Study of Itraconazole in Castrate-resistant Prostate Cancer (CRPC) Post-chemotherapy

Study Overview
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Brief Summary
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This study evaluates if itraconazole causes a reduction in the serum levels of prostate-specific antigen (PSA) in male subjects with castration-resistant prostate cancer (CRPC).

Detailed Description
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Castration-resistant prostate cancer (CRPC) is also known as androgen-insensitive or hormone-refractory prostate cancer. While numerous therapies impact biochemical response in the setting of CRPC, there remains unmet medical need, largely expressed as the lack of durable response. New therapies that extend survival of patients beyond that provided by chemotherapy are needed. It is hypothesized that the triazole antifungal drug itraconazole, through its activity as a potent inhibitor of the Hedgehog (Hh) signaling pathway via the Smoothened (Smo) pathway, may provide clinical benefit in the treatment of prostate cancer. The Hh signaling pathway is a critical embryonic developmental pathway whose aberrant activity has been implicated in the growth and metastases of a variety of tumor types including prostate cancer. Itraconazole is structurally related to ketoconazole, demonstrated to reduce serum PSA by more than 50% in about 20 to 25% of treated prostate cancer subjects. This study will assess efficacy on the basis of serum levels of PSA, an established surrogate endpoint for efficacy in prostate cancer.

Official Title
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A Phase 2 Study of Itraconazole in Castrate-resistant Prostate Cancer Post-chemotherapy

Conditions
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Prostate Cancer, Prostatic Neoplasms, Castrate-resistant Prostate Cancer (CRPC), Androgen-insensitive Prostate Cancer, Hormone-refractory Prostate Cancer, Metastatic Disease

Intervention / Treatment
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* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Male aged ≥ 18 years Life expectancy ≥ 6 months Histologically- or cytologically-confirmed adenocarcinoma of the prostate Metastatic disease or prior history of metastases, as documented by positive bone scan or metastatic lesions on CT or MRI Prostate cancer progression, as documented by PSA according to PCWG2 or radiographic progression according to RECIST criteria version 1.1 Progression must have been during or after docetaxel based chemotherapy. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is currently being treated with LHRH agonists (patient who have not undergone an orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and treatment must be continued throughout the study. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Hemoglobin ≥ 10.0 g/dL Platelet count ≥100,000 microliters Serum creatinine ≤ 2, OR a calculated creatinine clearance ≥ 40 mL/min Serum bilirubin < 1.5 x ULN (except for patients Gilbert's disease) AST or ALT < 2.5 x ULN Able to swallow the study drug whole as a tablet Willing and able to provide written informed consent EXCLUSION CRITERIA Known brain metastasis Radiation therapy within 4 weeks of Cycle 1, Day 1 Prior systemic treatment with an azole drug (eg, fluconazole, ketoconazole) within 4 weeks of Cycle 1, Day 1 Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients whose PSA did not decline for ≥ 3 months months in response to antiandrogen given as a 2nd line or later intervention will require only a 2-week washout prior to Cycle 1,Day 1) Prior Bicalutamide (Casodex), nilutamide (Nilandron) treatment within 6 weeks of Cycle 1 Day 1 (patients whose PSA did not decline for ≥ 3 months in response to antiandrogen given as a 2nd line or later intervention will require only a 2-week washout prior to Cycle 1 Day 1) Known active or symptomatic viral hepatitis or chronic liver disease Clinically significant heart disease as evidenced by myocardial infarction or arterial thrombotic events in the past 6 months; severe or unstable angina Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of recurrence within 24 months Administration of an investigational therapeutic within 30 days of Cycle 1, Day 1 Any condition which, in the opinion of the investigator, would preclude the patient's participation in this trial. No more than 3 prior chemotherapy regimens.

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: Itraconazole<br>600 mg/day oral (PO) | Drug: Itraconazole<br>* 600 mg/day oral (PO) IUPAC name: (2R,4S)-rel-1-(Butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one<br>* Other names: R51211;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Serum PSA | Number of subjects with > 50% drop in serum PSA as compared to baseline, at 12 weeks and confirmed at 15 weeks | 12 weeks treatment, with primary outcome assessed at 15 weeks |