Prostate Cancer
Conditions
Keywords
Metastatic Hormone Refractory Prostate Cancer
Brief summary
This is a two-arm, randomized Phase II study of intermittent chemotherapy with and without GM-CSF. All patients will receive six 21-day cycles of docetaxel 75 mg/m2 on Day 2 of each cycle and 5 mg prednisone twice a day on Days 1-21. Following six cycles of chemotherapy, eligible subjects will be randomized to no maintenance therapy or to maintenance GM-CSF therapy. The GM-CSF group dose schedule will be 250 mcg/m2 subcutaneous (SQ) daily Days 15-28 every 28 days. Patients in both groups will continue until disease progression at which time GM-CSF will be discontinued and chemotherapy will again be administered.
Interventions
DRUGDocetaxel
Docetaxel 75mg/m2 every 21 days
DRUGDocetaxel and GM-CSF
Docetaxel 75mg/m2 every 21 days and GM-CSF 250mcg/m2 SQ days 15-28
Sponsors
Genzyme, a Sanofi Company
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age over 18 years 2. Histologically documented adenocarcinoma of the prostate 3. Progressive metastatic prostate cancer 4. Castrate levels of testosterone (\<50 ng/ml) must be maintained 5. Prior hormonal therapy or medications : Patients who are receiving an anti-androgen, secondary hormonal therapy (i.e. ketoconazole, aminoglutethimide, megestrol acetate, diethylstilbestrol), 5-alpha reductase inhibitor (i.e. finasteride (Proscar), dutasteride (Avodart)) or herbal prostate medication (i.e. saw palmetto, PC-SPES, PC-PLUS) must discontinue the drug by the date of initiation of chemotherapy on study 6. ≥ 4 weeks since major surgery and fully recovered 7. ≥ 4 weeks since any prior radiation with any toxicity attributable to radiation resolved to ≤grade 1 8. ≥ 8 weeks since the last dose of strontium or samarium 9. Sexually active patients must agree to use adequate contraception 10. Karnofsky Performance Status ≥ 60% 11. Life expectancy \>12 weeks 12. Required initial laboratory values Absolute neutrophil count \> 1500/ul Platelets \> 100,000/ul Hemoglobin \> 8.0 g/dl Creatinine ≤ 2.0 X upper limit of normal Bilirubin ≤upper limit of normal (ULN) aspartate aminotransferase (AST) / alanine aminotransferase (ALT) / alkaline phosphatase: AST AND ALT AND alkaline phosphatase must be within the range allowing for eligibility In determining eligibility, the more abnormal of the 2 values (AST or ALT should be used. An abnormal alkaline phosphatase must be attributed to liver dysfunction and not metastatic bone involvement (i.e elevated gamma-glutamyl transpeptidase (GGTP) or evidence of liver metastases) Inclusion criteria for late enrolling patients: 1. Age over 18 years 2. Histologically documented adenocarcinoma of the prostate 3. ≤3 cycles of prior docetaxel chemotherapy for metastatic disease permitted prior to enrollment 4. Docetaxel must have been administered on an every 3 week schedule 5. Each docetaxel dose must have been between 60 and 75 mg/m2 6. Castrate levels of testosterone \<50 ng/mL 7. Daily use of other steroids (hydrocortisone, dexamethasone) instead of prednisone or no steroids, is permitted up until time of enrollment 8. A Prostate-specific antigen (PSA) level must have been documented within 6 weeks of initiating docetaxel chemotherapy
Exclusion criteria
1. Prior systemic chemotherapy for prostate cancer, other than q 3-week docetaxel/prednisone. Prior neoadjuvant or adjuvant chemotherapy is permitted if there was no evidence of disease relapse within 12 months of the last dose of chemotherapy. 2. \>3 cycles of q3 week docetaxel/prednisone chemotherapy has already been administered to the patient 3. Peripheral neuropathy \>grade 1 4. Prior immunotherapy including systemic GM-CSF or vaccines utilizing GM-CSF; prior G-CSF support of chemotherapy-related neutropenia is permitted 5. Prior biologic agents (i.e.,anti-angiogenic agents, anti-Epithelial Growth Factor Receptor (EGFR) inhibitors)≤ 4 weeks prior to registration 6. More than two prior therapies with an investigational agent, completed ≤ 4 weeks prior to enrollment (no prior immunotherapeutics are allowed) 7. Myocardial infarction or significant change in anginal pattern within the last 6 months, symptomatic congestive heart failure (NYHA Class III or higher) or uncontrolled cardiac arrhythmia 8. Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded 9. Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 will be excluded 10. Poorly controlled diabetes (fasting blood glucose \>250) despite optimization of medical therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Up to 7 years | The Kaplan-Meier product limit method with 95% confidence intervals will be used to estimate the median time to disease progression during initial course of randomized treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 7 years | The Kaplan-Meier product limit method will be used to estimate the median overall survival |
| Number of Participants With PSA Response to Successive Series of Chemotherapy | Up to 6 years | PSA partial response is defined by at least a 50% decline from PSA value from the baseline measurement to 12 weeks of protocol therapy. The decline must be confirmed by a second PSA value obtained 4 or more weeks later For those patients whose PSA have decreased but has not reached response criteria defined above, progressive disease is defined as 25% increase over the nadir PSA value provided that the increase is at least 5ng/mL and is confirmed. |
| Cumulative Duration of Time on and Off Docetaxel-based Therapy | Up to 7 years | Median percentage of time will be calculated to summarize the total duration of chemotherapy and amount of docetaxel/prednisone administered while the patient is on study. The same results will be tabulated for each. For the on-chemotherapy period: will be estimated from the date of starting protocol therapy; if a patient received docetaxel on day 2 of a cycle, he will be considered to have received a full 21 days on therapy. For the off-chemotherapy period: will be calculated from the date of starting the observation or GM-CSF period to the date of resuming chemotherapy |
Countries
United States
Participant flow
Pre-assignment details
Patients had to complete 6 cycles of induction chemotherapy and have a ≥ 50% decline in prostate-specific antigen to be eligible for randomization.
Participants by arm
| Arm | Count |
|---|---|
| All Patients Accrued There were a total of 125 patients whom were accrued to the study and assigned to at least one course of docetaxel | 125 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Course 1 | Adverse Event | 0 | 0 | 6 |
| Course 1 | nonprotocol therapy | 0 | 2 | 2 |
| Course 1 | Physician Decision | 0 | 2 | 4 |
| Course 1 | Withdrawal by Subject | 0 | 8 | 2 |
Baseline characteristics
| Characteristic | All Patients Accrued |
|---|---|
| Age, Customized Median Age Range | 70 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Gleason Score <=6 | 22 Participants |
| Gleason Score 7 | 33 Participants |
| Gleason Score 8-10 | 70 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 111 Participants |
| Region of Enrollment United States | 125 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 125 |
| other Total, other adverse events | 0 / 125 |
| serious Total, serious adverse events | 20 / 125 |
Outcome results
Primary
Time to Progression
The Kaplan-Meier product limit method with 95% confidence intervals will be used to estimate the median time to disease progression during initial course of randomized treatment
Time frame: Up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and Observation | Time to Progression | 1.5 months |
| Docetaxel and GM-CSF | Time to Progression | 3.3 months |
Secondary
Cumulative Duration of Time on and Off Docetaxel-based Therapy
Median percentage of time will be calculated to summarize the total duration of chemotherapy and amount of docetaxel/prednisone administered while the patient is on study. The same results will be tabulated for each. For the on-chemotherapy period: will be estimated from the date of starting protocol therapy; if a patient received docetaxel on day 2 of a cycle, he will be considered to have received a full 21 days on therapy. For the off-chemotherapy period: will be calculated from the date of starting the observation or GM-CSF period to the date of resuming chemotherapy
Time frame: Up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and Observation | Cumulative Duration of Time on and Off Docetaxel-based Therapy | 24.7 months |
| Docetaxel and GM-CSF | Cumulative Duration of Time on and Off Docetaxel-based Therapy | 30.9 months |
| Overall Survival | Cumulative Duration of Time on and Off Docetaxel-based Therapy | 8.3 months |
| Docetaxel and GM-CSF ON Chemotherapy | Cumulative Duration of Time on and Off Docetaxel-based Therapy | 7.6 months |
Secondary
Number of Participants With PSA Response to Successive Series of Chemotherapy
PSA partial response is defined by at least a 50% decline from PSA value from the baseline measurement to 12 weeks of protocol therapy. The decline must be confirmed by a second PSA value obtained 4 or more weeks later For those patients whose PSA have decreased but has not reached response criteria defined above, progressive disease is defined as 25% increase over the nadir PSA value provided that the increase is at least 5ng/mL and is confirmed.
Time frame: Up to 6 years
Population: Twenty-six participants total resumed a second course of the Docetaxel, and five participants went on to resume a third course of treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel and Observation | Number of Participants With PSA Response to Successive Series of Chemotherapy | PSA response to Course 2 chemotherapy | 4 Participants |
| Docetaxel and Observation | Number of Participants With PSA Response to Successive Series of Chemotherapy | PSA response to Course 3 chemotherapy | 1 Participants |
| Docetaxel and GM-CSF | Number of Participants With PSA Response to Successive Series of Chemotherapy | PSA response to Course 2 chemotherapy | 8 Participants |
| Docetaxel and GM-CSF | Number of Participants With PSA Response to Successive Series of Chemotherapy | PSA response to Course 3 chemotherapy | 0 Participants |
Secondary
Overall Survival
The Kaplan-Meier product limit method will be used to estimate the median overall survival
Time frame: Up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and Observation | Overall Survival | 14 months |
| Docetaxel and GM-CSF | Overall Survival | 28.4 months |
| Overall Survival | Overall Survival | 15.6 months |