| 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 |
|
| 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 compare pembrolizumab plus docetaxel plus prednisone to placebo plus docetaxel plus prednisone with respect to overall survival (OS)
2. To compare pembrolizumab plus docetaxel plus prednisone to placebo plus docetaxel plus prednisone 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)
|
|
| E.2.2 | Secondary objectives of the trial |
1.Compare pembrolizumab plus docetaxel plus prednisone to placebo plus docetaxel plus prednisone with respect to time to initiation of the first subsequent anti-cancer therapy or death
2.Evaluate pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone with respect to:PSA response rate;and ORR and DOR per PCWG-modified RECIST 1.1 as assessed by BICR
3.Compare pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone with respect to:TTPP based on BPI-SF item 3 “worst pain in 24 hours” and opiate analgesic use;time to first SSRE;and time to PSA progression
4.Compare pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone with respect to the time to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1,as assessed by BICR
5.Evaluate the safety and tolerability of pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone |
|
| 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 |
| Exploratory Biomarker Research, Genetic (DNA) analysis from tumor, Tumor and blood RNA analyses, Proteomics and immunohistochemistry (IHC) using blood or tumor, Other biomarkers, Future Biomedical Research |
|
| E.3 | Principal inclusion criteria |
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 androgen deprivation therapy (or post bilateral orchiectomy) 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 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 antiandrogen 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 received prior treatment with one (but not more than one) NHA (eg, abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for mHSPC or CRPC and either
a) progressed through treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression)
OR
b) have become intolerant of the drug (minimum 4 weeks treatment)
6. Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<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 (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks prior to randomization
8. Demonstrate adequate organ function; all screening labs should be performed in the 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 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 pembrolizumab or 180 days after the last dose of docetaxel, whichever is longer:
a) Refrain from donating sperm
PLUS either:
b) 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
a) 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 childbearing 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 |
|
| E.4 | Principal exclusion criteria |
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. Replacement therapy 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 trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant, 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
7. Is unable to swallow tablets/capsules
8. Has an active infection requiring systemic therapy
9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
10. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
11. Has known active human immunodeficiency virus, hepatitis B virus or hepatitis C virus. Testing at screening is not required unless mandated by local regulations
12. Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to randomization
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
14. Has CTCAE Grade ≥2 peripheral neuropathy, except when due to trauma
15. Has ascites and/or clinically significant pleural effusion
16. Has symptomatic congestive heart failure
17. Has received a whole blood transfusion in the last 120 days prior to entry into the study. Packed red blood cells and platelet transfusions are acceptable if not given within 28 days of the first dose of study intervention
18. Has received colony-stimulating factors within 28 days prior to the first dose of study intervention
19. Has had a prior anticancer mAb within 4 weeks prior to randomization or who has not recovered from AEs due to mAbs administered more than 4 weeks prior to randomization
20. 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 treatment randomization
21. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
22. 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
23. Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
24. Has hypersensitivity to docetaxel or polysorbate 80
25. Participant is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
26. Has received prior targeted small molecule therapy or abiraterone acetate, enzalutamide, apalutamide or darolutamide within 4 weeks prior to the first dose of study intervention, or has not recovered from AEs due to a previously administered agent
27. Has received prior radiotherapy within 2 weeks of start of study intervention. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
28. Has received a live vaccine within 30 days prior to randomization
29. Has received treatment with 5α reductase inhibitors, estrogens, and/or cyproterone within 4 weeks prior to randomization
30. Has received prior treatment with ketoconazole for prostate cancer
31. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
32. Has a “superscan” bone scan
33. Is expecting to conceive or father children within the projected duration of the study,starting with the screening visit through 120 days after the last dose of study intervention
34. Has had an allogenic tissue/solid organ transplant.
|
|
| 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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 28 months
2. Up to approximately 28 months
|
|
| 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. Objective Response Rate (ORR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
4. Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
5. Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 (“Worst Pain in 24 Hours”) and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] Score)
6. Time to First Symptomatic Skeletal-related Event (SSRE)
7. Time to Prostate-specific Antigen (PSA) Progression
8. Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
9. Number of Participants Who Experience an Adverse Event (AE)
10. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 28 months
2. Up to approximately 28 months
3. Up to approximately 28 months
4. Up to approximately 28 months
5. Up to approximately 28 months
6. Up to approximately 28 months
7. Up to approximately 28 months
8. Up to approximately 28 months
9. Up to approximately 28 months
10. Up to approximately 28 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Russian Federation |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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