Clinical trial NCT04907227: 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)-China Extension
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Prostatic Neoplasms
Keywords: Programmed Cell Death 1 (PD 1, PD-1)
Programmed Cell Death 1 Ligand 1 (PDL 1, PD-L1)
Programmed Cell Death 1 Ligand 2 (PDL 2, PD-L2)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-05-28
Enrollment: 81
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 Chinese 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.

Detailed description: The China extension study will include participants previously enrolled in China in the global study for MK-3475-921 (NCT03834506) plus those enrolled during the China extension enrollment period.

With Amendment 6 (effective date: 29-Sep-2022), all participants were unblinded and placebo treatment was stopped. Participants deemed to derive clinical benefit from treatment may have continued at the discretion of the investigator.

Eligibility 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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 19.8 months
measure: 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)
timeFrame: Up to 19.8 months
Secondary outcomes:
measure: Time to Initiation of the First Subsequent Anti-cancer Therapy (TFST)
timeFrame: Up to 19.8 months
measure: Prostate-specific Antigen (PSA) Response Rate
timeFrame: Up to 19.8 months
measure: 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)
timeFrame: Up to 19.8 months
measure: 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)
timeFrame: Up to 19.8 months
measure: 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 Assessed by the Analgesic Quantification Algorithm [AQA] Score
timeFrame: Up to 19.8 months
measure: Time to First Symptomatic Skeletal-related Event (SSRE)
timeFrame: Up to 19.8 months
measure: Time to Prostate-specific Antigen (PSA) Progression
timeFrame: Up to 19.8 months
measure: 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)
timeFrame: Up to 19.8 months
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 17 months
measure: Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)
timeFrame: Up to 14 months
Other outcomes:
Locations:
city: Hefei
country: China
facility: Second Affiliated hospital of Anhui Medical University-Urology (Site 1339)
state: Anhui
city: Beijing
country: China
facility: Peking University First Hospital ( Site 1303)
state: Beijing
city: Beijing
country: China
facility: The Fifth Medical Center of PLA General Hospital ( Site 1307)
state: Beijing
city: Beijing
country: China
facility: Peking University Third Hospital (Site 1304)
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital ( Site 1305)
state: Beijing
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University ( Site 1319)
state: Fujian
city: Guangzhou
country: China
facility: Sun Yat Sen Memorial Hospital ( Site 1323)
state: Guangdong
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University ( Site 1330)
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center (Site 1334)
state: Guangdong
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital (Site 1326)
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital ( Site 1321)
state: Henan
city: Wuhan
country: China
facility: Hubei Cancer Hospital ( Site 1329)
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital ( Site 1320)
state: Hunan
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital ( Site 1312)
state: Jiangsu
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University ( Site 1301)
state: Shanghai
city: Shanghai
country: China
facility: Renji Hospital Shanghai Jiao Tong University School of Medicine (Site 1335)
state: Shanghai
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center ( Site 1300)
state: Shanghai
city: Xian
country: China
facility: The First Affiliated Hospital of Xi an Jiaotong University (Site 1315)
state: Shanxi
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhejiang University School of Medicine ( Site 1309)
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Provincial People's Hospital ( Site 1310)
state: Zhejiang
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: