Androgen-insensitive Prostate Cancer, Castrate-resistant Prostate Cancer (CRPC), Hormone-refractory Prostate Cancer, Metastatic Disease, Prostate Cancer, Prostatic Neoplasms
Conditions
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).
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.
Interventions
DRUGItraconazole
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
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Serum PSA | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Itraconazole 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 | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Itraconazole |
|---|---|
| Age, Continuous | 78 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
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
Time frame: 12 weeks treatment, with primary outcome assessed at 15 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole | Reduction in Serum PSA | 0 participants |