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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Rakesh Singal, University of Miami
ClinicalTrials.gov Identifier:
NCT00503984
First received: July 17, 2007
Last updated: July 29, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Prostate Cancer
Pain
Drug: Azacitidine
Drug: Docetaxel
Drug: Prednisone
Genetic: Azacitidine induced demethylation of repetitive elements.
Genetic: GADD45α methylation and expression in prostate cancer tissue
Genetic: GADD45α methylation in serum DNA
Phase 1
Phase 2

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

Resource links provided by NLM:


Further study details as provided by University of Miami:

Primary Outcome Measures:
  • Phase I - Maximum tolerated dose (MTD) of azacitidine and docetaxel combination. [ Time Frame: It might not be reached given that only 4-6 dose levels will be tested. ] [ Designated as safety issue: Yes ]
  • Phase II - Response, defined as PSA response or complete or partial response, by RECIST criteria [ Time Frame: All patients will be under follow up for a minimum of 12 months. Expected total study duration is 4 to 4.5 years. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Phase I - Toxicity [ Time Frame: First treatment cycle ] [ Designated as safety issue: Yes ]
  • Phase II - Duration of response [ Time Frame: All patients will be under follow up for a minimum of 12 months.Expected total study duration is 4 to 4.5 years. ] [ Designated as safety issue: No ]
  • Progression-free survival (Phase II) [ Time Frame: All patients will be under follow up for a minimum of 12 months. Expected total study duration is 4 to 4.5 years. ] [ Designated as safety issue: No ]
  • Overall survival (Phase II) [ Time Frame: All patients will be under follow up for a minimum of 12 months. Expected total study duration is 4 to 4.5 years. ] [ Designated as safety issue: No ]

Estimated Enrollment: 42
Study Start Date: May 2007
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1 Drug: Azacitidine
Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.
Other Name: Vidaza®
Drug: Docetaxel
Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.
Other Name: Taxotere®
Drug: Prednisone
Patient will receive prednisone 5mg twice a day from Day 1 to 21 of each cycle.
Experimental: Phase 2 Drug: Azacitidine
Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.
Other Name: Vidaza®
Drug: Docetaxel
Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.
Other Name: Taxotere®
Genetic: Azacitidine induced demethylation of repetitive elements.
In phase II component of study, peripheral blood samples (2 red top and 1 green top tubes i.e. 30 ml) will be taken prior to and after azacitidine administration (i.e. on day 1 prior azacitidine administration, and on day 6 prior to docetaxel administration) of first and second cycles (total of 4 blood samples). Peripheral blood mononuclear cell DNA will be isolated. Bisulfite treatment will be performed and methylation quantitation of repetitive elements will be performed as described [17, 18]. Pre- and post-azacitidine methylation levels will be analyzed to determine the demethylation activity of azacitidine.
Genetic: GADD45α methylation and expression in prostate cancer tissue
Patients with accessible prostate tissue or metastases will undergo biopsy prior to treatment if they consent to do so.
Genetic: GADD45α methylation in serum DNA
Peripheral blood samples from patients will be collected as described in section 8.1 (total of 4 blood samples). DNA will be isolated from serum, bisulfite treated and evaluated for methylation by bisulfite genomic sequencing.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00503984

Locations
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami
Investigators
Principal Investigator: Rakesh Singal, MD University of Miami Sylvester Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Rakesh Singal, Associate Professor, University of Miami
ClinicalTrials.gov Identifier: NCT00503984     History of Changes
Other Study ID Numbers: 20061143, SCCC-2006080, WIRB-20070344
Study First Received: July 17, 2007
Last Updated: July 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami:
Adenocarcinoma of the prostate
Recurrent prostate cancer
Stage IV prostate cancer
Pain

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Docetaxel
Prednisone
Azacitidine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antimetabolites, Antineoplastic
Antimetabolites
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 16, 2014