Neoadjuvant ADT and Darolutamide With Pembrolizumab, Followed by Adjuvant Pembrolizumab in NCCN High-risk and Molecularly Stratified Prostate Cancer Patients
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Proportion of patients who achieve Minimal residual disease (MRD)
研究概览
简要总结
This is a single-arm, phase II study of neoadjuvant combination therapy of Androgen Deprivation Therapy (ADT), [Gonadotropin-Releasing Hormone (GnRH) agonist Leuprolide], androgen receptor (AR)-antagonist Darolutamide and Pembrolizumab in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-radical prostatectomy (RP).
Patients with National Comprehensive Cancer Network (NCCN) high-risk non-metastatic prostate cancer (localized or locally advanced) (defined as Gleason ≥8, disease stage >=cT3a, or PSA l >20 ng/mL) will be risk-stratified at a biopsy using Decipher, a commercial standard-of-care diagnostic assay. Patients satisfying all three criteria of high-risk genomic characteristics listed below as per the Decipher grid results will be enrolled in the study:
- Decipher Genomic classifier, GC>0.6
- AR activity score/AR-output gene signature (ARoS)>11.0
- High Luminal B score/ PAM50 subtype signature
详细描述
The objectives of this study are to evaluate if the neoadjuvant ADT, Darolutamide and Pembrolizumab treatment in high-risk prostate cancer patients stratified based on their genomic characteristics will lead to minimum residual disease (MRD).
A total of 40 men ≥ 18 years of age with non-metastatic adenocarcinoma of the prostate, having NCCN high risk localized disease, risk stratified at biopsy based on Decipher score, AR activity score and Luminal B score will be enrolled.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male Age ≥ 18 years at the time of consent
- •Subjects must have histopathologically confirmed adenocarcinoma of the prostate
- •Subjects must have unfavorable intermediate and high-risk localized or locally advanced prostate cancer (Gleason score ≥7 (4+3) and absence of distant metastasis or non-regional nodal involvement.
- •Subjects must be risk-stratified at biopsy and their cancer should have all the molecular features given below at baseline.
- •Decipher Genomic Classifier >0.45 (interpreted from decipher report) and/ or
- •Luminal B subtype (interpreted from decipher report).
- •The patient must have a performance status of 0-1 as determined by criteria set forward by the eastern cooperative oncology group.
- •Subjects with prior neoadjuvant hormonal therapy are allowed if they meet the following criteria.
- •have completed all treatments ≥ 12, months ago.
- •Recovered from all AEs due to previous therapies.
- •If subject has had a major surgery, he should have recovered from all complications and toxicities prior to enrolling in the study.
- •Adequate organ and marrow function as defined below:
- •Hematological
- •Absolute neutrophil count (ANC) ≥ 1,500/mcL
- •Platelets ≥ 100,000/mcl
- •Hemoglobin (Hb) ≥ 9 g/dL Hepatic
- •total bilirubin ≤ 1.5 mg/dl (except in patients with gilbert syndrome who can have total bilirubin <3.0 mg/dl)
- •Aspartate aminotransferase (AST) ≤ 2.5 x ULN
- •Alanine aminotransferase (ALT) ≤ 2.5 x ULN Renal
- •Creatinine OR Creatinine ≤ 1.5 ULN OR
- •Calculated creatinine clearance Creatinine clearance ≥ 30 ml/min
- •Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after completion of therapy. Subject must agree to partner use of an additional contraceptive method when having intercourse with women of childbearing potential (WOCBP).
- •Ability to understand and the willingness to sign a written informed consent.
- •Subjects who are HBs Ag positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
- •Note: Subjects should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
- •Hepatitis B screening tests are not required unless:
- •Known history of HBV infection
- •As mandated by local health authority
- •Subjects with a history of HCV infection are eligible if HCV viral load is undetectable at screening.
- •Note: Subjects must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
- •Hepatitis C screening tests are not required unless:
- •Known history of HCV infection
- •As mandated by local health authority
- •Subjects with a known history of Human immunodeficiency virus (HIV) infection are eligible as long as they have an undetectable viral. HIV positive participants must be taking stable ART for ≥ 12 weeks and have an undetectable HIV viral load within 28 days before enrollment. Minor fluctuations up to 200 copies/mL are acceptable.
排除标准
- •Subjects with metastatic disease
- •Subjects with Gleason score ≤7 (3+4)
- •Subjects with Biopsy Decipher score ≤0.
- •Subjects have had prior hormonal therapy (please see inclusion criteria for exceptions).
- •Subjects have had prior radiation therapy or chemotherapy for prostate cancer.
- •Subjects with active cardiac disease defined as having any of the following within 6 months prior to the start of treatment:
- •myocardial infarction,
- •severe/unstable angina pectoris,
- •congestive heart failure,
- •hospitalization for any cardiac event
- •Subject has active GI disorder that will interfere with absorption of study drug Darolutamide Subject has prior treatment with androgen receptor inhibitors, such as apalutamide, Darolutamide, enzalutamide, abiraterone acetate or other investigational CYP17 inhibitor.
- •Inability to swallow oral medications.
- •Subject has active infection requiring systemic therapy within 7 days of Week
- •Subject has received prior therapy with anti-PD1, anti-PDL1, anti-PDL2 or with other checkpoint inhibitors or T-cell costimulatory/inhibitory agents (e.g., CD137, OX-40, CTLA4).
- •Subject with an active viral Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive or detectable [qualitative] Hepatitis b virus [HBV] DNA or defined as Hepatitis V virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), known Human Immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver disease with a need of treatment.
- •Subject has a known active or known history of TB (Bacillus tuberculosis) or active history of non-infectious pneumonitis.
- •Subject who are immunodeficient or are receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days of study intervention. Topical or inhaled steroids are permitted in absence of immunodeficiency or autoimmune disease.
- •Subject have active auto-immune disease that has required systemic therapy (use of disease modifying agents, corticosteroids, or immunosuppressive drugs) in the past 2 years. However, subjects receiving replacement therapy (e.g., insulin, thyroxine, or physiological corticosteroid replacement therapy for adrenal and pituitary insufficiency) are eligible.
- •Has history or current evidence of any condition, therapy that might confound results of the study. - Has known psychiatric, epileptic or substance abuse history or disorder that would interfere with participant's ability to cooperate with the requirements of the study.
- •Subjects with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- •Known history of allergic reactions attributed to compounds of similar chemical or biologic composition to Agent(s) or other agents used in study.
研究组 & 干预措施
Participants with Prostate Cancer
Neoadjuvant ADT plus AR- antagonist, Darolutamide plus Pembrolizumab (5 cycles) prior to radical prostatectomy (RP) in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-RP.
干预措施: Darolutamide (Drug)
Participants with Prostate Cancer
Neoadjuvant ADT plus AR- antagonist, Darolutamide plus Pembrolizumab (5 cycles) prior to radical prostatectomy (RP) in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-RP.
干预措施: Pembrolizumab (Drug)
Participants with Prostate Cancer
Neoadjuvant ADT plus AR- antagonist, Darolutamide plus Pembrolizumab (5 cycles) prior to radical prostatectomy (RP) in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-RP.
干预措施: Lupron (Drug)
结局指标
主要结局
Proportion of patients who achieve Minimal residual disease (MRD)
时间窗: at time of surgery (At Week 17)
MRD is defined as residual cancer burden (RCB) ≤0.25cm³ at final pathology, where RCB is calculated by multiplying the residual tumor volume with the tumor cellularity. The proportion of patients who achieve MRD will be collected at the time of surgery.
次要结局
- Complete pathological response (pCR)(After Week 17)
- Proportion of patients who had had their tumor downstaged(at time of surgery (At Week 17))
- Adverse events assessed by NCI CTCAE (v.5.0).(Week 1 to Week 16, Week 19 to Week 52)
- Biochemical progression free survival bPES(Week 22 and until 5 years after Week 17)
- Metastasis free survival (MFS)(Week 17 and until 5 years after Week 17)
- Tumor Volumes(Week 0 to Week 17)
- Immunological responses in blood(Week 0 to Week 52)
- Whole exome-sequencing (WES)(Week 0 to Week 17)
- RNA sequencing (RNA-seq)(Week 0 to Week 17)
研究者
Ashutosh Kumar Tewari
Urology Chair
Icahn School of Medicine at Mount Sinai