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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Prostatic Neoplasms, Prostate Neoplasms, Prostate Cancer

Intervention / Treatment
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* Drug: 5-Azacitidine
* Drug: all trans retinoic acid
* Drug: Lupron


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (5-AZA) + (ATRA) combination<br>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<br>* subcutaneously on days 1-5 at a dose of 40 mg/m^2<br>* Other names: 5-AZA;Drug: all trans retinoic acid<br>* 45 mg/m^2, will be taken orally on days 3-7 of each cycle, divided into two doses<br>* Other names: ATRA;Drug: Lupron<br>* 7.5 mg x 1<br>|
| Active Comparator: Lupron only<br>No treatment after one month of Lupron | Drug: Lupron<br>* 7.5 mg x 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response Rate | Proportion of patients with PSA response, as defined by PSA decreased > 30% from baseline. | Baseline and 24 weeks | 
| Percentage of adverse events by grade | 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. | 24 weeks | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSA, Prostate Neoplasms, Prostatic Neoplasms, 5-Azacitidine, all-trans retinoic acid