| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Castration-Resistant 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 | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 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 pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to overall survival (OS)
2. To compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR)
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|
| E.2.2 | Secondary objectives of the trial |
1. To compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to the time to initiation of the first subsequent anti-cancer therapy or death
2. To compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to the: prostate-specific antigen response rate; PSA undetectable rate; and the objective response rate and duration of response per PCWG-modified RECIST 1.1 as assessed by BICR
3. To compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to the: time to PSA progression; time to first symptomatic skeletal-related event; time to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1, as assessed by BICR; and time to pain progression based on Brief Pain Inventory-Short Form Item 3 “ worst pain in 24 hours” and opiate analgesic use Algorithm score
4. To evaluate the safety and tolerability of pembrolizumab plus enzalutamide versus placebo plus enzalutamide
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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/or tissue and/or others) 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 |
A participant will be eligible for inclusion in the study if the participant:
1. 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.
2. Have prostate cancer progression while on ADT (or post bilateral orchiectomy) within 6 months prior to randomization, 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 consecutive rising PSA levels with an interval of ≥1 week between each
assessment where the PSA value at screening should be ≥1 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 based on PCWG defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.
3. Have progression under the following conditions if the participant 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.
4. Have current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by CT/MRI. Participants whose disease spread is limited to regional pelvic lymph nodes are not eligible.
5. Have met one of the following criteria with regards to abiraterone acetate exposure:
a. not received prior abiraterone acetate (ie, abiraterone naïve)
b. received prior abiraterone acetate for the treatment of mHSPC, for a minimum of 4 weeks and must not have progressed while on treatment.
c. received prior abiraterone acetate for the treatment of mCRPC and either progressed on treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression) or become intolerant of the drug after a minimum of 4 weeks treatment.
6. Have ongoing androgen deprivation with serum testosterone <50 ng/mL (<2.0 nM). If the participant is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists (participants who have not undergone an orchiectomy) this therapy must have been initiated at least 4 weeks prior to randomization and treatment must be continued throughout the study.
7. Participants receiving bone resorptive therapy must have been on stable doses for ≥4 weeks prior to randomization.
8. Demonstrate adequate organ function as defined in Protocol; all screening labs should be performed in central laboratory within 10 days of the first dose of study intervention.
9. Participant is male.
10. Participant is ≥18 years of age on day of signing the informed consent.
11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days after the last dose of study intervention:
• Refrain from donating sperm PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
• Must agree to use contraception, unless confirmed to be azoospermic (vasectomized or secondary to medical cause), as detailed below:
• Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of child-bearing potential (WOCBP) who is not currently pregnant.
12. Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
13. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
14. Have provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed; other exceptions may be considered after Sponsor consultation). Participants with bone only or bone predominant disease may provide a bone biopsy sample. However, if obtaining a fresh biopsy is not feasible, then participants may provide an archival tumor tissue sample after Sponsor consultation (SCF). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archive tissue.
15. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization.
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| E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant:
1. Has a known additional malignancy that is progressing or has required active treatment in the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded.
2. 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 (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.
4. 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 participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
5. Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications.
6. Has a gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer disease within last 3 months).
7. Is unable to swallow tablets/capsules.
8. Has an active infection (including tuberculosis) requiring systemic therapy.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
10. Has known active human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus (HCV) (eg, HCV RNA. Testing is not required unless mandated by local regulation.
11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to randomization 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 randomization. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
13. Has a history of seizure or any condition that may predispose to seizure.
14. Has a history of loss of consciousness within 12 months of the Screening Visit.
15. Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization.
16. Has a history of clinically significant ventricular arrhythmias.
17. Has a history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
18. Has hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at the Screening Visit.
19. Has bradycardia as indicated by a heart rate of <50 beats per minute on the Screening electrocardiogram (ECG).
20. Has uncontrolled hypertension as indicated by systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg at the Screening visit.
21. Has hypersensitivity to pembrolizumab and/or enzalutamide and / or any of their excipients.
22. Has history of prostate cancer progression on ketoconazole.
23. Has had prior treatment with any second-generation androgen receptor inhibitor.
24. 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. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer.
26. Has had prior chemotherapy for mCRPC. Prior docetaxel for mHSPC is allowed if more than 4 weeks have elapsed from the last dose of docetaxel.
27. Has received prior targeted small molecule therapy or abiraterone treatment within 4 weeks prior to randomization or who has not recovered, with the exception of Grade ≤2 neuropathy or Grade ≤2 alopecia from AEs due to a previously
administered agent.
28. Has received an anticancer mAb within 4 weeks prior to randomization or has not recovered from AEs due to mAbs administered more than 4 weeks prior to randomization.
29. Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior to randomization.
30. Has received treatment with 5-α reductase inhibitors, estrogens, and/or cyproterone within 4 weeks prior to randomization.
31. Has received a live vaccine within 30 days prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall Survival (OS)
2. Radiographic Progression-free Survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 52 months
2. Up to approximately 52 months
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|
| E.5.2 | Secondary end point(s) |
1. Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST)
2. Prostate-specific Antigen (PSA) Response Rate
3. Prostate-specific Antigen (PSA) Undetectable Rate
4. Objective Response Rate (ORR) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
5. Duration of Response (DOR) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
6. Time to Prostate-specific Antigen (PSA) Progression
7. Time to Radiographic Soft Tissue Progression per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
8. Time to Pain Progression (TTPP)
9. Time to First Symptomatic Skeletal-Related Event (SSRE)
10. Number of Participants Who Experienced At Least One Adverse Event (AE)
11.Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 52 months
2. Up to approximately 52 months
3. Up to approximately 52 months
4. Up to approximately 52 months
5. Up to approximately 52 months
6. Up to approximately 52 months
7. Up to approximately 52 months
8. Up to approximately 52 months
9. Up to approximately 52 months
10. Up to approximately 52 months
11. Up to approximately 52 months
10. Up to approximately 52 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 109 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Canada |
| Chile |
| Colombia |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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