Itraconazole in Treating Patients With Biochemically Relapsed Prostate Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well itraconazole works in treating patients with biochemically relapsed prostate cancer. Itraconazole may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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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.

Official Title
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Hedgehog Inhibition as a Non-Castrating Approach to Hormone Sensitive Prostate Cancer: A Phase II Study of Itraconazole in Biochemical Relapse

Conditions
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Prostate Adenocarcinoma, Recurrent Prostate Carcinoma, Stage I Prostate Adenocarcinoma AJCC v7, Stage II Prostate Adenocarcinoma AJCC v7, Stage III Prostate Adenocarcinoma AJCC v7

Intervention / Treatment
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* Drug: Itraconazole
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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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

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 (itraconazole)<br>Patients receive twice/day 300mg itraconazole (oral) | Drug: Itraconazole<br>* Given PO<br>* Other names: Sporanox;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Achieve a Greater Than or Equal to 50% Decline in Serum Prostate Specific Antigen (PSA) | The number of patients with biochemically relapsed disease after prior definitive local therapy who achieve a ≥ 50% decline from baseline in serum PSA after 12 weeks of therapy with itraconazole, confirmed by repeat measurement at least 2 weeks later. | At 12 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change in PSA Doubling Time | The mean percent change in PSA doubling time from pre-treatment to after 12 weeks of protocol therapy | Up to 12 weeks | 
| Median Time to PSA Progression | PSA progression defined as: 1. If no PSA decline is observed on therapy, PSA progression will be defined as an increase in serum PSA > 50% above the baseline PSA, and an absolute increase of > 2 ng/mL above baseline, confirmed by repeat measurement at least 2 weeks later. 2. If PSA declines on therapy, PSA progression will be defined as an increase in serum PSA > 50% above the nadir PSA on therapy, and an absolute increase > 2 ng/mL above the nadir, confirmed by repeat measurement at least 2 weeks later. The probability distribution of the time to PSA progression will be estimated using the Kaplan-Meier product limit method measured from the start of protocol therapy. The results will be summarized by the estimated median with 95% confidence intervals. | Up to 2 years | 
| Median Time to Clinical Progression | Clinical progression will be defined as the first occurrence of either the development of metastases or initiation of non-protocol therapy, and will exclude PSA-only progression. The probability distribution of the time to clinical progression will be estimated using the Kaplan-Meier product limit method measured from the time of start of protocol therapy. The results will be summarized by the estimated median with 95% confidence intervals. | Up to 2 years | 
| Median Metastasis-free Survival | The probability distribution of the time to first metastasis will be estimated using the Kaplan-Meier product limit method measured from the time of start of protocol therapy. The results will be summarized by the estimated median with 95% confidence intervals. | Up to 2 years | 
| Percentage of Participants With Treatment-related, Adverse Changes in Vital Signs | All patients who receive at least one dose of study drug will be analyzed for safety endpoints. All adverse events will be graded and classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4. Percentage of patients with grade 1 or higher, treatment-related adverse events based on the following vital sign assessments will be reported: blood pressure, pulse, respiration rate and temperature. | Up to 2 years | 
| Percentage of Participants With Treatment-related, Clinical Laboratory Adverse Events | All patients who receive at least one dose of study drug will be analyzed for safety endpoints. All adverse events will be graded and classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.. Percentage of patients with grade 1 or higher, treatment-related adverse events based on the following labs will be reported: potassium, sodium, alkaline phosphatase, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), Hematocrit, Hemoglobin, platelets, white blood cells, atypical lymphs, basophils, eosinophils, monocytes, neutrophils, blood urea nitrogen, and creatinine. | Up to 2 years | 
| Mean Steady-state Trough Level of Serum Itraconazole | Descriptive statistics including the mean, standard deviation, and range of steady-state trough serum levels of itraconazole and its active metabolite hydroxy-itraconazole will be determined. | Up to 4 weeks | 
| Mean Steady-state Trough Level of Hydroxy-itraconazole | Descriptive statistics including the mean, standard deviation, and range of steady-state trough serum levels of itraconazole and its active metabolite hydroxy-itraconazole will be determined. | Up to 4 weeks |