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Study of Pembrolizumab (MK-3475) Plus Docetaxel Versus Placebo Plus Docetaxel in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-921/KEYNOTE-921)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03834506
Recruitment Status : Active, not recruiting
First Posted : February 8, 2019
Last Update Posted : November 28, 2022
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:

The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and docetaxel in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC but have progressed on or are intolerant to Next Generation Hormonal Agent (NHA).

There are two primary study hypotheses.

Hypothesis 1: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone with respect to Overall Survival (OS).

Hypothesis 2: The combination of pembrolizumab plus docetaxel plus prednisone is superior 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.


Condition or disease Intervention/treatment Phase
Prostatic Neoplasms Biological: Pembrolizumab Drug: Docetaxel Drug: Prednisone Drug: Placebo Drug: Dexamethasone Phase 3

Detailed Description:
With Amendment 6 (effective date: 29-Sep-2022), all participants will be unblinded and placebo treatment will be stopping. Participants who are deemed to be deriving clinical benefit from treatment may continue at the discretion of the investigator.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1090 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone Versus Placebo Plus Docetaxel Plus Prednisone in Participants With Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-921)
Actual Study Start Date : May 2, 2019
Actual Primary Completion Date : June 20, 2022
Estimated Study Completion Date : October 4, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Pembrolizumab+Docetaxel
On Day 1 of each 21-day cycle, participants receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours and 1 hour prior to docetaxel administration PLUS docetaxel 75 mg/m^2 by intravenous (IV) infusion for up to a maximum of 10 cycles (approximately 7 months). Participants receive prednisone 5 mg by oral tablets twice daily during each docetaxel cycle up to a maximum of 10 cycles (approximately 7 months). Participants also receive pembrolizumab 200 mg by IV infusion on day 1 of each 21-day cycle for up to a maximum of 35 cycles (approximately 2 years).
 Biological: Pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Docetaxel
IV infusion
Other Name: TAXOTERE®

Drug: Prednisone
Oral tablets

Drug: Dexamethasone
Oral tablets
Other Name: DECADRON®
Placebo Comparator: Placebo+Docetaxel

On Day 1 of each 21-day cycle, participants receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours and 1 hour prior to docetaxel administration PLUS docetaxel 75 mg/m^2 by IV infusion for up to a maximum of 10 cycles (approximately 7 months). Participants receive prednisone 5 mg by oral tablets twice daily during each docetaxel cycle up to a maximum of 10 cycles (approximately 7 months).

Participants also receive placebo by IV infusion on day 1 of each 21-day cycle for up to a maximum of 35 cycles (approximately 2 years).

 Drug: Docetaxel
IV infusion
Other Name: TAXOTERE®

Drug: Prednisone
Oral tablets

Drug: Placebo
IV infusion
Other Name: Normal saline or dextrose infusion

Drug: Dexamethasone
Oral tablets
Other Name: DECADRON®


Outcome Measures
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Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to approximately 36 months ]
    Time from randomization to death due to any cause

  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 [ Time Frame: Up to approximately 36 months ]
    Time from randomization to radiographic progression, or death due to any cause, whichever occurs first


Secondary Outcome Measures :
  1. Time to Initiation of the First Subsequent Anti-cancer Therapy (TFST) [ Time Frame: Up to approximately 36 months ]
    Time from randomization to initiation of the first subsequent anti-cancer therapy or death, whichever occurs first

  2. Prostate-specific Antigen (PSA) Response Rate [ Time Frame: Up to approximately 36 months ]
    Percentage of participants in the analysis population who have a negative change (decrease) in PSA level of ≥50% measured twice ≥3 weeks apart

  3. 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 [ Time Frame: Up to approximately 36 months ]
    Percentage of participants in the analysis population who have a best overall response of either confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified 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) as Assessed by Blinded Independent Central Review [ Time Frame: Up to approximately 36 months ]
    Time from first documented evidence of confirmed Complete Response (CR) or Partial Response (PR) per PCWG-modified RECIST 1.1 until disease progression or death from any cause, whichever occurs first

  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) [ Time Frame: Up to approximately 36 months ]
    Time from randomization to pain progression. In this study, pain progression will be assessed by participant responses to Item 3 of the BPI-SF and participant AQA Scores which are both assessed by participants daily for 7 consecutive days

  6. Time to First Symptomatic Skeletal-related Event (SSRE) [ Time Frame: Up to approximately 36 months ]
    Time from randomization to the first SSRE. SSRE is defined as radiation to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathological fracture, spinal cord compression, or surgery to bone

  7. Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: Up to approximately 36 months ]
    Time from randomization to PSA progression. PSA progression date is defined as the date of 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, or 2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline

  8. 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 [ Time Frame: Up to approximately 36 months ]
    Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1

  9. Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 36 months ]
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment

  10. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 36 months ]
    The number of participants who discontinue study treatment due to an AE will be presented


Eligibility Criteria
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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
  • Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to screening
  • Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI)
  • Has received prior treatment with one (but not more than one) NHA (eg, abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC) and either a) progressed through treatment OR b) has become intolerant of the drug
  • Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)
  • Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
  • Participants must agree to the following during the study treatment period and for at least 120 days after the last dose of pembrolizumab or for at least 180 days after the last dose of docetaxel (whichever is longer): Refrain from donating sperm PLUS Use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
  • Participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex
  • Has 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). Participants with bone only or bone predominant disease may provide a bone biopsy sample
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization

Exclusion Criteria:

  • Has a known additional malignancy that is progressing or has required active treatment in the last 3 years
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
  • 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
  • Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules
  • Has an active infection (including tuberculosis) requiring systemic therapy
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
  • Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
  • Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization or who has not recovered (i.e., Grade ≤1 or at baseline) from AEs due to mAbs
  • Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g. saw palmetto) prior to randomization
  • Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
  • Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137)
  • Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
  • Has hypersensitivity to docetaxel or polysorbate 80
  • Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
  • Has received prior targeted small molecule therapy or abiraterone acetate, enzalutamide, apalutamide, or darolutamide within 4 weeks prior to the first dose of study treatment, or has not recovered (i.e., Grade ≤1 or at baseline) from AEs due to a previously administered agent
  • Has received prior radiotherapy to within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
  • Has received a live vaccine within 30 days prior to randomization
  • Has received treatment with 5α reductase inhibitors (eg, finasteride or dutasteride), estrogens, and/or cyproterone within 4 weeks prior to randomization
  • Has received prior treatment with ketoconazole for prostate cancer
  • 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 treatment
  • Has a "superscan" bone scan
  • 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 treatment
  • Has had an allogenic tissue/solid organ transplant
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03834506


Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT03834506    
Other Study ID Numbers: 3475-921
MK-3475-921 ( Other Identifier: Merck )
KEYNOTE-921 ( Other Identifier: Merck )
JAPAC-CTI ( Registry Identifier: 194831 )
2018-004116-22 ( EudraCT Number )
First Posted: February 8, 2019    Key Record Dates
Last Update Posted: November 28, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme LLC:
Programmed Cell Death-1 (PD1, PD-1)
Programmed Cell Death 1 Ligand 1 (POL 1, PD-L 1)
Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Genital Diseases
Urogenital Diseases
Prostatic Diseases
Male Urogenital Diseases
Dexamethasone
Prednisone
Docetaxel
Pembrolizumab
Anti-Inflammatory Agents
 Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological