatment or treatment with other therapeutic radiopharmaceuticals for prostate cancer.
6. 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 or squamous cell carcinoma of the skin that has undergone potentially curative therapy.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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 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 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 virus (e.g., hepatitis B surface antigen reactive) or hepatitis C virus (HCV) (e.g., HCV RNA [qualitative] is detected).
15. Has received a live vaccine within 30 days of the first dose of trial treatment.
16. Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) within 4 weeks prior to treatment allocation
17. Has known active central nervous system metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate in
Cohorts A (pembrolizumab + olaparib) or B (pembrolizumab + docetaxel) provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to treatment allocation 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 trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
18. Has had prior chemotherapy, targeted small molecule therapy, abiraterone acetate treatment, enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose of trial treatment or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due to a previously administered agent.
19. Has a "superscan" bone scan. This is defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated
20. Has had prior solid, organ or bone marrow transplant.
Cohort specific exclusion criteria are to be found in the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-PSA response: PSA decline of ≥50% from baseline measured twice at least 3 weeks apart
-Objective Response Rate: Complete response or partial response per RECIST 1.1 assessed by BICR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-PSA response: From Baseline Measured Every 3 Weeks Until Radiographic Progression
-Objective Response Rate : Assessed Over the Duration of the Study |
|
| E.5.2 | Secondary end point(s) |
-Time to PSA progression,
-ORR per PCWG3-Modified RECIST 1.1 assessed by BICR
-Disease control: Complete response, or partial response, or stable disease per 1) RECIST 1.1 assessed by BICR and 2) PCWG3-modified RECIST 1.1 assessed by BICR
-Duration of Response (DOR) per 1) RECIST 1.1 assessed by BICR and 2) PCWG3-modified RECIST 1.1 assessed by BICR
-rPFS per PCWG3-modified RECIST 1.1 assessed by BICR
-Overall Survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be assessed Over the Duration of the Study
|
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| 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 | 4 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| France |
| Germany |
| New Zealand |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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