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

• ClinicalTrials.gov Identifier: NCT01450683
• Recruitment Status: Terminated
• First Posted: October 12, 2011
• Results First Posted: September 8, 2014
• Last Update Posted: April 11, 2017
• Sponsor: Stanford University
• Information provided by (Responsible Party): Sandy Srinivas, Stanford University

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Prostate Cancer; Prostatic Neoplasms; Castrate-resistant Prostate Cancer (CRPC); Androgen-insensitive Prostate Cancer; Hormone-refractory Prostate Cancer; Metastatic Disease	Drug: Itraconazole	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Itraconazole in Castrate-resistant Prostate Cancer Post-chemotherapy
• Study Start Date: September 2010
• Actual Primary Completion Date: April 2011
• Actual Study Completion Date: April 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Itraconazole; 600 mg/day oral (PO)	Drug: Itraconazole; 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; Other Names: Sporanox; R51211

Outcome Measures

Primary Outcome Measures :

1. Reduction in Serum PSA [ Time Frame: 12 weeks treatment, with primary outcome assessed at 15 weeks ]
   Number of subjects with > 50% drop in serum PSA as compared to baseline, at 12 weeks and confirmed at 15 weeks

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Stanford University

Investigators

• Principal Investigator: Dr. Sandy Srinivas; Stanford University

More Information

• Responsible Party: Sandy Srinivas, Associate Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT01450683
• Other Study ID Numbers: IRB-19413; SU-12032010-7271 ( Other Identifier: Stanford University ); PROS0037 ( Other Identifier: OnCore )
• First Posted: October 12, 2011
• Results First Posted: September 8, 2014
• Last Update Posted: April 11, 2017
• Last Verified: March 2017

Additional relevant MeSH terms:

Prostatic Neoplasms; Neoplasm Metastasis; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Neoplastic Processes; Pathologic Processes; Itraconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors