Decitabine/Cedazuridine and Enzalutamide for the Treatment of Metastatic Castrate Resistant Prostate Cancer

Castration-Resistant Prostate Carcinoma Clinical Trial

Official title:

A Phase 1b Clinical Trial: Improving Outcomes With Androgen Pathway Inhibitors by Targeting DNA Methyltransferase Activity

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05037500
• Other study ID #: I 1373721
• Secondary ID: NCI-2021-08860I
• Status: Recruiting
• Phase: Phase 1
• Start date: January 26, 2022
• Est. completion date: January 30, 2025

Study information

• Verified date: October 2023
• Source: Roswell Park Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase Ib trial is to find out the best dose decitabine/cedazuridine and possible benefits and/or side effects of decitabine/cedazuridine and enzalutamide in treating patients with castrate resistant prostate cancer that has spread to other places in the body (metastatic). Chemotherapy drugs, such as decitabine/cedazuridine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Enzalutamide blocks the use of androgen by the tumor cells. Giving decitabine/cedazuridine together with enzalutamide may reverse or help prevent the acquired therapeutic resistance that is observed when enzalutamide is used alone. Drug resistance occurs when cancer cells stop responding to a chemotherapy that had previously been effective.

Description:

PRIMARY OBJECTIVE: I. To determine the safety of oral decitabine and cedazuridine (decitabine/cedazuridine) in combination with enzalutamide in patients with metastatic castrate resistant prostate cancer (mCRPC). SECONDARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of oral decitabine/cedazuridine in combination with enzalutamide in patients with metastatic castrate resistant prostate cancer (mCRPC). OUTLINE: This is a dose-escalation study of decitabine and cedazuridine. Patients receive decitabine and cedazuridine orally (PO) once daily (QD) on either days 1-3, 1-4, or 1-5 and enzalutamide PO QD on days 1-28. Treatments repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 3 months for 24 months.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: January 30, 2025
• Est. primary completion date: January 30, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male >= 18 years of age
• Histological or cytological documentation of diagnosis of prostate cancer
• Documented progressive metastatic castrate resistant prostate cancer (mCRPC) based on

at least one of the following criteria:

• Prostate specific antigen (PSA) progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1week interval and a minimum PSA of 2 ng/mL
• Soft-tissue progression defined as an increase >= 20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions
• Progression of bone disease (evaluable disease) or (new bone lesion[s]) by bone scan
• Biopsy is preferred where feasible (NOT mandatory) (nodal and visceral disease), particularly in patient at the recommended Phase 2 dose
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Have testosterone < 50 ng/dL if not currently on primary androgen deprivation with an LHRH analogue (agonist or antagonist). Note: Patients who are currently on primary androgen deprivation with an LHRH analogue (agonist or antagonist) and have not undergone orchiectomy must continue with this regimen and for these patients, testosterone measurement is not required for eligibility.
• Patient has adequate bone marrow and organ function as defined by the following

laboratory values:

• White blood cells >= 1.5 x 10^9/L (obtained within 14 days prior to treatment start)
• Platelets >= 100 x 10^9/L (obtained within 14 days prior to treatment start)
• Hemoglobin (HGB) >= 9 g/dL (obtained within 14 days prior to treatment start)
• Creatinine clearance > 50 mL/min (obtained within 14 days prior to treatment start)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN (obtained within 14 days prior to treatment start). If the patient has liver metastases, ALT and AST must still be =< 2.5 x ULN. Patients with liver metastases and AST/ALT above this limit will not be enrolled
• Total bilirubin =< 1.5 x ULN; or total bilirubin (TBILI) =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome (obtained within 14 days prior to treatment start)
• Ability to swallow and retain oral medication (without crushing, dissolving, or chewing tablets)
• Initial dose escalation/de-escalation: Prior enzalutamide treatment and/or other approved treatments for CRPC for the dose finding phase (determination of MTD) of the study is allowed
• Expansion cohort: Once the MTD has been determined from the dose escalation/de-escalation portion of the study, patient eligibility for the expansion cohort will be genomically driven and will be restricted to metastatic CRPC patients with detectable genomic alterations in RB1 and/or TP53
• Sexually active males must agree to use a condom during intercourse while taking the study drug and for at least 3 months after stopping study treatment. Sexually active males should not father a child during this period. A condom is required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
• NOTE: For blood chemistry labs, Roswell Park clinical blood chemistries are performed on plasma unless otherwise indicated

Exclusion Criteria:

• Participant has a concurrent malignancy or malignancy within 3 years of treatment start, with the exception of adequately treated, basal or squamous cell carcinoma or non-melanomatous skin cancer
• Participant has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
• Participant has clinically significant, uncontrolled heart disease and/or recent

events including any of the following:

• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to treatment start
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Should not have active heart disease: uncompensated CHF; untreated arrhythmia, and no history of MI in the last 6 months
• Patient is currently receiving any of the following medications and cannot be

discontinued 7 days prior to treatment start:

• Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids and pummelos, star-fruit and Seville oranges
• Herbal preparations/medications
• Patient who has received radiotherapy =< 4 weeks prior to start of treatment or limited field radiation for palliation =< 2 weeks prior to treatment start and, who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom >= 30% of the bone marrow was irradiated
• Patients with central nervous system (CNS) involvement
• Patients with seizure disorder
• Patient has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade <1 (Exception to this criterion: patients with any grade of alopecia are allowed to enter the study)
• Unwilling or unable to follow protocol requirements
• Participant has any other concurrent severe and/or uncontrolled medical condition that would cause, in the investigator's judgment, an unacceptable safety risk
• Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug

Related Conditions & MeSH terms

• Castration-Resistant Prostate Carcinoma
• Prostatic Neoplasms
• Stage IV Prostate Cancer AJCC v8
• Stage IVA Prostate Cancer AJCC v8
• Stage IVB Prostate Cancer AJCC v8

Intervention

Drug:
• Decitabine and Cedazuridine
Given PO
• Enzalutamide
Given PO

Locations

Country	Name	City	State
United States	Roswell Park Cancer Institute	Buffalo	New York

Sponsors (2)

Lead Sponsor	Collaborator
Roswell Park Cancer Institute	National Comprehensive Cancer Network

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of adverse events (AEs)	Assesses using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Up to 30 days post-treatment
Secondary	Maximum tolerated dose (MTD)	The MTD will be defined as the dose level at which 0 out of 3 or < 2 out of 6 patients within the same cohort experience dose-limiting toxicity (DLT). DLTs will be defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with decitabine in cycle 1. These will be assessed using the NCI CTCAE version 5.0.	Up to cycle 1 (1 cycle = 28 days)