Pain, Prostate Cancer
Conditions
Keywords
Adenocarcinoma of the prostate, Recurrent prostate cancer, Stage IV prostate cancer, Pain
Brief summary
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
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.
Interventions
DRUGAzacitidine
Intravenous infusion over 30 minutes Days 1 - 5 of each 3 weekly cycle.
DRUGDocetaxel
Intravenous infusion over 1 hour on day 6 of each 3 weekly cycle.
DRUGPrednisone
Patient will receive prednisone 5mg twice a day from Day 1 to 21 of each cycle.
GENETICGADD45α 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.
DRUGPegfilgrastim
Growth factor support.Granulocyte-colony stimulating factor (G-CSF)
DRUGFilgrastim
Growth factor support. Granulocyte-colony stimulating factor (G-CSF)
Sponsors
University of Miami
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 120 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Up to 4.5 years | 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; |
| Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Azacitidine and Docetaxel) | Up to 1.5 years | 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. |
| Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Prednisone) | Up to 1.5 years | 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. |
| Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | Up to 4.5 years. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Up to 4.5 years. | 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. |
| Progression-Free Survival (PFS) | Up to 4.5 years | 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. |
| Overall Survival (OS) | Up to 4.5 years. | The time from the date of initiation of study treatment until date of death from any cause. |
| Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy. | Up to 4.5 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 All Phase 1 participants who received at least one dose of the combination of Azacitidine (Aza) and Docetaxel (Doc) and 5mg of Prednisone at one of the starting dose levels:
* Level 1: 75 mg/m2 Aza + 60 mg/m2 Doc
* Level 2: 75 mg/m2 Aza + 75 mg/m2 Doc
* Level 3: 100 mg/m2 Aza + 75 mg/m2 Doc
* Level 4: 150 mg/m2 Aza + 75 mg/m2 Doc | 15 |
| Phase 2 All Phase 2 participants who received at least one dose of the combination of Azacitidine and Docetaxel with 5 mg of Prednisone at the recommended phase two dose level (RPTD). | 7 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1 | Phase 2 | Total |
|---|---|---|---|
| Age, Customized 60 - 69 years | 8 participants | 3 participants | 11 participants |
| Age, Customized < 60 years | 3 participants | 1 participants | 4 participants |
| Age, Customized >= 70 years | 4 participants | 3 participants | 7 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 6 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 6 Participants | 17 Participants |
| Region of Enrollment United States | 15 participants | 7 participants | 22 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 7 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 12 / 12 |
| serious Total, serious adverse events | 1 / 3 | 0 / 4 | 1 / 3 | 4 / 12 |
Outcome results
Primary
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;
Time frame: Up to 4.5 years
Population: Number of evaluable participants with measurable disease on CT scan. Only 10 of the 19 evaluable participants had measurable disease on CT Scan.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Aza + Doc | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Complete Response (CR) | 0 participants |
| Phase 1 - Aza + Doc | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Partial Response (PR) | 0 participants |
| Phase 1: Level 3 - 100 Aza + 75 Doc | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Partial Response (PR) | 0 participants |
| Phase 1: Level 3 - 100 Aza + 75 Doc | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Complete Response (CR) | 1 participants |
| Phase 1: Level 4 - 150 Aza + 75 Doc | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Partial Response (PR) | 1 participants |
| Phase 1: Level 4 - 150 Aza + 75 Doc | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Complete Response (CR) | 0 participants |
| Phase 2 - Aza + Doc Initial RPTD | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Complete Response (CR) | 0 participants |
| Phase 2 - Aza + Doc Initial RPTD | Number of Participants Achieving Complete Response (CR) or Partial Response (CR) to Protocol Therapy. | Partial Response (PR) | 1 participants |
Primary
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.
Time frame: Up to 4.5 years.
Population: Of the 22 participants enrolled, only 19 were evaluable because they completed 2 or more cycles of protocol therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Aza + Doc | Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | 0 participants |
| Phase 1: Level 2 - 75 Aza + 75 Doc | Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | 1 participants |
| Phase 1: Level 3 - 100 Aza + 75 Doc | Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | 2 participants |
| Phase 1: Level 4 - 150 Aza + 75 Doc | Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | 4 participants |
| Phase 2 - Aza + Doc Initial RPTD | Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | 3 participants |
| Phase 2 - Aza + Doc Reduced RPTD | Number of Participants Achieving Prostate-specific Antigen (PSA) Response. | 0 participants |
Primary
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.
Time frame: Up to 1.5 years
Population: Number of participants enrolled in the Phase 1 portion of the study. The initial RPTD was 150 mg/m2 Azacitidine + 75 mg/m2 Docetaxel, with 5mg of Prednisone. However, due to the death of one patient, the Data and Safety Monitoring Board (DSMB) recommended that the RPTD be reduced to 75 mg/m2 Azacitidine + 75 mg/m2 Docetaxel, with 5mg of Prednisone.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Aza + Doc | Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Azacitidine and Docetaxel) | Initial RPTD Azacitidine (mg/m2) | 150 mg/m2 |
| Phase 1 - Aza + Doc | Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Azacitidine and Docetaxel) | Initial RPTD Docetaxel (mg/m2) | 75 mg/m2 |
| Phase 1 - Aza + Doc | Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Azacitidine and Docetaxel) | Reduced RPTD Azacitidine (mg/m2) | 75 mg/m2 |
| Phase 1 - Aza + Doc | Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Azacitidine and Docetaxel) | Reduced RPTD Docetaxel (mg/m2) | 75 mg/m2 |
Primary
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.
Time frame: Up to 1.5 years
Population: Number of participants enrolled in the Phase 1 portion of the study. The initial RPTD was 150 mg/m2 Azacitidine + 75 mg/m2 Docetaxel, with 5mg of Prednisone. However, due to the death of one patient, the Data and Safety Monitoring Board (DSMB) recommended that the RPTD be reduced to 75 mg/m2 Azacitidine + 75 mg/m2 Docetaxel, with 5mg of Prednisone.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Aza + Doc | Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Prednisone) | Initial RPTD Prednisone (mg) | 5 mg |
| Phase 1 - Aza + Doc | Phase I - Recommended Phase Two Dose (RPTD) of Azacitidine and Docetaxel in Combination With Prednisone. (Prednisone) | Reduced RPTD Prednisone (mg) | 5 mg |
Secondary
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.
Time frame: Up to 4.5 years.
Population: The 10 participants in both Phase 1 and Phase 2 who achieved PSA response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Aza + Doc | Duration of Response | 20.5 weeks |
Secondary
Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy.
Time frame: Up to 4.5 years
Population: All study participants who received at least one dose of combination Azacitidine + Docetaxel, and 5 mg of Prednisone in either Phase 1 or Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Aza + Doc | Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy. | 3 participants |
| Phase 1: Level 2 - 75 Aza + 75 Doc | Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy. | 4 participants |
| Phase 1: Level 3 - 100 Aza + 75 Doc | Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy. | 3 participants |
| Phase 1: Level 4 - 150 Aza + 75 Doc | Number of Participants Experiencing Adverse Events After Beginning Protocol Therapy. | 12 participants |
Secondary
Overall Survival (OS)
The time from the date of initiation of study treatment until date of death from any cause.
Time frame: Up to 4.5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Aza + Doc | Overall Survival (OS) | 19.5 months |
Secondary
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.
Time frame: Up to 4.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Aza + Doc | Progression-Free Survival (PFS) | 4.9 months |