1. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to radiographic progression free survival (rPFS)2. To compare pembrolizumab plus enzalutamide plus ADT versus placebp plus enzalutamide…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
- Prostatic disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus
enzalutamide plus ADT with respect to radiographic progression free survival
(rPFS)
2. To compare pembrolizumab plus enzalutamide plus ADT versus placebp plus
enzalutamide plus ADT with respect to overall survival (OS)
Secondary outcome
- time from randomisation to initiation of the first subsequent anti-cancer
therapy or death, whichever comes first
- time from randomisation to the first skeletal symptoms
- time to PSA progression
- time to radiographic soft tissue progression
- time from randomisation to pain progression
- time from randomisation to disease progression as determined by investigator
- a PSA decline of >=50% from baseline
- PSA <0.2 mg/ml during study intervention
- duration of the respons
- safety and tolerability (adverse events)
Background summary
Prostate cancer represents the second most common malignancy diagnosed in men
worldwide. While many men diagnosed with locally confined disease may be
treated definitively with radiation or surgery, approximately one third of men
have recurrent disease and go on oo develop metastatic prostate cancer. Once
prostate cancer has become metastatic there are no longer any curative
treatments and expected median survival is less than five years. Patients with
metastases have traditionally been treated first with ADT, usually with LHRH
agonist or antagonist that results in suppression of testosterone production in
the testes. This alone often succeeds in controlling disease for some time,
years in many cases. However, prostate cancer progresses invariably and
requires additional systemic therapies to re-establish control of disease.
The current standard of care for patients with high-volume of high-risk mHSPC
is a combination docetaxel or abiraterone owht ADT upfront. More recently, it
was shown that a combination of ADT with second-generation androgen receptor
inhibitors apalutamide and enzalutamide results in a significant prolongation
of overall survival. While these therapies are inititally effective, patients
invariably succumb to their disease and the effectiveness of subsequent
therapies diminishes after progression on the prior therapy. Thus, there
remains a significant unmet need for novel therapies or combination regimens
for patients with metastatic prostate cancer.
Pembrolizumab is a potent humanized IgG4 monoclonal anitbody with high
specifity of binding to the PD-1 receptor. thus inhibiting its interaction with
PD-1L and PD-L2. Based on preclinical in vitro data, pembrolizumab has high
affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an
acceptable preclinical safety profile and is in clinical development as an IV
immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated
for the treatment of patients across a number of indications.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to
suppress immune control. The normal function of PD-1, expessed on the cell
surface of activated T-celld under healthy conditions, is to down-modulate
unwanted or excessive immune responses, including autoimmune reactions. As a
consequence, the PD-1/PD-1L pathway is an attractive target for therapeutic
intervention in mHSPC.
Study objective
1. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus
enzalutamide plus ADT with respect to radiographic progression free survival
(rPFS)
2. To compare pembrolizumab plus enzalutamide plus ADT versus placebp plus
enzalutamide plus ADT with respect to overall survival (OS)
Study design
This is a randomized, multicenter, dubble-blind, placebo-controlled, phase 3
trial in participants with mHSPC with either pembrolizumab in combination with
enzalutamide and ADT versus placebo in combination with enzalutamide and ADT.
Around 1232 participants will be randomly assigned 1:1 to one of the two
treatment arms aftyer a screening period of no longer than 42 days. Cross-over
is not possible.
Arm 1: Pembrolizumab 200mg every three weeks (Q3W) in combination with
enzalutamide 160 mg daily (QD)
Arm 2: Placebo Q3W in combination with enzalutamide 160mg QD
Intervention
Arm 1: Pembrolizumab 200mg every three weeks (Q3W) in combination with
enzalutamide 160 mg daily (QD)
Arm 2: Placebo Q3W in combination with enzalutamide 160mg QD
Study burden and risks
For this study, patients will be subjected to invasive procedures such as blood
collection, IV line insertion, CT/MRI or bone scans, physical exams, possibly
confrontational questionnaires and patients will be asked to visit the hospital
regularly.
Patients will be administered with pembrolizumab or placebo thourgh IV line,
during three-week cycles, up to a maxmimum of 35 treatments. Enzalutamide (160
mg PO QD) treatment will begin on the same day as day 1, cycle 1 of
pembrolizumab/placebo and will be continued on a daily dosing cycle until
criteria for discontinuation are met (eg. disease progression)
It cannot be guaranteed that participants in clinical studies will directly
benefit from study intervention during participation, as clinical studies are
designed to provide information about the safety and effectiveness of an
investigational drug. Pembrolizumab has been administered in a large number of
cancer patients with a well characterized safety profile and has received
regulatory approval for multiple malignancies. Overall, pembrolizumab is well
tolerated at doses up to 10 mg/kg every 2 weeks (Q2W). Pembrolizumab has also
demonstrated anticancer clinical activity and efficacy in a broad range of
cancer indications.
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Listed location countries
Age
Inclusion criteria
1. Has histologically- or cytologically-confirmed adenocarcinoma of the
prostate without small cell histology
2. Has metastatic disease as assessed by investigator and verified by BICR
(prior to randomization) by either >=2 bone lesions on bone scan and/or visceral
disease by CT/MRI
3. Once randomized, participant must be willing to maintain continuous ADT with
a LHRH agonists or antagonists during study treatment or have a history of
bilateral orchiectomy
4. Has an ECOG performance status of 0 or 1 assessed within 10 days of
randomization.
5. Participants receiving bone resorptive therapy must have been on stable
doses for >=4 weeks prior to randomization.
6. Demonstrates adequate organ function
7. Is male, >=18 years of age at the time of signing the informed consent
8. 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
lifestyleand agree to remain abstinent
OR
• Must agree to use contraception, unless confirmed to be azoospermic
(vasectomized or secondary to medical cause)
9. The participant (or legally acceptable representative if applicable)
provides written informed consent/assent for the study.
10. Has provided newly obtained core or excisional biopsy (obtained within 12
months of screening) from soft tissue not previously irradiated. However, if
obtaining a new biopsy is not feasible, then participants may provide an
archival tumor tissue sample after Sponsor consultation (SCF).
Exclusion criteria
1. Has a known additional malignancy that is progressing or has required active
treatment in the last 3 years
2. Has an active autoimmune disease that has required systemic treatment in
past 2 years
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.
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 has
current pneumonitis.
10. Has known active HIV, hepatitis B virus
11. Has known or suspected CNS metastases and/or carcinomatous meningitis or
HCV
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) New York Heart Association class III or IV congestive
heart failure
17. Has a history of clinically significant ventricular arrhythmias
18. Has a history of Mobitz II second degree or third degree heart block
without a permanent pacemaker in place
19. Has hypotension as indicated by systolic blood pressure <86 mm Hg at the
Screening Visit.
20. Has bradycardia as indicated by a heart rate of <50 beats per minute on the
Screening ECG
21. Has uncontrolled hypertension as indicated by systolic blood pressure >170
mm Hg or diastolic blood pressure >105 mm Hg at the Screening visit
22. Has severe hypersensitivity (Grade >=3) to pembrolizumab and/or any of its
excipients.
23. Has hypersensitivity reaction to enzalutamide or any of its capsule
components, including Labrasol, butylated hydroxyanisole, and butylated
hydroxytoluene.
24. Has received any prior pharmacotherapy, radiation therapy or surgery for
metastatic prostate cancer with the following exceptions:
a. Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with
or without concurrent first-generation antiandrogens prior to randomization,
with no radiographic evidence of disease progression or rising PSA prior to
randomization if participant was not treated with docetaxel for metastatic
prostate cancer.
b. May have 1 course of palliative radiation or surgical therapy to treat
symptoms resulting from metastatic disease if it was administered at least 4
weeks prior to randomization
c. For participants with low-volume metastatic disease (defined as <4 bone
lesions), may have 1 course of definitive radiotherapy (ie, EBRT) to the
prostate if it was administered at least 4 weeks prior to randomization.
d. Up to 6 cycles of docetaxel therapy with final treatment administration
completed within 2 months of randomization and no evidence of disease
progression during or after completion of docetaxel therapy. In these
participants, up to 6 months of ADT with LHRH agonists or antagonists or
orchiectomy with or without concurrent first-generation antiandrogens is
permitted.
25. Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic
prostate cancer for >39 months in duration or within 9 months prior to
randomization or with evidence of disease progression while receiving ADT
26. Has had prior treatment with a next generation hormonal agent
27. 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
28. 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
29. Has received treatment with 5-α reductase inhibitors, estrogens,
cyproterone acetate and/or androgens within 4 weeks prior to randomization.
30. Has received a live vaccine within 30 days prior to randomization.
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 randomization.
32. Has a *superscan* bone scan
33. Has had an allogenic tissue/solid organ transplant.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003633-41-NL |
| CCMO | NL72054.056.20 |