PHASE 3, RANDOMIZED, DOUBLE-BLIND TRIAL OF PEMBROLIZUMAB (MK-3475) PLUS ENZALUTAMIDE PLUS ADT VERSUS PLACEBO PLUS ENZALUTAMIDE PLUS ADT IN PARTICIPANTS WITH METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (MHSPC) (KEYNOTE-991)
Public Title
PHASE 3, RANDOMIZED, DOUBLE-BLIND TRIAL OF PEMBROLIZUMAB (MK-3475) PLUS ENZALUTAMIDE PLUS ADT VERSUS PLACEBO PLUS ENZALUTAMIDE PLUS ADT IN PARTICIPANTS WITH METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (MHSPC) (KEYNOTE-991)
Authorized with 117-2020-OGITT-INS Date 08/04/2020
Responsabilities
Others
MERCK SHARP & DOHME PERÚ S.R.L
Inform to the OGITT of the NIH when the first subject is enrolled in Peru, and the end date of enrollment in the country.
Submit progress reports to the National Health Institute during the execution of the Clinical Trial.
Submit to the OGITT of the NIH the final reports as well as the results, conclusions, and publication of the clinical trial
Notify to the OGITT of the NIH the adverse events and deviations as established in the Clinical Trials Regulation.
Inform and describe the reasons for a suspension and cancellation of the clinical trial.
Provide the facilities for the inspection of the execution of the clinical trial by the staff of the General Office of Research and Technology Transfer (OGITT) of the National Institute of Health.
Study clinical phase:
III
Protocol Code
MK-3475-991-00/MK-3475-991
Secondary ID(s) :
WHO UTN:
N/A
CLINICALTRIALS.GOV:
N/A
EUDRACT N°:
2019-003633-41
Study Design
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind/mask study of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT in participants with mHSPC.
Approximately 1232 participants will be randomly assigned in a 1:1 ratio to 1 of 2 treatment arms following a screening period of up to 42 days. There will be no planned crossover between treatment arms.
Arm 1: pembrolizumab 200 mg Q3W plus enzalutamide 160 mg QD plus ADT
Arm 2: placebo Q3W plus enzalutamide 160 mg QD plus ADT
Participant must maintain continuous ADT with a LHRH agonist or antagonist during study treatment or have a history of bilateral orchiectomy. Prior to randomization, participants will be stratified by prior treatment with docetaxel (yes vs no), and presence of high-volume disease (yes vs no).
Insurance policy due date
20/07/2023
Assignation method
Randomized
Non randomized
Type of blinding
Assignation
Simple
Double
Triple
Open
Single arm
Parallel
Crossed
Factorial
Others:
Purpose
- To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to rPFS per PCWG-modified RECIST 1.1 as assessed by BICR where soft tissue will be assessed per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and bone disease will be assessed per PCWG criteria. Hypothesis (H1): The combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to rPFS per PCWGmodified RECIST 1.1 as assessed by BICR.
- To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to OS. Hypothesis (H2): The combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to OS.
Research Product Information
Name of the product
Generic Name
Type of product
ATC
MK-3475
Pembrolizumab
RESEARCH PRODUCT ORIGEN BIOLOGIC
L01
XTANDI
Enzalutamida
L01
Intervention(s) description:
Group name
Type of group
N° of participants
Intervention(s) description
Pembrolizumab + Enzalutamide
Experimental
Control
21
Pembrolizumab 200 mg Q3W treatment will begin on Day 1 of each 3-week cycle and will continue for up to 35 cycles (approximately 2 years) + Four 40-mg capsules/tablets orally QD or two 80-mg tablets orally QD.
Placebo + Enzalutamide
Experimental
Control
21
Placebo, saline solution, Q3W treatment will begin on Day 1 of each 3-week cycle and will continue for up to 35 cycles (approximately 2 years) + Four 40-mg capsules/tablets orally QD or two 80-mg tablets orally QD.
Inclusion Criteria
1_
Has 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_
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 (eg, lung
or liver) by CT/MRI. Participants whose metastatic disease is limited to lymph nodes are
not eligible.
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 (including, but not limited to,
bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks prior to
randomization.
6_
Demonstrates adequate organ function as defined in Table 4; all screening labs should be
performed in central laboratory within 10 days of the first dose of study intervention.
7_
Is male, ≥18 years of age at the time of signing the informed consent.
8_
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.
9_
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.
10_
The participant (or legally acceptable representative if applicable) provides written
informed consent/assent for the study.
Please refer to the protocol for more information.
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 (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 (in dosing exceeding 10 mg daily of prednisone or equivalent) 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 HIV, hepatitis B virus (eg, hepatitis B surface antigen reactive) or HCV (eg, HCV RNA [qualitative] is detected). Testing for Hepatitis B and Hepatitis C is not required unless mandated by local regulation.
11. Has known or suspected CNS metastases and/or carcinomatous meningitis.
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 (including, but not limited to prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect).
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 New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure.
17. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsades de pointes).
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 millimeters of mercury (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.
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 (eg, abiraterone, enzalutamide, apalutamide, darolutamide).
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 (eg, CTLA-4, OX-40, CD137).
28. Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto) within 4 weeks prior to randomization.
29. Has received treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride), estrogens, cyproterone acetate and/or androgens within 4 weeks prior to randomization.
30. Has received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
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. 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.
33. Has had an allogenic tissue/solid organ transplant.
Please refer to the protocol for more information
Worldwide enrolment start date
31/01/2020
Enrolment start date in Peru (Initial)
31/03/2020
Enrolment start date in Peru
15/07/2020
Peru enrolment status
Without starting enrollment
Enrollment stopped
In enrollment
Enrollment closed
Clinical Trial Total Duration
96 months
Medical Speciality
ONCOLOGY
Studied Condition (CIE-10 code)
-D075 Prostate
Number of subjects to be included in all the countries
1232
Number of subjects to be included in Peru (initial)
Number of subjects to be included in Peru (posterior)
42
42
Countries where the enrolment is conducted :
- China
- Korea South
- Israel
- Japan
- Thailand
- Taiwan
- Turkey
- Germany
- Austria
- Denmark
- Spain
- Finland
- France
- Netherlands
- Ireland
- Italy
- Poland
- United Kindgdom
- Russian Federation
- Switzerland
- Australia
- New Zealand
- Brazil
- Canada
- Chile
- Colombia
- United States
Number of participants per gender (Initial)
Female:
0
Male
:
0
Number of participants per gender (Posterior)
Female:
0
Male
:
0
Range of age of subjects to be included :
- Adults (18-64 years)
Yes
No
- Elderly (>= 65 years)
Yes
No
- Under 18 years
Yes
No
If yes, specify:
- In Utero
Yes
No
- Preterm newborn infants (up to gestational age < 37 weeks)
Yes
No
- Newborns (0-27 días)
Yes
No
- Infants and toddlers (28 days-23 months)
Yes
No
- Children (2 - 11 years)
Yes
No
- Adolescents (12 - 17 years)
Yes
No
Subjects' treatment time
24
month(s)
Subjects' follow up time
30 day(s)
Primary Outcome
Name of the outcome
Metric or method of measurement
Time point for the outcome
Radiographic progression-free survival (rPFS)
Kaplan-Meier Method
Interim analyses for rPFS will occur approximately every 7 months until 53 months starting at month
32 and then every 12 months until at least 652 rPFS
events have accrued.
Overall survival (OS)
Kaplan-Meier Method
After final rPFS analysis, analyses for OS will occur approximately every 12 months until at least 600 OS events achieved. Predicted to occur approximately 77 months after first participant enrolled.
Secondary Outcome
Name of the outcome
Metric or method of measurement
Time point for the outcome
time to initiation of the first subsequent anti-cancer therapy (TFST)
Kaplan-Meier Method
Until approximately 65 months after the randomization of the first participant starting at month 32 months after the randomization of the first participant.
Time to symptomatic skeletal-related event (TTSSRE)
Kaplan-Meier Method
After final rPFS analysis, analyses for OS and TTSSRE will occur approximately every 12 months until at least 600 OS events achieved. An analysis may be delayed up to 3 months if 600 OS events predicted to accrue in that time window.
3. RESEARCH SITE, PRINCIPAL INVESTIGATOR, ETHICS COMMITTEE
Research site where the clinical trial will be conducted
Principal Investigator
Institutional Research Ethics Committee (CIEI) that approved the trial for the site
Observations
Research Institution
RCI
Research site
Full name
RCEI
Ethics Committe Name
Status
Approval date
End approval date
Term
Telephone number
Email addrees
CLÍNICA RICARDO PALMA
RCI 1080
Instituto de Oncología y Radioterapia
MANUEL JESUS PHILCO SALAS
RCEI-32
VÍA LIBRE - COMITÉ INSTITUCIONAL DE BIOÉTICA DE VÍA LIBRE
Approved
10/12/2019
09/12/2020
12
7126450
opshi@vialibre.org.pe
Co-Investigator
- MANUEL HUMBERTO LEIVA GALVEZ
CLÍNICA PERUANO AMERICANA S.A.
RCI 442
Centro de Investigación Clínica Trujillo E.I.R.L
JOSE DAVID ZORRILLA SILVERA
RCEI-32
VÍA LIBRE - COMITÉ INSTITUCIONAL DE BIOÉTICA DE VÍA LIBRE
Approved
10/12/2019
09/12/2020
12
7126450
opshi@vialibre.org.pe
Co-Investigator
- Carol Marianella Gonzales Gonzales
HOSPITAL MILITAR CENTRAL “LUIS ARIAS SCHEREIBER”
RCI-301
CENTRO DE INVESTIGACIÓN DEL HOSPITAL MILITAR CENTRAL
RUTH MILAGROS HUARINGA LEIVA
RCEI-32
VÍA LIBRE - COMITÉ INSTITUCIONAL DE BIOÉTICA DE VÍA LIBRE
Approved
10/12/2019
09/12/2020
4331396
opshi@vialibre.org.pe
- Research Site Extension R.D. 169-2020-OGITT-INS with date 04/06/2020
Co-Investigator
HOSPITAL NACIONAL GUILLERMO ALMENARA IRIGOYEN
RCI-73
SERVICIO DE ONCOLOGÍA MÉDICA
DENCY PILLAR MILLA BERNABÉ
RCEI-9
HOSPITAL NACIONAL GUILLERMO ALMENARA IRIGOYEN - ESSALUD - COMITÉ DE ÉTICA EN INVESTIGACIÓN DEL HOSPITAL NACIONAL GUILLERMO ALMENARA IRIGOYEN - ESSALUD
Approved
06/03/2020
05/03/2021
3242983
demetrio.molero@essalud.gob.pe
- Research Site Extension R.D. 558-2020-OGITT/INS with date 21/12/2020
Co-Investigator
HOSPITAL NACIONAL III-1 CARLOS ALBERTO SEGUÍN ESCOBEDO
RCI-380
CENTRO DE INVESTIGACIÓN DE LA RED ASISTENCIAL AREQUIPA
JORGE ALDO BECERRA GIRALDEZ
RCEI-83
HOSPITAL NACIONAL CARLOS ALBERTO SEGUÍN ESCOBEDO - AREQUIPA - COMITÉ DE ÉTICA EN INVESTIGACIÓN DE LA RED ASISTENCIA AREQUIPA - ESSALUD
