Neoadjuvant ADT + Darolutamide With Pembrolizumab, Followed by Adjuvant Pembrolizumab in Molecularly Stratified High-Risk Prostate Cancer

Официальное название

Neoadjuvant ADT and Darolutamide With Pembrolizumab, Followed by Adjuvant Pembrolizumab in NCCN High-risk and Molecularly Stratified Prostate Cancer Patients

Обзор

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: 1. Decipher Genomic classifier, GC\>0.6 2. AR activity score/AR-output gene signature (ARoS)\>11.0 3. High Luminal B score/ PAM50 subtype signature

Подробное описание

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.

Вмешательства

• Препарат Darolutamide
  Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg for 16 weeks prior to RP.
• Препарат Pembrolizumab
  Administered at the dose of 200 mg intravenously, every 3 weeks, for a total of 5 cycles prior to RP (Neoadjuvant phase, study weeks 1, 4, 7, 10, 13 \& 16), and every 3 weeks, for a total of 12 cycles post-RP (Adjuvant phase, study weeks, 19, 22, 25, 28, 31, 34, 37, 40 43, 46, 49, \& 52). Total Pembrolizumab cycles=17
• Препарат Lupron
  Androgen deprivation, GnRH agonist Leuprolide will be administered at a dose of 22.5 mg SQ (Eligard)/IM Lupron every 12 weeks prior to RP (Study weeks, 1 and 13).

Первичные конечные точки

• Proportion of patients who achieve Minimal residual disease (MRD) [Срок оценки: at time of surgery (At Week 17)]

Вторичные конечные точки (9)

• Complete pathological response (pCR) [Срок оценки: After Week 17]
• Proportion of patients who had had their tumor downstaged [Срок оценки: at time of surgery (At Week 17)]
• Adverse events assessed by NCI CTCAE (v.5.0). [Срок оценки: Week 1 to Week 16, Week 19 to Week 52]
• Biochemical progression free survival bPES [Срок оценки: Week 22 and until 5 years after Week 17]
• Metastasis free survival (MFS) [Срок оценки: Week 17 and until 5 years after Week 17]
• Tumor Volumes [Срок оценки: Week 0 to Week 17]
• Immunological responses in blood [Срок оценки: Week 0 to Week 52]
• Whole exome-sequencing (WES) [Срок оценки: Week 0 to Week 17]
• RNA sequencing (RNA-seq) [Срок оценки: Week 0 to Week 17]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• Subjects with metastatic disease
• Subjects with Gleason score ≤7 (3+4)
• Subjects with Biopsy Decipher score ≤0.45.
• 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 1.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Icahn School of Medicine at Mount Sinai — New York

Идентификаторы

NCT: NCT07027124 · STUDY-23-01400

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗