A Pilot Study of 5-AZA and ATRA for Prostate Cancer With PSA-only Recurrence After Local Treatment

Sponsor

Icahn School of Medicine at Mount Sinai (Other)

Overall Status

Completed

CT.gov ID

NCT03572387

Collaborator

(none)

Enrollment

Location

Arms

46.6

Actual Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective, open-label, randomized, cross-over, pilot study of reprogramming therapy in patients with recurrent PCa based on rising PSA only. The primary objectives are to compare the disease progression-free rate at the end of 12 weeks between 5-AZA+ATRA and no therapy and to assess safety of the 5-AZA and ATRA combination. All study enrollees will receive Lupron. After one month, they will be assigned in a 1:1 randomization to either the '5-AZA+ATRA' group or the 'no therapy' group. Patients in the '5-AZA + ATRA' group will receive treatment on a 28-day cycle, in the absence of prohibitive toxicities, for 3 cycles. Patients will initially be observed for 3 cycles under either no therapy or combination therapy, before crossing over to receive the opposite treatment for another 3 cycles in the absence of prohibitive toxicities. After the treatment period, all patients will be followed for a total of 24 months from the start of the study or until the events leading to discontinuation are observed.

Condition or Disease	Intervention/Treatment	Phase
Prostatic Neoplasms Prostate Neoplasms Prostate Cancer	Drug: 5-Azacitidine Drug: all trans retinoic acid Drug: Lupron	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

14 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Subjects will be assigned in a 1:1 randomization to either the '5-AZA+ATRA' group or the 'no therapy' group. Patients in the '5-AZA + ATRA' group will receive treatment on a 28-day cycle, in the absence of prohibitive toxicities, for 3 cycles. Patients will initially be observed for 3 cycles under either no therapy or combination therapy, before crossing over to receive the opposite treatment for another 3 cycles in the absence of prohibitive toxicities.Subjects will be assigned in a 1:1 randomization to either the '5-AZA+ATRA' group or the 'no therapy' group. Patients in the '5-AZA + ATRA' group will receive treatment on a 28-day cycle, in the absence of prohibitive toxicities, for 3 cycles. Patients will initially be observed for 3 cycles under either no therapy or combination therapy, before crossing over to receive the opposite treatment for another 3 cycles in the absence of prohibitive toxicities.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Pilot Study of the Combination of 5-azacitidine (5-AZA) and All-trans Retinoic Acid (ATRA) for Prostate Cancer (PCa) With PSA-only Recurrence After Definitive Local Treatment

Actual Study Start Date :

Aug 20, 2018

Actual Primary Completion Date :

Jun 19, 2022

Actual Study Completion Date :

Jul 8, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: (5-AZA) + (ATRA) combination Combination of 5-Azacitidine (5-AZA) + all trans retinoic acid (ATRA) group after one month of Lupron, group will receive treatment on a 28-day cycle, in the absence of prohibitive toxicities, for 3 cycles.	Drug: 5-Azacitidine subcutaneously on days 1-5 at a dose of 40 mg/m^2 Other Names: 5-AZA Drug: all trans retinoic acid 45 mg/m^2, will be taken orally on days 3-7 of each cycle, divided into two doses Other Names: ATRA Drug: Lupron 7.5 mg x 1
Active Comparator: Lupron only No treatment after one month of Lupron	Drug: Lupron 7.5 mg x 1

Arm

Intervention/Treatment

Experimental: (5-AZA) + (ATRA) combination

Combination of 5-Azacitidine (5-AZA) + all trans retinoic acid (ATRA) group after one month of Lupron, group will receive treatment on a 28-day cycle, in the absence of prohibitive toxicities, for 3 cycles.

Drug: 5-Azacitidine

subcutaneously on days 1-5 at a dose of 40 mg/m^2

Other Names:

5-AZA

Drug: all trans retinoic acid

45 mg/m^2, will be taken orally on days 3-7 of each cycle, divided into two doses

Other Names:

ATRA

Drug: Lupron

7.5 mg x 1

Active Comparator: Lupron only

No treatment after one month of Lupron

Drug: Lupron

7.5 mg x 1

Outcome Measures

Primary Outcome Measures

PSA Response Rate [Baseline and 24 weeks]
Proportion of patients with PSA response, as defined by PSA decreased > 30% from baseline.
Percentage of adverse events by grade [24 weeks]
Safety will be assessed by the recording of adverse events. Adverse events will be graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The percentage of patients for each observed adverse effect will be reported by grade.

Secondary Outcome Measures

Proportion of patients with prolongation of PSA doubling time (PSADT) post-treatment (compared to baseline) [24 weeks]
PSADT measured at baseline and after treatment with 3 cycles of Aza and ATRA
Measurement of TGFβ2 dormancy biomarker levels [up to 24 months]
The measurement of dormancy biomarker levels in relation to disease states: tumor progression and disease progression.
Measurement of BMP7 dormancy biomarker levels [up to 24 months]
The measurement of dormancy biomarker levels in relation to disease states: tumor progression and disease progression.
Measurement of BMP4 dormancy biomarker levels [up to 24 months]
The measurement of dormancy biomarker levels in relation to disease states: tumor progression and disease progression.
Measurement of GAS6 dormancy biomarker levels [up to 24 months]
The measurement of dormancy biomarker levels in relation to disease states: tumor progression and disease progression.
Measurement of retinoic acid dormancy biomarker levels [up to 24 months]
The measurement of dormancy biomarker levels in relation to disease states: tumor progression and disease progression.
Measurement of NR2F1 dormancy biomarker levels [up to 24 months]
The measurement of dormancy biomarker levels in relation to disease states: tumor progression and disease progression.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed adenocarcinoma of the prostate
Rising PSA
PSADT ≤ 10 months prior to initiation of ADT
No evidence of regional or active distant metastases, except for regional metastasis where salvage radiation therapy is not an option
Indication for ADT after receiving definitive local therapy
Males ≥ 18 years.
ECOG performance status of ≤ 2
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
Ability to understand and the willingness to sign a written informed consent
Ability to adhere to the study visit schedule and requirements of the protocol

Exclusion Criteria:

Patients who have received ADT and/or other chemotherapy within 3 months prior to entering the study.
Patients who have had radiotherapy or surgery within 4 weeks prior to entering the study. Minimally-invasive procedures for the purpose of diagnosis or staging of the disease are permitted.
Patients may not be receiving any other investigational agents.
Patients 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.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-AZA and ATRA.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Significant active cardiac disease within the previous 6 months
Inadequate organ and marrow function as defined below:
leukocytes ≤ 3,000/mcL
absolute neutrophil count ≤ 1,500/mcL
platelets ≤ 100,000/mcl
total bilirubin above normal institutional limits
AST(SGOT)/ALT(SPGT) ≥ 2.5 X institutional upper limit of normal
creatinine above normal institutional limits