Temsirolimus to Reverse Androgen Insensitivity for Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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This study evaluates if temsirolimus 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. New therapies that extend survival of patients beyond that provided by chemotherapy are needed. The mechanisms of tumor progression to castration-resistance are unclear, but preclinical studies suggest that functional loss of the tumor suppressor gene PTEN and subsequent up-regulation of Akt, which is upstream of mTOR, may be involved in prostate cancer progression and metastasis. Based on these observations, it is hypothesized that mTOR inhibitor temsirolimus may prolong hormone sensitivity and delay disease progression in castration-resistant prostate cancer patients before antiandrogen withdrawal. 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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Temsirolimus, an mTOR Inhibitor, to Reverse Androgen Insensitivity in Patients With Castration-resistant Prostate Cancer

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: Temsirolimus
* Drug: Casodex (bicalutamide)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Histologically-confirmed adenocarcinoma of the prostate, characterized as symptomatic castration-resistant prostate cancer (CRPC) Serum PSA ≥ 2 ng/mL Rising PSA on 3 consecutive occasions at least 1 week apart (not limited to the 30-day screening period) Failure of bilateral orchiectomy and/or therapy with an LHRH agonist and bicalutamide Castrate level of testosterone (< 50 ng/dL) Currently being treated with bicalutamide No prior antiandrogen therapy except bicalutamide Age ≥ 18 years Life expectancy > 6 months Performance status Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 OR Karnofsky performance status ≥ 80% Ability to understand and the willingness to sign a written informed consent EXCLUSION CRITERIA Radiotherapy for prostate cancer within 28 days prior to Day 1, except single-fraction radiotherapy for pain control Prior treatment with mTOR inhibitors Prior treatment with chemotherapy for prostate cancer Symptomatic bone metastases (ie, asymptomatic bone metastases are eligible) Visceral metastases Absolute neutrophil count (ANC) < 1500/uL Platelet count ≤ 100 x 10e9/L Total bilirubin ≥ 1.5 x Upper Limit of Normal (ULN) Alkaline phosphatase > 2.5 x ULN AST > 2.5 x ULN ALT > 2. 5x ULN Serum creatinine > 2.0 mg/dL Hemoglobin < 9 g/dL Men with reproductive potential who do not agree to use an accepted and effective method of contraception during the study treatment period and for at least 3 months after completion of the study treatment History of other malignancies within 5 years except for tumors with a negligible risk for metastasis or death, such as adequately-controlled basal cell carcinoma, squamous-cell carcinoma of the skin, or early-stage bladder cancer Participation in another experimental drug study either planned or within 4 weeks of the first study treatment Persistent Grade ≥ 1 AEs due to prior drug therapy, including investigational drugs, administered more than 14 days before study enrollment Previously treated or other known brain metastases Ongoing or active infection Symptomatic congestive heart failure, New York Heart Association Grade II or greater Unstable angina pectoris Cardiac arrhythmia Significant vascular disease (eg, aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Psychiatric illness/social situations that would limit compliance with study requirements Other uncontrolled intercurrent illness Known to be positive for the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapies (HIV positive not requiring antiretroviral therapy iseligible if all other entry criteria are meet) Inability to comply with study and/or follow-up procedures

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: Temsirolimus + Bicalutamide<br>Temsirolimus 25 mg administered intravenously (IV) once weekly for 12 weeks Casodex (bicalutamide) administered 50 mg/day orally (PO) | Drug: Temsirolimus<br>* Temsirolimus is an inhibitor of the mammalian target of rapamycin (MTOR, aka HGNC:3942) IUPAC name: (1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate<br>* Other names: CCI-779;Drug: Casodex (bicalutamide)<br>* Casodex (bicalutamide) 50 mg/day PO<br>* Other names: Kalumid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Serum PSA | Proportion of subjects with > 50% drop in serum PSA as compared to baseline, assessed at 16 weeks | 12 weeks treatment, with primary outcome assessed at 16 weeks |