Itraconazole in Treating Patients With Biochemically Relapsed Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine whether the proportion of patients who achieve a >= 50% decline in serum
prostate-specific antigen (PSA) after 12 weeks of protocol therapy with itraconazole dosed at
300 mg orally (PO) twice daily (BID) is superior to a historical control based upon the
observed PSA response proportion in prior studies of non-castrating systemic therapy in men
with biochemically relapsed hormone sensitive prostate cancer.

SECONDARY OBJECTIVES:

I. To determine the median time to PSA progression from the start of protocol therapy with
itraconazole among men with biochemically relapsed prostate cancer.

II. To determine the median time to clinical progression measured from the start of protocol
therapy with itraconazole among men with biochemically relapsed prostate cancer.

III. To determine the median metastasis-free survival measured from the start of protocol
therapy in patients treated with itraconazole for biochemically relapsed prostate cancer.

IV. To determine the mean percent change from baseline after 12 weeks of protocol therapy
compared with pre-treatment in PSA doubling time.

V. To characterize the safety profile of itraconazole in the biochemically relapsed hormone
sensitive prostate cancer population, as graded by Common Toxicity Criteria (CTCAE) version
4.03. All adverse events will be tabulated by grade according to the worst grade experienced.

VI. To determine the mean steady-state itraconazole and hydroxy-itraconazole serum levels
after 4 weeks of therapy with itraconazole.

Inclusion Criteria:

- Histologic confirmation of adenocarcinoma of the prostate

- Biochemically relapsed disease with a rising PSA on at least two successive
measurements at least two weeks apart after prior definitive local therapy (radical
prostatectomy, external beam radiation, or brachytherapy) or combination of radical
prostatectomy and radiotherapy (RT) with curative intent; if the confirmatory PSA
value is less than the screening PSA value, then an additional test for rising PSA
will be required to documents progression

- Prior primary or salvage radiation or not a candidate for salvage radiation due to
patient preference or clinical assessment based upon disease characteristics and/or
patient co-morbidities

- Minimum PSA:

- If no prior androgen deprivation therapy (ADT) for biochemical relapse:

- 1.0 ng/mL if prior radical prostatectomy with or without adjuvant/salvage
radiation therapy, confirmed by repeat measurement at least 2 weeks later,
or

- Nadir + 2 ng/mL if prior RT alone without prior radical prostatectomy,
confirmed by repeat measurement at least 2 weeks later

- If prior ADT for biochemical relapse:

- 4.0 ng/mL or > 2 ng/mL above nadir on prior cycle of ADT, whichever is
higher, confirmed by repeat measurement at least 2 weeks later

- No evidence of metastatic disease on imaging by whole body bone scan (technetium-99 or
sodium fluoride [Na-F] positron emission tomography [PET] bone scan) and
cross-sectional imaging of the abdomen/pelvis (computed tomography [CT] or magnetic
resonance imaging [MRI]) within 6 weeks of day 1 of protocol therapy

- Prior androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone
(LHRH) agonist and/or antagonist allowed for either (neo)adjuvant treatment with local
therapy or for biochemical relapse

- Last effective dose of LHRH agonist/antagonist ?expired? > 3 months prior to study
entry; for example, a patient receiving LHRH agonist injection every 3 months would be
eligible provided their last injection was > 6 months prior to day 1 of protocol
therapy; a patient receiving LHRH agonist injections every 4 months will be eligible
provided last injection was > 7 months prior to day 1 of protocol therapy

- Serum testosterone level:

- If no prior androgen deprivation therapy:

- A single measurement greater than 150 ng/dL within 3 months of day 1 of
protocol therapy

- If prior androgen deprivation therapy (either in adjuvant or biochemical relapse
setting):

- The two most recent measurements of serum testosterone prior to day 1 of
protocol therapy must fulfill the following criteria:

- Both measurements are greater than 150 ng/dL

- The two measurements are spaced at least 14 days apart

- Both must be measured within 3 months of day 1 of protocol therapy

- There must not be an increase of > 50 ng/dL between these two
successive measurements

- PSA doubling time (PSADT) =< 15 months, calculated based upon all serum PSA
measurements obtained within 3 months prior to day 1 of protocol therapy, with a
minimum of three PSA measurements spaced at least 14 days apart ; PSA values obtained
when serum testosterone was known to be less than 150 ng/dL, prior to local therapy,
or within three months of last dose of LHRH agonist/antagonist or antiandrogen will be
excluded from the calculation of the PSADT

- Total bilirubin less than 1.5 times upper limit of normal (ULN), or less than 3 times
ULN at study entry in a patient with documented Gilbert?s disease

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels less than
1.5 times ULN at study entry

- Serum potassium greater than 3.5 mmol/L without oral supplementation

- No history of uncontrolled hypertension (blood pressure > 160/100 mm Hg despite
anti-hypertensive medication)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Estimated life expectancy greater than 5 years

- Ability to sign written informed consent

- Ability to swallow study drug whole as a capsule

- Primary prostate cancer tissue available for analysis is not required for inclusion
onto this study but is strongly encouraged

- Patients who have partners of childbearing potential must be willing to use a method
of birth control with adequate barrier protection as determined to be acceptable by
the principal investigator and sponsor during the study and for 1 week after last
study drug administration

Exclusion Criteria:

- Castrate-resistant disease, as evidenced by either:

- Rising PSA on 2 consecutive measurements at least 2 weeks apart with concurrent
documented serum testosterone < 50 ng/dL at the time of PSA measurement, or

- Rising PSA on 2 consecutive measurements at least 2 weeks apart measured within 3
months after last LHRH agonist/antagonist injection

- Prior bilateral orchiectomy

- Congestive heart failure of New York Heart Association (NYHA) class III or higher
severity at study entry

- History of chronic active hepatitis

- Grade 2 or higher peripheral neuropathy at the time of study entry

- Use of 5-alpha reductase antagonist (i.e. finasteride, dutasteride) or antiandrogen
(i.e. flutamide, bicalutamide) within 6 weeks of day 1 of protocol therapy

- Use of systemic steroids at an equivalent dose of prednisone 5 mg/day or higher within
6 weeks of day 1 of protocol therapy

- Use of medications or herbal supplements which are known to potentially lower serum
PSA within 6 weeks of day 1 of protocol therapy

- Use of other medications that may potentially interact with itraconazole within 1 week
of study entry

- Use of other investigational agents within 6 weeks of day 1 of protocol therapy

- Prior pathology consistent with small cell carcinoma or prostate cancer with
predominantly neuroendocrine differentiation