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

18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

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

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.

Inclusion Criteria:

1. Performance status ≤2

2. Documented adenocarcinoma of the prostate with histologic confirmation

3. Treated with continuous androgen ablative therapy (either surgical castration or LHRH
agonist for ≥ 1 year)

4. Documented castrate level of serum testosterone (<50 ng/dl)

5. Evidence of rising PSA on two successive dates > 1 month apart

6. Treatment with ≤ 2 prior chemotherapeutic regimens allowed

7. Treatment with ≤2 prior second line hormone therapies allowed.

8. Prior treatment with ketoconazole is allowed.

9. Patients must be withdrawn from antiandrogens for ≥ 6 weeks and have documented PSA
increase after the 6 week withdrawal period.

10. 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.

11. Patients will considered for repeat treatment with testosterone if they meet the
following criteria:

1. 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.

2. Must continue to meet inclusion/exclusion criteria as described above

3. Must have been off testosterone therapy for ≥ 3 months

4. Must have castrate level of serum testosterone

5. Must have evidence of rising PSA on two occasions at least 2 weeks apart

6. 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:

1. 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)

2. Abnormal liver function (bilirubin, AST, ALT ≥ 2 x upper limit of normal)

3. Abnormal kidney function (serum creatinine ≥ 2 x upper limit of normal)

4. Inability to provide informed consent

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in PSA levels over the course of therapy Time to PSA progression after 3 months of testosterone and etoposide therapy

Outcome Description:

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

Outcome Time Frame:

2 weeks

Safety Issue:


Principal Investigator

Samuel Denmeade, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center


United States: Institutional Review Board

Study ID:

J09121, NA_00033419



Start Date:

March 2010

Completion Date:

December 2014

Related Keywords:

  • Prostate Cancer
  • Prostatic Neoplasms



Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer CenterBaltimore, Maryland  21205