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

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.

Azacitidine can reverse clinical resistance to docetaxel through upregulation of Growth Arrest and DNA Damage inducible alpha (GADD45α) and other epigenetically regulated genes.

Study Overview

• Status: Terminated
• Conditions: Pain; Prostate Cancer
• Intervention / Treatment: Drug: Azacitidine; Drug: Docetaxel; Drug: Prednisone; Genetic: GADD45α methylation and expression analysis; Drug: Pegfilgrastim; Drug: Filgrastim

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 </= 1.5 times the upper limit of the normal range for the laboratory (ULN). Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis.
    • AST and ALT </= 2.5 ULN. (In determining eligibility the more abnormal of the two values (AST or ALT) should be used.)
  • Serum creatinine </= 2.0 mg/dl or </= 1.5 x institutional upper limit of normal.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 - Aza + Doc; Phase 1 Azacitidine (Aza) and Docetaxel (Doc) with dose escalation/de-escalation design, and Prednisone, with growth factor support; GADD45α methylation and expression analysis, with optional growth factor support (pegfilgrastim/filgrastim).	Drug: Azacitidine; Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.; Other Names: Vidaza®; Drug: Docetaxel; Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.; Other Names: Taxotere®; Drug: Prednisone; Patient will receive prednisone 5mg twice a day from Day 1 to 21 of each cycle.; Genetic: GADD45α methylation and expression analysis; 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. Patients with accessible prostate tissue or metastases will undergo biopsy prior to treatment if they consent to do so.; Drug: Pegfilgrastim; Growth factor support.Granulocyte-colony stimulating factor (G-CSF); Other Names: Neulasta; Drug: Filgrastim; Growth factor support. Granulocyte-colony stimulating factor (G-CSF); Other Names: Neupogen
Experimental: Phase 2 - Aza + Doc RPTD; Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel; and Prednisone; with optional growth factor support (pegfilgrastim/filgrastim).	Drug: Azacitidine; Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.; Other Names: Vidaza®; Drug: Docetaxel; Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.; Other Names: Taxotere®; Drug: Prednisone; Patient will receive prednisone 5mg twice a day from Day 1 to 21 of each cycle.; Drug: Pegfilgrastim; Growth factor support.Granulocyte-colony stimulating factor (G-CSF); Other Names: Neulasta; Drug: Filgrastim; Growth factor support. Granulocyte-colony stimulating factor (G-CSF); Other Names: Neupogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Azacitidine and Docetaxel)	Determination of 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.	Up to 1.5 years
Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Prednisone)	Determination of 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.	Up to 1.5 years
Number of Participants Achieving Prostate-specific Antigen (PSA) Response.	Number of participants achieving prostate-specific antigen (PSA) response according to Prostate Cancer Working Group 1 (PCWG1) criteria. PSA response according to PCWG1 is defined as an least 50 percent decline in PSA level from baseline that was maintained for at least three weeks.	Up to 4.5 years.
Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy.	Number of participants achieving Complete Response (CR) or Partial Response to protocol therapy according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 Criteria. Per RECIST 1.0 for target lesions and assessed by MRI: "Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; "	Up to 4.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	Length of time from the date of first observation of complete response (CR) or partial response (PR) to the date of first observation of disease progression, according to prostate-specific antigen (PSA) response according to Prostate Cancer Working Group 1 (PCWG1) criteria. PSA response according to PCWG1 is defined as an least 50 percent decline in PSA level from baseline that was maintained for at least three weeks.	Up to 4.5 years.
Progression-Free Survival (PFS)	The time from the date of start of treatment until the first documented or confirmed disease progression, or death related to prostate cancer, whichever is earlier.	Up to 4.5 years
Overall Survival (OS)	The time from the date of initiation of study treatment until date of death from any cause.	Up to 4.5 years.
Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy.		Up to 4.5 years

Collaborators and Investigators

• Sponsor: University of Miami
• Investigators: Principal Investigator: Rakesh Singal, MD, University of Miami Sylvester Comprehensive Cancer Center

Publications and helpful links

General Publications

• Singal R, Ramachandran K, Gordian E, Quintero C, Zhao W, Reis IM. Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Clin Genitourin Cancer. 2015 Feb;13(1):22-31. doi: 10.1016/j.clgc.2014.07.008. Epub 2014 Aug 1.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: July 17, 2007
• First Submitted That Met QC Criteria: July 17, 2007
• First Posted (Estimate): July 19, 2007

Study Record Updates

• Last Update Posted (Estimate): June 9, 2016
• Last Update Submitted That Met QC Criteria: May 3, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Pain; Adenocarcinoma of the prostate; Recurrent prostate cancer; Stage IV prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Docetaxel; Prednisone; Azacitidine
• Other Study ID Numbers: 20061143; SCCC-2006080 (Other Identifier: University of Miami Sylvester Comprehensive Cancer Center); WIRB-20070344 (Other Identifier: Western Institutional Review Board); 20140376 (Other Identifier: University of Miami)