Phenelzine Sulfate and Docetaxel in Treating Patients With Prostate Cancer With Progressive Disease After First-Line Therapy With Docetaxel

Study Overview
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Brief Summary
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This phase II trial studies how well giving phenelzine sulfate together with docetaxel works in treating patients with prostate cancer that is growing, spreading, or getting worse after first-line therapy with docetaxel. Phenelzine sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Phenelzine sulfate may also help docetaxel work better by making tumor cells more sensitive to the drug. Giving phenelzine sulfate together with docetaxel may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the proportion of patients who experience a prostate specific antigen (PSA) decline of at least 30% within 12 weeks of initiation of combination therapy when phenelzine (phenelzine sulfate) is added to docetaxel in patients who have evidence of progression on standard docetaxel. SECONDARY OBJECTIVES: I. To determine duration of progression free survival after initiation of combination phenelzine and docetaxel therapy. II. To determine the response rate in measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria after initiation of combination phenelzine and docetaxel therapy. III. To report the maximum change in PSA from baseline to 12 weeks (or earlier in patients who discontinue early) by waterfall plot after initiation of combination phenelzine and docetaxel therapy. IV. To determine the toxicity of the combination regimen in castration-resistant prostate cancer (CRPC) previously treated with docetaxel. V. To determine time to death from all causes. VI. To determine the frequency of monoamine oxidase A (MAOA) overexpression in CRPC tumors that are progressing on docetaxel. VII. To compare the level of MAOA expression in primary diagnostic tissue (e.g. biopsy or radical prostatectomy) with CRPC tumors that are progressing on docetaxel. VIII. To correlate MAOA overexpression in CRPC tumors with response to combination study treatment. IX. To collect blood and tissue specimens for future molecular correlative studies. X. To validate MAOA assessment in circulating tumor cells. XI. To assess correlation with tissue expression of MAOA. XII. To measure hypoxia-inducible factor (HIF)-1alpha expression and other potential biomarkers in circulating tumor cells as a potential measure of MAO activity. TERTIARY OUTCOMES: I. To measure expression of lysine-specific histone demethylase 1 (LSD1) in CRPC tumors that are progressing on docetaxel and correlate with the endpoints described in the primary objective and secondary objectives I, II, III, and V. II. To conduct gene expression studies in CRPC tumors that are progressing on docetaxel and correlate them with and correlate with the endpoints described in the primary objective and secondary objectives I, II, III and V. OUTLINE: This is a dose-escalation study of phenelzine sulfate. Patients receive phenelzine sulfate orally (PO) once daily (QD) on days -7 to -4, and then twice daily (BID) on days -3 to 21. Patients receive docetaxel intravenously (IV) over 60 minutes on day 1. Treatment repeats every 21 days for at least 12 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

Official Title
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A Phase II Study of MAOA Inhibitor Plus Docetaxel in Patients Receiving and Progressing on Docetaxel Therapy

Conditions
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Hormone-Resistant Prostate Cancer, Metastatic Prostatic Adenocarcinoma, Prostate Adenocarcinoma, Recurrent Prostate Carcinoma

Intervention / Treatment
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* Procedure: Biopsy of Prostate
* Drug: Docetaxel
* Other: Laboratory Biomarker Analysis
* Drug: Phenelzine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of adenocarcinoma of the prostate Radiographic evidence of regional or distant metastases with suspected tumor in an area that is safe to biopsy Willingness to undergo tumor biopsy Evidence of CRPC indicated by history of progression despite standard hormonal therapy (by PSA and/or imaging studies) Planned or recent initiation of standard docetaxel therapy; patients may be enrolled after receiving standard docetaxel therapy as long as the patient has not demonstrated evidence of progression for more than 45 days before enrollment (late enrollers) For patients who have been on anti-androgen therapy and had evidence of response to the addition of an anti-androgen (i.e., PSA reduction), patients must have discontinued anti-androgen therapy for at least six weeks (4 weeks for flutamide) without current evidence of an anti-androgen withdrawal response Serum testosterone levels < 50 ng/dL (unless surgically castrate); patients must continue androgen deprivation with an luteinizing hormone releasing hormone (LHRH) agonist if they have not undergone orchiectomy Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Has recovered from all therapy-related toxicity to =< grade 2 (except alopecia, anemia and any signs or symptoms of androgen deprivation therapy) Absolute neutrophil count >= 1500/uL Platelets >= 100,000 Creatinine =< 1.5 times upper limit of normal (ULN) Bilirubin =< 1.5 times ULN (if total bilirubin elevated, but direct is within normal limits [WNL], patient is eligible) Alanine aminotransferase (ALT) =< 2.5 times ULN PSA > 2 ng/mL (at the time of enrollment or prior to initiation of docetaxel) Life expectancy > 3 months Signed informed consent Exclusion Criteria: Significant peripheral neuropathy defined as grade 2 or higher A second active malignancy except adequately treated non-melanoma skin cancer or other non-invasive or in situ neoplasm Significant active concurrent medical illness or infection precluding protocol treatment or survival Current uncontrolled hyperthyroidism Pheochromocytoma Carcinoid Syndrome Known or suspected brain metastases Treatment with radiotherapy within the past 4 weeks or radiopharmaceutical therapy (strontium, samarium) within the past 8 weeks Concurrent therapy with a Selective Serotonin Reuptake Inhibitor (SSRI), tricyclic antidepressant, or Monoamine Oxidase Inhibitor (MAOi); clinical judgment should be used in a decision to discontinue antidepressants; a minimum of a 1 week washout period is required for any tricyclic or related antidepressant, or any SSRI (2 weeks for paroxetine or sertraline, 5 weeks for fluoxetine); minimum 2 week washout for any MAOi Concurrent therapy with any excluded medications that cannot be safely discontinued prior to initiation of combination therapy; discontinuation prior to enrollment is not required, but discontinuation prior to combination therapy must be possible Caution should be exercised in patients who are regularly taking narcotic analgesics, particularly higher doses; the doses of narcotic analgesics may need to be reduced, patients may need to be monitored closely for drug interactions, and the risks and benefits of participation in the study should be considered; clinical judgment should be exercised to manage this potential drug interaction

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (antiangiogenesis, chemosensitizer, chemotherapy)<br>Patients receive phenelzine sulfate PO QD on days -7 to -4, and then BID on days -3 to 21. Patients receive docetaxel IV over 60 minutes on day 1. Treatment repeats every 21 days for at least 12 weeks in the absence of disease progression or unacceptable toxicity. | Procedure: Biopsy of Prostate<br>* Undergo transrectal ultrasound (TRUS) guided prostate biopsy OR image-guided (CT or ultrasound) core bone or soft tissue biopsy<br>* Other names: Prostatic Biopsy;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Phenelzine Sulfate<br>* Given PO<br>* Other names: Nardil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Experience a PSA (Prostate-Specific Antigen) Decline of at Least 30% | PSA response: A ≥ 30% reduction from baseline within 12 weeks of initiation of therapy (confirmed on a second measurement at least 3 weeks later). | Within 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression Free Survival After Initiation of Combination Phenelzine and Docetaxel Therapy | Progression free survival is calculated as the time from Day 1 of Combination therapy to first evidence of progression (by PSA, Measureable Disease, or Clinical Progression). For subjects who did not meet progression criteria, date of new therapy or date of death was used. Outcome is reported as mean. | Up to 6 years | 
| Frequency of MAOA (Monoamine Oxidase A) Overexpression in CRPC (Castration-Resistant Prostate Cancer) Tumors That Are Progressing on Docetaxel | Reported as Number of participants with MAOA expression greater than 5%. | Baseline | 
| HIF-1alpha Expression in CTC (Circulating Tumor Cells) as a Potential Measure of MAO Activity |  | Up to 6 years | 
| MAOA Expression in CTC (Circulating Tumor Cells) and Comparison to Biopsy MAOA Expression | A Pearson's correlation will be used to correlate tumor biopsy MAOA expression and circulating tumor cells MAOA expression. | Up to 6 years | 
| Maximum Change in PSA | Measured from Day 1 of Combination therapy to PSA at 12 Weeks on therapy (or earlier if subject not on therapy for 12 weeks). | 12 weeks (or earlier in patients who discontinued early) | 
| Response Rate in Measurable Disease by RECIST (Response Evaluation Criteria In Solid Tumors) Criteria | Response in measurable disease is defined as a 30% decrease in the sum of diameters of target lesions (as described by RECIST 1.1). | Up to 6 years | 
| Time to Death From All Causes | Time to death is calculated from Day 1 of Combination therapy to death from any cause. | Up to 6 years | 
| Toxicity of the Regimen | Number of participants who experienced an Adverse Event. Detail of Adverse Events is reported in the Adverse Event Section | Up to 6 years |