A Pilot Study of Parenteral Testosterone and Oral Etoposide as Therapy for Men With Castration Resistant Prostate Cancer
| Status: | Recruiting |
|---|---|
| Conditions: | Prostate Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 5/27/2013 |
| Start Date: | March 2010 |
| Contact: | Avery Spitz, RN |
| Email: | aspitz2@jhmi.edu |
| Phone: | 410-502-2043 |
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.
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.
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
We found this trial at
1
site
Baltimore, Maryland 21205
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