A Pilot Study of Parenteral Testosterone and Oral Etoposide as Therapy for Men With Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Pilot Study of Parenteral Testosterone and Oral Etoposide as Therapy for Men With Castration Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Testosterone injection
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Performance status ≤2 Documented adenocarcinoma of the prostate with histologic confirmation Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist for ≥ 1 year) Documented castrate level of serum testosterone (<50 ng/dl) Evidence of rising PSA on two successive dates > 1 month apart Treatment with ≤ 2 prior chemotherapeutic regimens allowed Treatment with ≤2 prior second line hormone therapies allowed. Prior treatment with ketoconazole is allowed. Patients must be withdrawn from antiandrogens for ≥ 6 weeks and have documented PSA increase after the 6 week withdrawal period. Patients with rising PSA only or ≤ 5 sites of asymptomatic bone metastases and < 10 total sites of disease including bone and soft tissue documented within 28 days of enrollment on trial. Patients will considered for repeat treatment with testosterone if they meet the following criteria: Had either PSA decline from baseline following treatment with testosterone or had return of PSA levels to pretreatment baseline once serum testosterone reached a castrate level. Must continue to meet inclusion/exclusion criteria as described above Must have been off testosterone therapy for ≥ 3 months Must have castrate level of serum testosterone Must have evidence of rising PSA on two occasions at least 2 weeks apart Are allowed to have had additional treatment with up to 2 additional hormonal therapies that include anti-androgens (e.g. flutamide, bicalutamide, nilutamide, enzalutamide), CYP17 inhibitors (e.g. ketoconazole, abiraterone acetate) or other investigational hormonal therapies. Exclusion Criteria: Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, spinal metastases with concern over spinal cord compression, lymph node disease with concern for ureteral obstruction) Abnormal liver function (bilirubin, AST, ALT ≥ 2 x upper limit of normal) Abnormal kidney function (serum creatinine ≥ 2 x upper limit of normal) Inability to provide informed consent

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: Etoposide and Testosterone<br>Patients will receive an intramuscular gluteal injection with testosterone cypionate at a dose of 400 mg every month for a total of 3 injections (i.e. 3 months of therapy).On the day of testosterone injection (i.e. day 1 of each cycle) patients will begin therapy with oral etoposide at a dose of 100 mg/day given in divided doses (one 50 mg etoposide capsule q 12 h) for 14 consecutive days. | Drug: Testosterone injection<br>* Patients will receive an intramuscular gluteal 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 route and dose of testosterone 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.<br>* Other names: Testosterone Cypionate;Drug: Etoposide<br>* On the day of testosterone injection (i.e. day 1 of each cycle) patients will begin therapy with oral etoposide at a dose of 100 mg/day given in divided doses (one 50 mg etoposide capsule q 12 h) for 14 consecutive days. This dose was selected based on Phase II studies of the combination of oral estramustine and oral etoposide. In these trials, myelosuppression was observed when etoposide was given for 21 days out of a 28 day cycle. Therefore, to minimize toxicity, in this study etoposide will be administered for 14 days of a 28 day cycle.<br>* Other names: Toposar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Completing at Least 3 Months of Therapy With a PSA Below Baseline. |  | 3 months | 
| Time to PSA Progression | Time to a PSA increase above the PSA level obtained after 3 months on testosterone treatment over two successive measurements 2 weeks apart. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With RECIST Response (i.e. Complete Response or Partial Response) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT scan or MRI. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 2 years |