Paclitaxel Poliglumex and Estradiol in Treating Patients With Stage IV Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as paclitaxel poliglumex, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Estradiol may kill prostate cancer cells that no longer respond to hormone therapy. Giving paclitaxel poliglumex together with estradiol may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving paclitaxel poliglumex together with estradiol works in treating patients with stage IV prostate cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the PSA response rate in patients with androgen independent metastatic prostate cancer treated with paclitaxel poliglumex and transdermal estradiol. Secondary Determine the toxicity of this regimen in these patients. Determine the response rate in patients treated with this regimen. Determine the time to PSA progression and measurable disease progression in patients treated with this regimen. Determine time to death from all causes in patients treated with this regimen. Correlate levels of serum estradiol, serum cathepsin B, and bone turnover markers with PSA response in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive transdermal estradiol continuously (patches changed every 7 days) until the PSA level rises. Patients whose PSA increases above baseline or PSA decreases < 10% after 4 weeks of estradiol therapy or whose serum PSA reduction is < 50% after 12 weeks of estradiol therapy also receive paclitaxel poliglumex therapy. These patients receive paclitaxel poliglumex IV over 10-20 minutes on day 1. Treatment with paclitaxel poliglumex repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 6 months. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
-----------------
A Phase II Study of Paclitaxel Poliglumex (PPX) in Combination With Transdermal Estradiol for the Treatment of Androgen Independent Prostate Cancer After Docetaxel Chemotherapy

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: transdermal estradiol
* Drug: paclitaxel poliglumex


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the prostate Stage IV disease Radiographic evidence of regional or distant metastases Evidence of disease progression (by PSA and/or imaging studies) despite standard hormonal therapy and after exposure to docetaxel-containing chemotherapy, as evidenced by any of the following: Measurable or evaluable disease progression, defined as the appearance of new lesion(s) or unequivocal increase in previously existing lesions or masses Disease progression by PSA*, defined by 1 of the following: 3 consecutively rising PSA with the second PSA taken ≥ 1 week after the first PSA 2 consecutively rising PSA with a fourth PSA > the second PSA NOTE: *The last required PSA must be after the required antiandrogen washout period for patients who have been on antiandrogen therapy Must have received prior therapy with at least two 3-weekly doses or six weekly doses of docetaxel Patients may have discontinued therapy due to progression, intolerance, completion of planned therapy, or other reasons Prior treatment with combinations of docetaxel with estramustine phosphate sodium or noncytotoxic agents (biologic agents) allowed Serum testosterone < 50 ng/dL (unless surgically castrate) Patients must continue androgen deprivation with a luteinizing hormone-releasing hormone agonist if they have not undergone orchiectomy No known or suspected brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 3 months Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN AST and ALT ≤ 2.5 times ULN No other active malignancy except adequately treated nonmelanoma skin cancer or other noninvasive or in situ neoplasm No other significant active medical illness or infection that would preclude study compliance No significant cardiovascular illness, including any of the following: NYHA class III or IV congestive heart failure Unstable angina Myocardial infarction within the past 6 months Acute deep venous thrombosis Acute pulmonary embolism No significant peripheral neuropathy ≥ grade 2 PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 6 weeks since prior antiandrogen therapy (4 weeks for flutamide) No current evidence of an antiandrogen withdrawal response More than 4 weeks since prior radiotherapy More than 8 weeks since prior radiopharmaceutical therapy (strontium chloride Sr 89, samarium Sm 153 lexidronam pentasodium) No prior paclitaxel No other concurrent cytotoxic agents No other concurrent chemotherapy or biologic response modifiers No concurrent supplements known or suspected to contain supplemental estrogens

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

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: transdermal estradiol|Transdermal estradiol given 0.2mg/day for duration of study.|
|Drug: paclitaxel poliglumex|Paclitaxel poliglumex (PPX) is a macromolecular polymer-drug conjugate of paclitaxel. PPX was given every 28 days, at a dose of 150 mg/m2|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Specific Antigen (PSA) Response Rate: Number of Subjects With Decreases in PSA of at Least 50% | PSA response rate is defined at the number of patients who experienced a PSA decline of equal to or greater than 50%, confirmed by a second measurement at least 4 weeks later. | While receiving study agents (on average, 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurable Disease Response Rate (Soft Tissue) | Measurable disease response rate by RECIST criteria. Response is defined as at least a 30% decrease in the sum of the longest diameter in measurable lesions (larger than 10mm at baseline). | While receiving study agents (on average, 3 months) | 
| Time to Disease Progression | Time from Day 1 to Day of meeting criteria for PSA or Measurable Disease Progression | At time of progression by PSA or RECIST criteria | 
| Time to Death | Defined as time from Day 1 of study regimen to Date of death from any cause. | Measured at Date of Death from any cause | 
| Correlation of Levels of Serum Estradiol, Serum Cathepsin B, and Bone Turnover Markers With PSA Response | These correlative analyses were not completed. As there were no PSA responses, it was not possible to correlate serum estradiol, serum cathepsin B, or bone turnover markers with PSA response. | Measured after 4 cycles of combination therapy | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adenocarcinoma of the prostate, recurrent prostate cancer, stage IV prostate cancer