A Pilot Study of Parenteral Testosterone and Oral Etoposide as Therapy for Men With Castration Resistant Prostate Cancer
The objective of the study is to determine if men with evidence of progressive prostate cancer while on chronic androgen ablation of ≥ 1 year duration will exhibit a clinical response following administration of parenteral testosterone and oral etoposide.
Treatment Plan: Eligible patients will continue on androgen ablative therapy with luteinizing hormone-releasing hormone (LHRH) agonist (i.e. Zoladex or Lupron) if not surgically castrated. Patients will receive intramuscular injection with testosterone cypionate at a dose of 400 mg every month for a total of 3 injections (i.e. 3 months of therapy). This dose was selected based on data demonstrating that it produces an initial supraphysiologic serum level of testosterone (i.e. > 3-5 times normal level) with eugonadal levels achieved at the end of two weeks. Beginning the day of the testosterone injection, patients will also receive oral etoposide 100 mg/day in divided doses (50 mg q 12h) x 14 days out of 28 days per cycle. After 3 months on therapy, patients will have repeat prostate specific antigen (PSA) and bone/computed tomography (CT) scans to establish the effect of combined testosterone and etoposide treatment on these parameters (i.e. "testosterone effect baseline"). Patients with sustained elevations in PSA ≥ 50% above pre-testosterone treatment PSA levels after the initial three months of testosterone and etoposide therapy will not receive continued therapy and will come off study. Patients with PSA levels less than the peak serum PSA level seen over the three month period (PSA decline) or patients with PSA ≤ 50% of pretreatment baseline will receive a second 3 month course of monthly testosterone and etoposide therapy until evidence of disease progression. Disease progression is defined as a PSA increase above the PSA level obtained after 3 months on testosterone treatment over two successive measurements 2 weeks apart or evidence of new lesions or progression on bone/CT scans compared to baseline studies. Patients who respond to initial treatment with testosterone and etoposide and then show signs of progression will have the option of retreatment with testosterone alone after a period of 3 months or greater off of the original therapy.
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study of Parenteral Testosterone and Oral Etoposide as Therapy for Men With Castration Resistant Prostate Cancer|
- Change in PSA levels over the course of therapy Time to PSA progression after 3 months of testosterone and etoposide therapy [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]Patients with evidence of PSA and or measurable disease response after 3 months of therapy will continue to receive treatment with monthly injection of testosterone cypionate and 14 day treatments with oral etoposide per 28 day cycle. Patients will undergo response assessment with PSA levels and CT scans every 3 months and bone scans every 6 months
|Study Start Date:||March 2010|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Drug: Testosterone injection
Based on our preclinical data, high levels of androgens can lead to significant growth suppressive effects in prostate cancer cells in vitro and in vivo. Mechanistic data in in vitro models suggests that this growth suppression may be due to the accumulation of androgen induced TOP2B mediated double strand breaks at AR target sites occurring after stimulation of prostate cancer cells with high levels of androgens. Provocatively, the number of double strand breaks was significantly increased (Figure 3 B) if the cells were treated with etoposide, an agent that leads to formation of double strand breaks at TOP2 target sites, concurrently with high-dose androgen stimulation. We hypothesize that co-administration of testosterone with etoposide could produce high levels of double strand breaks in prostate cancer cells, overwhelming DNA repair and survival mechanisms and leading to cancer cell death or growth arrest. To test whether this possibility holds promise for therapy of advanced prostate cancer, we propose the following clinical trial of parenteral testosterone therapy in combination with oral etoposide in men with evidence of progressive prostate cancer during chronic androgen ablation.
|United States, Maryland|
|Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center|
|Baltimore, Maryland, United States, 21205|
|Principal Investigator:||Samuel Denmeade, MD||Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center|
|Study Chair:||Alberto J Pacheco, BA||Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center|
|Study Director:||Ting Wang, MS||Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center|