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

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

Detailed Description
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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.

Official Title
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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.

Conditions
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Prostate Cancer, Pain

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Docetaxel
* Drug: Prednisone
* Genetic: GADD45α methylation and expression analysis
* Drug: Pegfilgrastim
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Aza + Doc<br>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<br>* Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.<br>* Other names: Vidaza®;Drug: Docetaxel<br>* Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.<br>* Other names: Taxotere®;Drug: Prednisone<br>* Patient will receive prednisone 5mg twice a day from Day 1 to 21 of each cycle.<br>Genetic: GADD45α methylation and expression analysis<br>* 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.<br>Drug: Pegfilgrastim<br>* Growth factor support.Granulocyte-colony stimulating factor (G-CSF)<br>* Other names: Neulasta;Drug: Filgrastim<br>* Growth factor support. Granulocyte-colony stimulating factor (G-CSF)<br>* Other names: Neupogen;|
| Experimental: Phase 2 - Aza + Doc RPTD<br>Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel; and Prednisone; with optional growth factor support (pegfilgrastim/filgrastim). | Drug: Azacitidine<br>* Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.<br>* Other names: Vidaza®;Drug: Docetaxel<br>* Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.<br>* Other names: Taxotere®;Drug: Prednisone<br>* Patient will receive prednisone 5mg twice a day from Day 1 to 21 of each cycle.<br>Drug: Pegfilgrastim<br>* Growth factor support.Granulocyte-colony stimulating factor (G-CSF)<br>* Other names: Neulasta;Drug: Filgrastim<br>* Growth factor support. Granulocyte-colony stimulating factor (G-CSF)<br>* Other names: Neupogen;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenocarcinoma of the prostate, Recurrent prostate cancer, Stage IV prostate cancer, Pain