Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
MEVROMETOSTAT, METASTATIC CASTRATION RESISTANT PROSTATE CANCER, PF-06821497, EZH2, enhancer of zeste homologue-2, enzalutamide, mCRPC, Prostrate Cancer, castrate resistant prostate cancer, prostatecancer-study.com, efficacy, safety, pharmacokinetics, pharmacodynamics
Brief summary
This study will explore whether a combination of the investigational drug PF-06821497 and enzalutamide will work better than taking enzalutamide alone in participants with mCRPC who are ARSi or abiraterone naïve.
Detailed description
This is a global, multicenter, randomized Phase 3 study evaluating PF-06821497 (mevrometostat) in combination with enzalutamide versus placebo in combination with enzalutamide in participants with mCRPC where no systemic anti-cancer treatments have been initiated after documentation of mCRPC with the exception of ADT (androgen deprivation therapy) and first-generation anti-androgen agents. Prior treatment with any of the ARSi's enzalutamide, darolutamide, apalutamide, or abiraterone acetate, is not permitted in any setting. Chemotherapy is permitted in the castrate sensitive setting. This study consists of a Screening Phase, Randomization, Treatment Phase, Safety Follow-up, and Long-Term Follow-up. Participants will be randomized on a 1:1 basis to receive (Arm A) PF-06821497 in combination with enzalutamide, or (Arm B) placebo in combination with enzalutamide.
Interventions
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind study. Participants will receive PF-06821497 or matching placebo in a blinded fashion, as indicated in Section 6.1. Participants, investigators and site staff, and sponsor staff will be aware that participants in both study arms are receiving enzalutamide. Enzalutamide will be provided in an open-label manner to participants in each treatment arm. Participants and their caregivers will be blinded to their assigned study intervention. Investigators and other site staff will be blinded to participants' assigned study intervention Sponsor staff will be blinded to participants' assigned study intervention, except for sponsor staff involved in the assignment or distribution of study intervention.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features. * Metastatic disease in bone documented on bone scan, or in soft tissue documented on CT/MRI scan. * Progressive disease in the setting of medical or surgical castration. * ECOG performance status 0 or 1, with a life expectancy of ≥12 months as assessed by the investigator.
Exclusion criteria
* Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation in the past year or suicidal behavior in the past 5 years or laboratory abnormality that make the participant inappropriate for the study. * Known history of active inflammatory gastrointestinal disease, chronic diarrhea, or previous gastric resection or lap-band surgery. * Clinically significant cardiovascular disease. * Known or suspected brain metastasis or active leptomeningeal disease or clinically significant history of seizure. * Any history of myelodysplastic syndrome, acute myeloid leukemia, or any other prior malignancy with a few exceptions. * Participants must be treatment naïve at the mCRPC stage, eg, no cytotoxic chemotherapy, radio-ligand therapy (i.e. 177Lu- PSMA-617), CDK4/6 inhibitors, 5-alpha reductase inhibitors for prostate cancer in any setting, androgen receptor signaling inhibitors (ARSi) including enzalutamide, apalutamide, darolutamide, poly ADP-ribose polymerase (PARP) monotherapy or other systemic anti-cancer treatment with the following exceptions: 1. Treatment with first-generation antiandrogen (ADT) agents, estrogens, progestins, cyproterone acetate; 2. Docetaxel treatment is allowed for mCSPC, as long as no signs of failure, or disease progression occurred during treatment or within 3 months of treatment completion. * Previous administration with an investigational product (drug or vaccine) within 30 days or 5 half-lives preceding the first dose of study intervention (whichever is longer). * Inadequate organ function.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression Free Survival (rPFS) | Randomization up to approximately 3 years | rPFS is defined as the time from the date of randomization to first objective evidence of radiographic progression as assessed in soft tissue per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or in bone per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines by BICR, or death, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | Randomization up to approximately 5 years | OS is defined as the time from the date of randomization to the date of death due to any cause. |
| To demonstrate that PF-06821497 in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging Time To Pain Progression (TTPP) | Randomization up to approximately 5 years | TTPP (alpha protected): assessed using time to first ≥2-point increase from baseline score on BPI-SF Item 3 (Worst Pain) observed at 2 consecutive visits or the initiation of short- or long-acting opioid use for pain |
| Objective Response Rate (ORR) | Randomization up to approximately 3 years | The objective response rate is defined as the proportion of participants with measurable soft tissue disease at baseline who have a confirmed objective response of complete response (CR) or partial response (PR) per RECIST v1.1 by BICR |
| Duration of Response (DoR) in measurable soft tissue disease | Randomization up to approximately 3 years. | The DoR is defined as the time from the first objective evidence of soft tissue response (CR or PR, whichever is earlier) to radiographic progression per BICR or death due to any cause whichever occurs first. |
| Time to prostate specific antigen (PSA) progression. | Randomization up to approximately 3 years | Time from the date of randomization to the date of the first PSA progression. PSA progression is defined as a ≥25% increase in PSA with an absolute increase of ≥2 ng/mL above the nadir (or baseline for participants with no PSA decline), confirmed by a second consecutive PSA value at least 21 days later. |
| Prostate Specific Antigen Response | Randomization up to approximately 3 years. | Proportion of participants with PSA response ≥50% in participants with detectable PSA values at baseline. |
| Time to initiation of antineoplastic therapy. | Randomization up to approximately 5 years. | Time from randomization to first use of new antineoplastic therapy. |
| Time to initiation of cytotoxic chemotherapy. | Randomization up to approximately 5 years | Time from randomization to first use of new cytotoxic chemotherapy. |
| Time to first symptomatic skeletal event | Randomization up to approximately 3 years. | Time from randomization to first symptomatic skeletal event (symptomatic bone fractures, spinal cord compression, surgery or radiation to the bone whichever is first). |
| Progression free survival on next line of therapy | Randomization up to approximately 5 years | the time from the date of randomization to the first occurrence of investigator-determined disease progression (PSA progression, progression on imaging, or clinical progression) or death due to any cause, whichever occurs first, while the participant was receiving first subsequent therapy for prostate cancer. |
| Incidence of Adverse Events | Randomization up to approximately 5 years | Type, incidence, severity \[as graded by National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v5.0\], seriousness and relationship to study medications of AEs. |
| To assess circulating tumor DNA (ctDNA) at baseline and on treatment to evaluate tumor burden. | Baseline up to approximately 3 years. | Evaluation of ctDNA burden at baseline and on study. |
| To evaluate the PK of PF-06821497 when dosed with enzalutamide | Cycle 1 Day 15 to last PK draw at Cycle 6 Day 1 (cycle length is 28 days) | PK characterized by pre-dose trough and post-dose plasma concentrations of PF-06821497 at selected visits |
| Change from baseline in patient reported pain symptoms per Brief Pain Inventory-Short Form (BPI-SF) | Randomization up to approximately 5 years | Analysis of Brief Pain Inventory-Short Form (BPI-SF) will be based on the pain severity score (mean of individual BPI-SF items 3, 4, 5 and 6), the pain interference score (mean of items 9A-9G), and the single BPI-SF Item 3 which asks the patient to rate pain at its worst in the last 24 hours. |
| Change from baseline in BPI-SF Item 3 (Worst Pain) at Cycle 7 Day 1 (Week 25) | Randomization up to Week 25 | Analysis of Brief Pain Inventory-Short Form (BPI-SF) will be based on the pain severity score (mean of individual BPI-SF items 3, 4, 5 and 6), the pain interference score (mean of items 9A-9G), and the single BPI-SF Item 3 which asks the patient to rate pain at its worst in the last 24 hours. |
| Change from baseline in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Randomization up to approximately 5 years | Change from baseline in HRQoL (FACT-P total score) will be presented. The FACT-P total score will be calculated based on the participant responses to the 39 items in the FACT-P questionnaire. Each item is rated on a 0 to 4 Likert-type scale and then combined to produce the FACT-P total score (0-156), with higher scores representing better health-related quality of life. |
| Change from baseline in patient reported health status per European Quality of Life 5-Dimension 5 Level (EQ-5D-5L) | Randomization up to approximately 5 years | Participants will self-rate their current state of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 5 possible responses that record the level of severity (no problems, slight problems, moderate problems, severe problems, or extreme problems) within each dimension. The questionnaire also includes a visual analog scale to self-rate general health state on a scale from "the worst health you can imagine" to "the best health you can imagine." |
| Symptomatic toxicity as measured by items from the Patient-Reported Outcome CTCAE (PRO-CTCAE) | Randomization up to approximately 5 years | Each selected PRO-CTCAE items will be assessed related to one or more attributes that include counts for the frequency, severity, and/or interference with usual or daily activities. |
| Overall side effect burden as measured by the FACT- GP5 | Randomization to approximately 5 years | The FACT-GP5 question assesses overall side effect burden with the following response options "I am bothered by side effects of treatment," is rated on a 5-point scale ranging from "not at all" (0) to "very much" (4) and counts will be presented. |
| Time to definitive deterioration in patient-reported health related quality of life (HRQoL) per FACT-P | Randomization up to approximately 5 years | Defined as the time from randomization to onset of definitive deterioration in FACT-P total score, which is defined as \>10 point decrease from baseline and no subsequent observations with a \<10 point decrease from baseline FACT-P total score |
Countries
Argentina, Brazil, Bulgaria, Canada, Chile, China, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Japan, Netherlands, New Zealand, Poland, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTPfizer CT.gov Call Center
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Outcome results
None listed