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

Phase 2

Terminated

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

Interventions: Procedure: Biopsy of Prostate
Drug: Docetaxel
Other: Laboratory Biomarker Analysis
Drug: Phenelzine Sulfate

Registration Number: NCT01253642

Lead Sponsor: OHSU Knight Cancer Institute

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 11

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (antiangiogenesis, chemosensitizer, chemotherapy)	Biopsy of Prostate	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.
Treatment (antiangiogenesis, chemosensitizer, chemotherapy)	Laboratory Biomarker Analysis	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.
Treatment (antiangiogenesis, chemosensitizer, chemotherapy)	Phenelzine Sulfate	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.
Treatment (antiangiogenesis, chemosensitizer, chemotherapy)	Docetaxel	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (3): Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States
OHSU Knight Cancer Institute
🇺🇸
Portland, Oregon, United States
Fred Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States