| 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 | 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)
|
|
| 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
|
|
| E.2.3 | Trial contains a sub-study | No |
| 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 regard to abiraterone
acetate exposure:
a. Not received prior abiraterone acetate (ie, abiraterone naïve)
b. Received prior abiraterone acetate for the treatment of mHSPC or
mCRPC, for a minimum of 4 weeks and must not have progressed while
on treatment.
c. Received prior abiraterone acetate for the treatment of mHSPC or
mCRPC and progressed on treatment after a minimum of 8 weeks
treatment (minimum 14 weeks for those with bone progression).
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. Participants are eligible to participate if they agree to the following
during the intervention period and for at least 45 days after the last dose
of enzalutamide:
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, documented from the site
personnel's review of the participant's medical records, medical
examination, or medical history interview) as detailed below:
∙Agree to use a male condom plus partner use of an additional
contraceptive method when having penile-vaginal intercourse with a
WOCBP who is not currently pregnant.
∙Contraceptive use by men should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies. If the contraception requirements in the local label for any of
the study interventions is more stringent than the requirements above,
the local label requirements are to be followed.
13. The participant (or legally acceptable representative if applicable)
provides written informed consent for the study.
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.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.Active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment
3.Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose
4.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 randomization and not recovered
6.Gastrointestinal disorder affecting absorption
7.Unable to swallow tablets/capsules
8.Active infection (including tuberculosis) requiring systemic therapy
9.History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis
10.Known active HIV, concurrent active hepatitis B or known active and hepatitis C virus
11.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 randomization. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
12.Known psychiatric or substance abuse disorders that would interfere with cooperation with requirements of the study
13.History of seizure or any condition that may predispose to seizure
14.History of loss of consciousness within 12 months of Screening Visit
15.Had myocardial infarction or uncontrolled angina within 6 months prior randomization
16.History of clinically significant ventricular arrhythmias
17.History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
18.Hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at Screening Visit
19.Bradycardia as indicated by a heart rate of <50 beats/minute on the Screening ECG
20.Uncontrolled hypertension as indicated by systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg at Screening Visit
21.Hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
22.History of prostate cancer progression on ketoconazole
23.Prior treatment with second-generation androgen receptor inhibitor or CYP17 inhibitor other than abiraterone acetate
24.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 coinhibitory Tcell receptor
25.Received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
26.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.Received prior targeted small molecule therapy or abiraterone treatment within 4 weeks prior randomization or who has not recovered, with exception of Grade ≤2 neuropathy or Grade ≤2 alopecia from AEs due to a previously administered agent
28.Has received anticancer mAb within 4 weeks prior randomization or has not recovered from AEs due to mAbs administered more than 4 weeks prior randomization
29.Used herbal products that may have hormonal antiprostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior randomization
30.Received treatment with 5-α reductase inhibitors, estrogens, and/or cyproterone within 4 weeks prior randomization
31.Received a live vaccine within 30 days prior randomization
32.Received prior radiotherapy within 2 weeks of randomization. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
33.Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior randomization
34.Has a "superscan" bone scan
35.Is to father children within the projected duration of the study, starting with screening visit through 90 days after last dose
36.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) as assessed by Blinded Independent Central Review (BICR)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~ 51 months
2. Up to ~ 51 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. 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~ 67 months
2. Up to ~ 67 months
3. Up to ~ 67 months
4. Up to ~ 67 months
5. Up to ~ 67 months
6. Up to ~ 67 months
7. Up to ~ 67 months
8. Up to ~ 67 months
9. Up to ~ 67 months
10. Up to ~ 67 months
11. Up to ~ 67 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 | 9 |
| 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 |
| 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
|
| Receipt of the last laboratory result or LVLS, whichever comes last. |
|
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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