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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02861573




Registration number
NCT02861573
Ethics application status
Date submitted
3/08/2016
Date registered
10/08/2016
Date last updated
30/01/2020

Titles & IDs
Public title
Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)
Scientific title
Phase Ib/II Trial of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-365)
Secondary ID [1] 0 0
2016-002312-41
Secondary ID [2] 0 0
3475-365
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Castration-Resistant Prostate Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab 200 mg
Treatment: Drugs - Olaparib 400 mg
Treatment: Drugs - Docetaxel 75 mg/m^2
Treatment: Drugs - Prednisone 5 mg
Treatment: Drugs - Enzalutamide 160 mg
Other interventions - Dexamethasone 8 mg
Treatment: Drugs - Olaparib 300 mg
Treatment: Drugs - Abiraterone acetate 1000 mg

Experimental: Pembrolizumab + Olaparib - Participants in Cohort A will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week dosing cycle (Q3W) and olaparib 400 mg capsules or 300 mg tablets by mouth (PO) twice a day (BID) continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue until progression or a maximum of 35 treatment cycles (up to 2 years). Treatment with olaparib will continue until progression. Participants who must discontinue 1 of the 2 drugs in the combination due to adverse events may continue the study with the other combination drug.

Experimental: Pembrolizumab + Docetaxel + Prednisone - Participants in Cohort B will receive pembrolizumab 200 mg IV on Day 1 Q3W, docetaxel 75 mg/m^2 IV on Day 1 Q3W, and prednisone 5 mg tablet PO BID continuously from Day 1 of Cycle 1. Participants will only be permitted to receive a maximum of 10 cycles of docetaxel and prednisone. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.

Experimental: Pembrolizumab + Enzalutamide - Participants in Cohort C will receive pembrolizumab 200 mg IV on Day 1 Q3W and enzalutamide 160 mg PO every day (QD) continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue until progression or a maximum of 35 treatment cycles (up to 2 years). Treatment with enzalutamide will continue until progression. Participants who must discontinue 1 of the 2 drugs in the combination due to adverse events may continue the study with the other combination drug.

Experimental: Pembrolizumab + Abiraterone + Prednisone - Participants in Cohort D will receive pembrolizumab 200 mg IV on Day 1 Q3W, abiraterone acetate 1000 mg PO QD and prednisone 5 mg tablet PO BID continuously from Day 1 of Cycle 1. Treatment with pembrolizumab will continue for a maximum of 35 cycles (up to 2 years) or until progression. Participants who must discontinue 1 of the 2 drugs due to adverse events in the combination may continue the study with the other combination drug.


Other interventions: Pembrolizumab 200 mg
IV Q3W

Treatment: Drugs: Olaparib 400 mg
Eight 50-mg capsules PO BID

Treatment: Drugs: Docetaxel 75 mg/m^2
IV Q3W

Treatment: Drugs: Prednisone 5 mg
One 5-mg tablet PO BID

Treatment: Drugs: Enzalutamide 160 mg
Four 40-mg capsules, four 40-mg tablets, or two 80-mg tablets PO QD

Other interventions: Dexamethasone 8 mg
Premedication for Cohort B given PO at 12, 3, and 1 hours prior to docetaxel infusion Q3W

Treatment: Drugs: Olaparib 300 mg
Two 150-mg tablets PO BID

Treatment: Drugs: Abiraterone acetate 1000 mg
Two 500-mg or four 250-mg tablets PO QD

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With a Decrease of =50% in Prostatic Specific Antigen (PSA)
Timepoint [1] 0 0
From Baseline Measured Every 3 Weeks Until Radiographic Progression Estimated to be Approximately 2 Years
Primary outcome [2] 0 0
Number of Participants with Adverse Events (AEs)
Timepoint [2] 0 0
Assessed Every 3 Weeks Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Primary outcome [3] 0 0
Number of Participants Discontinuing Study Drug Due to AEs
Timepoint [3] 0 0
Assessed Every 3 Weeks Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Primary outcome [4] 0 0
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR)
Timepoint [4] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [1] 0 0
Disease Control Rate (DCR) Based on Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 Assessed by BICR
Timepoint [1] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [3] 0 0
Duration of Response (DOR) Based on PCWG3-modified RECIST 1.1 Assessed by BICR
Timepoint [3] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [4] 0 0
ORR Based on PCWG3-modified RECIST 1.1 Assessed by BICR
Timepoint [4] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [5] 0 0
Time to PSA Progression
Timepoint [5] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [6] 0 0
Radiographic Progression-free Survival (rPFS) Based on PCWG3-modified RECIST 1.1 Assessed by BICR
Timepoint [6] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [7] 0 0
Composite Response Rate Defined as Any One of the Following: A. Response Based on RECIST 1.1; B. PSA Decrease of =50%; or C. Circulating Tumor-cell Count Conversion (Pembrolizumab + Olaparib Cohort Only)
Timepoint [7] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years
Secondary outcome [8] 0 0
ORR Based on PCWG3-modified RECIST 1.1 Criteria Assessed by BICR
Timepoint [8] 0 0
Assessed Over the Duration of the Study Which is Estimated to be Approximately 2 Years

Eligibility
Key inclusion criteria
- Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without
small cell histology

- Is able to provide tumor tissue from a site not previously irradiated as follows:
Cohort A must provide a core or excisional biopsy from soft tissue or bone biopsy
within 1 year of screening and after developing mCRPC; Cohort B: must provide an
archival tumor tissue sample or tumor tissue from a newly obtained core or excisional
biopsy from soft tissue if the lesion is clinically accessible; and Cohorts C and D
with soft tissue disease must provide a core or excisional biopsy from a soft tissue
lesion if clinically accessible within 1 year of screening and after developing mCRPC
and an archival specimen if available. Participants with bone metastasis only must
provide an archival tumor tissue specimen

- Has prostate cancer progression within 6 months prior to screening, as determined by
the investigator, by means of one of the following: PSA progression as defined by a
minimum of 2 rising PSA levels with an interval of =1 week between each assessment
where the PSA value at screening should be =2 ng/mL; radiographic disease progression
in soft tissue based on Response Evaluation Criteria In Solid Tumors Version 1.1
criteria with or without PSA progression; radiographic disease progression in bone
defined as the appearance of 2 or more new bone lesions on bone scan with or without
PSA progression

- Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM).
Treatment with luteinizing hormone-releasing hormone agonists or antagonists for all
Cohorts must have been initiated =4 weeks prior to first dose of study therapy and
must be continued throughout the study

- Participants receiving bone resorptive therapy (including, but not limited to
bisphosphonate or receptor activator of nuclear factor kappa-ß ligand inhibitor) must
be on stable doses for =4 weeks prior to first dose of study therapy

- Women of childbearing potential and male participants must agree to use adequate
contraception starting with the first dose of study therapy through 120 days after the
last dose of study therapy

- Has a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group
(ECOG) Performance Scale for Cohorts A and C and a performance status of 0 or 1 for
Cohort B within 10 days of study start

- For Cohort A: Has received docetaxel for mCRPC. Prior treatment with 1 other
chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations
(e.g., abiraterone acetate and/or enzalutamide) are allowed. Prior docetaxel for
metastatic hormone-sensitive prostate cancer is allowed if =4 weeks have elapsed from
the last dose of docetaxel prior to day 1 of Cycle 1

- For Cohort B: Has received prior treatment with either abiraterone acetate or
enzalutamide (but not both) in the prechemotherapy mCRPC state. Participants in Cohort
B must have received at least 4 weeks of either abiraterone or enzalutamide treatment
(but not both) who failed treatment or became intolerant of the drug

- For Cohort C: Has received prior treatment with abiraterone acetate in the
pre-chemotherapy mCRPC state without prior enzalutamide. Participants in Cohort C must
have received at least 4 weeks of abiraterone treatment who failed treatment or become
intolerant of the drug. Participants who received abiraterone acetate in the
hormone-sensitive state will not be eligible

- For Cohort D: Has not received chemotherapy for mCRPC and has either not had prior
second generation hormonal manipulation for mCRPC OR has previously been treated with
enzalutamide for mCRPC and failed treatment or has become intolerant of the drug.
Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if =4
weeks have elapsed from the last dose of docetaxel. Prior treatment with abiraterone
acetate in the hormone-sensitive metastatic setting is allowed as long as there was no
progression on this agent and abiraterone acetate was not discontinued due to adverse
events (AEs). Participants in Cohort D must have a performance status of 0 or 1 on the
ECOG Performance Scale
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
- Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first
dose study therapy or who has not recovered (i.e., Grade =1 or at baseline) from AEs
due to mAbs administered >4 weeks earlier

- Has had prior chemotherapy, targeted small molecule therapy abiraterone treatment,
enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose of
study therapy or who has not recovered (ie, Grade =1 or at baseline) from AEs due to a
previously administered agent

- Is currently participating in and receiving study therapy or has participated in a
study of an investigational agent and received study drug or used an investigational
device within 4 weeks of treatment allocation

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to treatment allocation

- Has had a prior radium treatment or treatment with other therapeutic
radiopharmaceuticals for prostate cancer

- Has an active autoimmune disease that has required systemic treatment in past 2 years

- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis

- Has previously participated in any other pembrolizumab (MK-3475) trial, or received
prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell
death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 1 (anti-PD-L2)

- Has a known history of Human Immunodeficiency Virus (HIV)

- Has known active Hepatitis B or Hepatitis C

- Has received a live vaccine within 30 days of the first dose of study therapy

- Has known active central nervous system metastases and/or carcinomatous meningitis

- Has a "superscan" bone scan 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

- Has had prior solid, organ or bone marrow transplant

- For Cohort A: Has experienced a seizure or seizures within 6 months of study start or
is currently being treated with cytochrome P450 enzyme (CYP) inducing anti-epileptic
drugs for seizures

- For Cohort A: Is currently receiving strong or moderate inhibitors of CYP3A4 including
azole antifungals; macrolide antibiotics; or protease inhibitors

- For Cohort A: Is currently receiving strong or moderate inducers of CYP3A4

- For Cohort A: Has myelodysplastic syndrome

- For Cohort A: Has symptomatic congestive heart failure (New York Heart Association
Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or
uncontrolled hypertension

- For Cohort B: Has received prior treatment with docetaxel or another chemotherapy
agent for metastatic prostate cancer

- For Cohort B: Has peripheral neuropathy Common Terminology Criteria for Adverse Events
=2 except due to trauma

- For Cohort B: Has ascites and/or clinically significant pleural effusion

- For Cohort B:Has symptomatic congestive heart failure (New York Heart Association
Class III or IV heart disease)

- For Cohort B: Is currently receiving any of the following classes of inhibitors of
CYP3A4: azole antifungals; macrolide antibiotics; or protease inhibitors

- For Cohort C: Has received prior chemotherapy for mCRPC. Prior docetaxel for
metastatic hormone-sensitive prostate cancer is allowed if =4 weeks elapsed from last
dose of docetaxel. Participants who received abiraterone acetate in the
hormone-sensitive state will not be eligible

- For Cohort C: 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)

- For Cohort C:Has known or suspected brain metastasis or leptomeningeal carcinomatosis

- For Cohort C: Has a history of loss of consciousness within 12 months of the screening
visit

- For Cohort C: Has hypotension (systolic blood pressure <86 millimeters of mercury
[mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic
blood pressure >105 mmHg) at the screening visit

- For Cohort C: Has received treatment with 5-a reductase inhibitors (e.g., finasteride,
dutasteride), estrogens, and/or cytproterone within 4 weeks prior to Cycle 1

- For Cohort C: Has a history of prostate cancer progression on ketoconazole

- For Cohort D: Has received prior treatment with docetaxel or another chemotherapy
agent for metastatic prostate cancer

- For Cohort D: Has progressed on prior abiraterone acetate for treatment of castration
sensitive or resistant metastatic prostate cancer

- For Cohort D: Has discontinued prior treatment with abiraterone acetate due to AEs

- For Cohort D: Has previously been treated with ketoconazole for prostate cancer for >7
days

- For Cohort D: Has received prior systemic treatment with an azole drug (eg,
fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1

- For Cohort D: Has uncontrolled hypertension (systolic BP = 160 mm Hg or diastolic BP =
95 mm Hg)

- For Cohort D: Has a history of pituitary or adrenal dysfunction

- For Cohort D: Has clinically significant heart disease as evidenced by myocardial
infarction, or arterial thrombotic events in the past 6 months, severe or unstable
angina, or New York Heart Association Class II-IV heart disease or cardiac ejection
fraction measurement of <50% at baseline

- For Cohort D: Has atrial fibrillation, or other cardiac arrhythmia requiring therapy

- For Cohort D: Has a history of chronic liver disease

- For Cohort D: Is currently receiving strong CYP3A4 inducers (eg, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone
acetate treatment, CYP2D6 substrates with a narrow therapeutic index (for example
thioridazine), or CYP2C8 substrates with a narrow therapeutic index (for example
pioglitazone)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
New Jersey
Country [3] 0 0
United States of America
State/province [3] 0 0
Washington
Country [4] 0 0
Canada
State/province [4] 0 0
Quebec
Country [5] 0 0
France
State/province [5] 0 0
Paris
Country [6] 0 0
New Zealand
State/province [6] 0 0
Auckland

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475)
combination therapy in patients with metastatic castrate resistant prostate cancer (mCRPC).
There will be four cohorts in this study: Cohort A will receive pembrolizumab + olaparib,
Cohort B will receive pembrolizumab + docetaxel + prednisone, Cohort C will receive
pembrolizumab + enzalutamide, and cohort D will receive pembrolizumab + abiraterone +
prednisone. Outcome measures will be assessed individually for each cohort.
Trial website
https://clinicaltrials.gov/show/NCT02861573
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Trialsites@merck.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02861573