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 temsirolimus 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. 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.
Interventions
DRUGTemsirolimus
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
DRUGCasodex (bicalutamide)
Casodex (bicalutamide) 50 mg/day PO
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
National Comprehensive Cancer Network
American Society of Clinical Oncology
Sandy Srinivas
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Serum PSA | 12 weeks treatment, with primary outcome assessed at 16 weeks | Proportion of subjects with \> 50% drop in serum PSA as compared to baseline, assessed at 16 weeks |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temsirolimus + Bicalutamide Temsirolimus 25 mg administered intravenously (IV) once weekly for 12 weeks
Casodex (bicalutamide) administered 50 mg/day orally (PO)
Temsirolimus: 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
Casodex (bicalutamide): Casodex (bicalutamide) 50 mg/day PO | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Temsirolimus + Bicalutamide |
|---|---|
| Age, Continuous | 73 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 4 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 |
Outcome results
Primary
Reduction in Serum PSA
Proportion of subjects with \> 50% drop in serum PSA as compared to baseline, assessed at 16 weeks
Time frame: 12 weeks treatment, with primary outcome assessed at 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temsirolimus + Bicalutamide | Reduction in Serum PSA | 0 participants |