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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.


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Male
Prostate Cancer, Pain

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Trial Information

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.


OBJECTIVES:

- 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.

OUTLINE:

- 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.

Inclusion Criteria


INCLUSION CRITERIA:

- Patient who had histologically confirmed adenocarcinoma of the prostate.

- Patient must have radiologically documented metastatic disease.

- Patients must have either relapsed or are refractory to prior docetaxel treatment.
Subjects must have received at least 6 weeks of docetaxel and have disease
progression during or within 6 months after cessation of 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/or,

- Appearance of new lesions on bone scan.

- Measurable disease

- Documented progression of disease by RECIST criteria demonstrating at least one
visceral or soft tissue metastatic lesion (including new lesion). 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 > 2 months.

- Patient with adequate organ function as defined as

- Absolute Neutrophils Count (ANC) greater than 1500 cells/mm3

- Platelets greater than 100,000 cells/mm3

- Hemoglobin greater than 10g/dL, hematocrit greater than 33mg/dL

- Adequate liver function as documented by:

- Total Bilirubin <= ULN

- AST and ALT and Alkaline Phosphatase must be within the range allowing for
eligibility.

- Serum creatinine less than 1.5mg/dL

- Male patient must be willing to use an acceptance barrier method for contraception.

- Patients may have a history of prior malignancy (5 years ago) provided that the
patient is currently disease free and off all therapy for that malignancy.

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

EXCLUSION CRITERIA:

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

- Evidence of significant active infection during screen eligibility.

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

- Patient 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.

- 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I - Maximum tolerated dose (MTD) of azacitidine and docetaxel combination.

Outcome Time Frame:

It might not be reached given that only 4-6 dose levels will be tested.

Safety Issue:

Yes

Principal Investigator

Rakesh Singal, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of Miami Sylvester Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

EPROST-20061143

NCT ID:

NCT00503984

Start Date:

May 2007

Completion Date:

Related Keywords:

  • Prostate Cancer
  • Pain
  • Adenocarcinoma of the prostate
  • Recurrent prostate cancer
  • Stage IV prostate cancer
  • Pain
  • Prostatic Neoplasms

Name

Location

University of Miami Sylvester Comprehensive Cancer CenterMiami, Florida  33136