Intermittent Chemotherapy With or Without Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) for Metastatic Hormone Refractory Prostate Cancer (HRPC)

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Phase II Study of Intermittent Chemotherapy or Intermittent Chemotherapy With Maintenance GM-CSF in Patients With Previously Untreated Hormone Refractory Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Docetaxel and GM-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age over 18 years Histologically documented adenocarcinoma of the prostate Progressive metastatic prostate cancer Castrate levels of testosterone (<50 ng/ml) must be maintained 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 ≥ 4 weeks since major surgery and fully recovered ≥ 4 weeks since any prior radiation with any toxicity attributable to radiation resolved to ≤grade 1 ≥ 8 weeks since the last dose of strontium or samarium Sexually active patients must agree to use adequate contraception Karnofsky Performance Status ≥ 60% Life expectancy >12 weeks 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: Age over 18 years Histologically documented adenocarcinoma of the prostate ≤3 cycles of prior docetaxel chemotherapy for metastatic disease permitted prior to enrollment Docetaxel must have been administered on an every 3 week schedule Each docetaxel dose must have been between 60 and 75 mg/m2 Castrate levels of testosterone <50 ng/mL Daily use of other steroids (hydrocortisone, dexamethasone) instead of prednisone or no steroids, is permitted up until time of enrollment A Prostate-specific antigen (PSA) level must have been documented within 6 weeks of initiating docetaxel chemotherapy Exclusion Criteria: 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. >3 cycles of q3 week docetaxel/prednisone chemotherapy has already been administered to the patient Peripheral neuropathy >grade 1 Prior immunotherapy including systemic GM-CSF or vaccines utilizing GM-CSF; prior G-CSF support of chemotherapy-related neutropenia is permitted Prior biologic agents (i.e.,anti-angiogenic agents, anti-Epithelial Growth Factor Receptor (EGFR) inhibitors)≤ 4 weeks prior to registration More than two prior therapies with an investigational agent, completed ≤ 4 weeks prior to enrollment (no prior immunotherapeutics are allowed) 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 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 Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 will be excluded Poorly controlled diabetes (fasting blood glucose >250) despite optimization of medical therapy Exclusion criteria for late enrolling patients: Prior immunotherapy including systemic GM-CSF or vaccines utilizing GM-CSF; prior G-CSF support for chemotherapy-related neutropenia is permitted Delay of ≥6 weeks between any 2 chemotherapy cycles prior to enrollment on study Cumulative delays ≥8 weeks between chemotherapy cycles prior to enrollment on study

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel + Observation<br>Intermittent docetaxel/prednisone with no maintenance therapy: Patients will discontinue docetaxel/prednisone and undergo observation until disease progression at which time they will re-initiate docetaxel/prednisone. Six cycles of docetaxel/prednisone will again be administered before subsequent discontinuation of chemotherapy | Drug: Docetaxel<br>* Docetaxel 75mg/m2 every 21 days<br>|
| Experimental: Docetaxel + GM-CSF<br>Intermittent docetaxel/prednisone with maintenance GM-CSF therapy: Patients will discontinue docetaxel/prednisone and will receive maintenance GM-CSF until disease progression at which time, they will discontinue GM-CSF and resume docetaxel/prednisone. Six cycles of docetaxel/prednisone will again be administered before discontinuation of chemotherapy and GM-CSF therapy is re-initiated. GM-CSF dose/schedule will be as previously described (250 mcg/m2 SQ daily, days 15-28 q28 days) | Drug: Docetaxel and GM-CSF<br>* Docetaxel 75mg/m2 every 21 days and GM-CSF 250mcg/m2 SQ days 15-28<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The Kaplan-Meier product limit method will be used to estimate the median overall survival | Up to 7 years | 
| 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. | Up to 6 years | 
| 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 | Up to 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Hormone Refractory Prostate Cancer