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

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.

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