A Phase I/II Study of Azacitidine (Vidaza), Docetaxel and Prednisone for Patients With Hormone Refractory Metastatic Prostate Cancer Previously Treated With a Taxotere Containing Regimen.
- The objective of the phase I component of study is to determine a safe and potentially
efficacious dose of azacitidine that can be used in combination with docetaxel and
prednisone for the treatment of docetaxel resistant metastatic prostate cancer.
- The objectives of the phase II component of study are:
- To determine the therapeutic efficacy of combined therapy of azacitidine,
docetaxel and prednisone in the treatment of docetaxel resistant metastatic
prostate cancer. The primary endpoint is response, defined as PSA response, or CR
or PR, by RECIST criteria. Secondary endpoints are toxicity, duration of response,
progression-free survival, and overall survival.
- To determine the association between methylation (in serum DNA as well as in tumor
tissue DNA) or expression (in tumor tissue) of GADD45α and clinical response.
- To assess pain response among patients presenting with pain at baseline (criteria
defined in section 9.8).
- To estimate time to pain progression among all patients.
- Hypothesis: Azacitidine can reverse clinical resistance to docetaxel through
upregulation of GADD45 alpha (GADD45α) gene expression.
- Study design: A phase I/II clinical trial in patients with hormone refractory
metastatic prostate cancer.
- Primary objective phase I component of study: To determine a safe and potentially
efficacious phase II dose of azacitidine in combination with docetaxel and prednisone
that can be used for the treatment of hormone refractory metastatic prostate cancer.
- Primary objective phase II component of study: To determine the therapeutic efficacy of
combined therapy of azacitidine, docetaxel, and prednisone, in the treatment of hormone
refractory metastatic prostate cancer. The primary measure of therapeutic efficacy is
response, defined as PSA response, CR, or PR.
- Sample size: Between 36 to 42 total patients. 12 to 18 patients will be required for
the phase I component of study and the phase II dose will be evaluated in 30 patients
as the phase II component of study. This includes the 6 phase I patients treated at the
recommended phase II dose.
- Treatment plan: Treatment-cycle consists of 3 weeks, with assigned dose of azacitidine
administered on days 1 to 5, assigned dose of docetaxel on day 6, and fixed dose of
prednisone at 5mg bid on days 1 to 21. At the discretion of the Principal Investigator,
patients will be given subsequent cycles of treatment, provided patient tolerates
treatment and there is evidence of clinical benefit.
- Phase I component of study: During the phase I component of study, the doses of
azacitidine and docetaxel will be escalated/de-escalated according to the standard
design, in order to establish a phase II dose of the combined treatment. The starting
dose level is azacitidine 75 mg/m2 and docetaxel 60 mg/m2. Dose levels -2 and -1 may
be tested as a result of dose de-escalation based on first cycle dose-limiting toxicity
(DLT), or within-patient dose reduction due to toxicity in any cycle. Within-patient
dose escalation is allowed at discretion of the Principal Investigator.
- Phase II component of study: During the phase II component of study, azacitidine and
docetaxel will be fixed at the phase II dose determined in the dose finding phase.
Patients will also receive fixed dose of prednisone, and will be treated according to
the same schedule.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I - Maximum tolerated dose (MTD) of azacitidine and docetaxel combination.
It might not be reached given that only 4-6 dose levels will be tested.
Rakesh Singal, MD
University of Miami Sylvester Comprehensive Cancer Center
United States: Food and Drug Administration
|University of Miami Sylvester Comprehensive Cancer Center||Miami, Florida 33136|