Itraconazole in Treating Patients With Biochemically Relapsed Prostate Cancer

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 and over125513
NCI-2013-02375, CC#125513, NCT01787331

Trial Description

Summary

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.

Further Study Information

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

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

TERTIARY OBJECTIVES:

I. To determine the mean percent change from baseline in serum androgen levels, including serum testosterone, dehydroepiandrosterone-sulfate (DHEA-S), and androstenedione, after 4 and 12 weeks of protocol therapy with itraconazole.

II. To determine the mean percent change from baseline in additional serum hormone levels, including adrenocorticotropic hormone (ACTH), aldosterone, deoxycorticosterone (DOC), 11-deoxycortisol, and cortisol after 4 and 12 weeks of protocol therapy with itraconazole.

III. To determine if there is a relationship between baseline and/or percent change in serum hormone levels and achieving a decline of >= 50% in serum PSA after 12 weeks of protocol therapy.

IV. To determine the proportion of patients treated with itraconazole who display a down-regulation of the Hedgehog pathway, as assessed by measurement of GLI family zinc finger 1 (GLI1) messenger ribonucleic acid (mRNA) expression by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on serial skin biopsies obtained at baseline and after 4 weeks of protocol therapy.

V. To determine if there is a relationship between down-regulation of the Hedgehog pathway and PSA modulation, including proportion of patients achieving a decline of >= 50% in serum PSA as well as time to PSA progression.

VI. To evaluate archived primary prostate cancer tissue (biopsy or prostatectomy specimen) for baseline Hedgehog pathway status, using both qRT-PCR-based mRNA expression analysis and protein-based immunohistochemical (IHC) analysis of key Hedgehog (Hh) pathway components (GLI1, patched 1 [PCTH1], smoothened [SMO]) and Sonic hedgehog ligand.

VII. To determine if there is a relationship between mRNA and ICH expression of components in the Hedgehog pathway in primary prostate cancer tissue and PSA modulation on itraconazole therapy, including the proportion of patients achieving a decline of >= 50% in serum PSA as well as time to PSA progression.

OUTLINE:

Patients receive itraconazole PO BID in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Eligibility Criteria

Inclusion Criteria:

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

Histologic confirmation of adenocarcinoma of the prostate

Biochemically relapsed disease with a rising PSA on at least two consecutive 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

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

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

Ability to swallow study drug whole as a capsule

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

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

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

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

Exclusion Criteria:

Prior bilateral orchiectomy

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

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

UCSF Medical Center-Mount Zion

  • National Cancer Institute
Rahul Raj Aggarwal, Principal Investigator

Trial Sites

U.S.A.

California
San Francisco

UCSF Medical Center-Mount Zion

Rahul Raj Aggarwal
Ph: 877-827-3222
Email: rahul.aggarwal@ucsf.edu

Rahul Raj Aggarwal
Principal Investigator

Maryland
Baltimore

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Emmanuel S. Antonarakis
Ph: 443-287-0553
Email: eantona1@jhmi.edu

Emmanuel S. Antonarakis
Principal Investigator

Massachusetts
Boston

Dana-Farber Cancer Institute

Christopher John Sweeney
Ph: 617-632-4524
Email: Christopher_Sweeney@DFCI.HARVARD.EDU

Christopher John Sweeney
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01787331

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.