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

Information source: University of Miami
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Prostate Cancer; Pain

Intervention: Azacitidine (Drug); Docetaxel (Drug); Prednisone (Drug); Azacitidine induced demethylation of repetitive elements. (Genetic); GADD45α methylation and expression in prostate cancer tissue (Genetic); GADD45α methylation in serum DNA (Genetic)

Phase: Phase 1/Phase 2

Status: Active, not recruiting

Sponsored by: University of Miami

Official(s) and/or principal investigator(s):
Rakesh Singal, MD, Principal Investigator, Affiliation: University of Miami Sylvester Comprehensive Cancer Center

Summary

RATIONALE: Drugs used in chemotherapy, such as azacitidine and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving azacitidine and docetaxel together with prednisone may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of azacitidine and docetaxel when given together with prednisone and to see how well they work in treating patients with metastatic prostate cancer that did not respond to hormone therapy.

Clinical Details

Official title: 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.

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

Primary outcome:

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

Phase II - Response, defined as PSA response or complete or partial response, by RECIST criteria

Secondary outcome:

Phase I - Toxicity

Phase II - Duration of response

Progression-free survival (Phase II)

Overall survival (Phase II)

Detailed description: 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Male.

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.

Locations and Contacts

University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 33136, United States
Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: May 2007
Last updated: July 29, 2014

Page last updated: August 23, 2015

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