A Phase I/II Study of Azacitidine, Docetaxel, and Prednisone for Metastatic Prostate Cancer Patients

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 prostate-specific antigen (PSA)
response, complete response (CR), or partial response (PR).

Secondary endpoints are toxicity, duration of response, progression-free survival, and
overall survival.

INCLUSION CRITERIA:

- Patient who had histologically confirmed adenocarcinoma of the prostate.

- Patient must have radiologically documented metastatic disease.

- Patients should have received at least 12 weeks of docetaxel chemotherapy or a
cumulative docetaxel dose of 300 mg/m2 and have disease progression on
docetaxel-based therapy. Patients must have progressed after prior hormonal therapy
(e.g. medical or surgical castration) as defined by a castrate level of testosterone
(less than 50 ng/mL). If patient underwent medical castration, it must be continued
during the study.

- Progressive disease may be documented by:

- Non-measurable disease:

- Serum PSA progression defined as a rise in at least 2 consecutive serum PSA
values, each obtained at least 1 week apart and an absolute value greater
than 2.0 ng/ml or,

- Appearance of two or more new lesions on bone scan.

- Patients with treated epidural lesions and no other epidural progression
will be eligible.

- Measurable disease

- Documented progression of disease by Response Evaluation Criteria In Solid
Tumors (RECIST) criteria demonstrating at least one visceral or soft tissue
metastatic lesion (including new lesion).

- Nodal or visceral progression will be sufficient for trial entry
independent of PSA

- Only lymph nodes ≥ 2 cm in diameter will be used to assess for a change in
size.

- Previously irradiated lesions, primary prostatic lesion, and bone lesions
will be considered non-measurable disease.

- Patient is 18 years or older.

- Patient had a Karnofsky Performance Status (KPS) of at least 70% or Eastern
Cooperative Oncology Group (ECOG) Performance Status score of 0-2.

- Life expectancy of > 6 months.

- Patient with adequate organ function as defined as

- Absolute Neutrophils Count greater than 1500 cells/mm3

- Platelets greater than 100,000 cells/mm3

- Hemoglobin greater than 8 g/dL,

- Adequate liver function as documented by:

- Total Bilirubin laboratory (ULN). Higher levels are acceptable if these can be attributed
to active hemolysis or ineffective erythropoiesis.

- AST and ALT the two values (AST or ALT) should be used.)

- Serum creatinine
- Male patient must be willing to use an acceptable barrier method for contraception;
and must agree not to father a child whilst receiving treatment with Azacitidine and
up to six months after last dose.

- Patients may have a history of prior malignancy (≥ 5 years prior) provided that the
patient is currently disease free and off all therapy for that malignancy. Patients
with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if
they have undergone complete resection.

- Patients must be informed of the investigational nature of the treatment and must
give signed written and informed consent.

EXCLUSION CRITERIA:

- Patients who have received strontium 89 (metastron®), Samarium 153 (quadramet®)
radiation therapy within 8 weeks of enrollment.

- Evidence of significant active infection during screening for eligibility.

- Patients who have had a psychiatric illness that could potentially interfere with
completion of treatment according to protocol.

- Patients who had chemotherapy or radiotherapy within 4 weeks prior to entering the
study or those who have not recovered from adverse events due to agents administered
more than 4 weeks earlier. There is no wash-out period for patients who received
Zytiga.

- Patient who had brain metastases.

- Patient who had history of allergic reactions attributed to compound or similar
chemical or biological composition to azacitidine (Vidaza®) or docetaxel or other
drugs formulated with polysorbate 80 or mannitol.

- Patient had major surgical procedure within 28 days before Day 1 of treatment.

- Hepatic malignancy.