Ixabepilone Compared With Mitoxantrone and Prednisone in Treating Patients With Refractory Metastatic Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial is studying ixabepilone to see how well it works compared to mitoxantrone and prednisone in treating patients with metastatic prostate cancer that has not responded to paclitaxel, docetaxel, or hormone therapy. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Some tumors become resistant to chemotherapy drugs. Ixabepilone may reduce resistance to the drugs and allow the tumor cells to be killed. It is not yet known which chemotherapy regimen is more effective in treating metastatic prostate cancer

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the efficacy of ixabepilone (BMS-247550) vs mitoxantrone and prednisone, in terms of decline in prostate-specific antigen (PSA) levels, in patients with taxane-resistant, hormone-refractory metastatic prostate cancer. SECONDARY OBJECTIVES: I. Determine the safety of these regimens in these patients. II. Determine the objective response rate in patients with measurable disease who are treated with these regimens. III. Determine the clinical activity of each of these regimens after crossover in patients who experience disease progression on their originally assigned treatment arm and switch to the other treatment arm. OUTLINE: This is a randomized, crossover, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1 or 2). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive ixabepilone (BMS-247550) IV over 3 hours on day 1. ARM II: Patients receive mitoxantrone IV over 30 minutes on day 1 and oral prednisone twice daily on days 1-21.In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who progress while on treatment after at least 2 courses or discontinue treatment for any other reason may cross over to the other arm and receive treatment as above, beginning within 12 weeks of last study treatment on original arm. Patients are followed every 3 months.

Official Title
-----------------
A Randomized Phase II Study Of BMS 247550 Or Mitoxantrone And Prednisone In Patients With Taxane Resistant Hormone Refractory Prostate Cancer

Conditions
-----------------
Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage IV Prostate Cancer

Intervention / Treatment
-----------------
* Drug: ixabepilone
* Drug: mitoxantrone hydrochloride
* Drug: prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed adenocarcinoma of the prostate Metastatic disease (positive bone scan or measurable disease) Progressive hormone-refractory disease Based on 1 of the following: Transaxial imaging Rise in prostate-specific antigen (PSA) Radionuclide bone scan Must have undergone primary hormonal treatment (e.g., orchiectomy or gonadotropin-releasing hormone analog with or without an antiandrogen) and demonstrated disease progression after antiandrogen discontinuation as defined below: Two consecutive rising PSA values, obtained at least 2 weeks apart, or documented osseous or soft tissue progression For patients receiving flutamide, at least 1 PSA value must be obtained at least 4 weeks after flutamide discontinuation For patients receiving bicalutamide or nilutamide, at least 1 PSA value must be obtained at least 6 weeks after antiandrogen discontinuation Ineligible if sole manifestation of progression is an increase in disease-related symptoms Meets 1 of the following criteria: Measurable disease and an elevated PSA Nonmeasurable disease and an elevated PSA, as follows: Positive bone scan PSA level at least 5 ng/mL, with increases on at least 2 successive occasions at least 2 weeks apart New metastatic lesions by radionuclide bone scan Must have received at least 2 courses of paclitaxel- or docetaxel-based therapy, with disease progression documented during therapy or no more than 60 days after cessation of therapy* Testosterone < 50 ng/dL No known active brain metastases Performance status - ECOG 0-2 At least 12 weeks Granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin < 1.5 times upper limit of normal (ULN) AST and ALT < 3 times ULN Creatinine ≤ 1.5 times ULN Creatinine clearance > 40 mL/min Ejection fraction ≥ lower limit of normal by MUGA or echocardiogram No myocardial infarction within the past 6 months No significant cardiovascular disease No New York Heart Association class III or IV congestive heart failure No active angina pectoris Fertile patients must use effective contraception before, during, and for 3 months after study therapy No prior hypersensitivity reaction to agents containing Cremophor®EL No serious infection No nonmalignant medical illnesses that are uncontrolled or whose control would be jeopardized by complications of study therapy No psychiatric illness or social situation that would preclude study compliance No motor or sensory neuropathy grade 2 or greater No currently active second malignancy except nonmelanoma skin cancer Patients are not considered to have a currently active malignancy provided they have completed therapy and are considered to have less than a 30% risk of relapse No concurrent prophylactic colony-stimulating factors for myelosuppression See Disease Characteristics No more than 1 prior chemotherapy regimen No prior mitoxantrone or epothilone No other concurrent chemotherapy See Disease Characteristics At least 4 weeks since prior antiandrogens (e.g., flutamide) (6 weeks for bicalutamide or nilutamide) Patients must continue primary androgen deprivation therapy with luteinizing hormone-releasing hormone agonist during study if prior orchiectomy was not performed At least 4 weeks since prior systemic (including oral) corticosteroids except corticosteroids as part of first-line chemotherapy tapered off over 10-14 days prior to study entry At least 4 weeks since any prior hormonal therapy, including megestrol or finasteride No other concurrent systemic steroids At least 4 weeks since prior radiotherapy More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium) No concurrent radiotherapy See Disease Characteristics At least 4 weeks since prior herbal products known to decrease PSA levels (e.g., Saw Palmetto or PC-SPES) More than 4 weeks since other prior antiprostate cancer therapy More than 4 weeks since prior systemic therapies for prostate cancer No other concurrent investigational agents

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive ixabepilone (BMS-247550) IV over 3 hours on day 1. | Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;|
| Experimental: Arm II<br>Patients receive mitoxantrone IV over 30 minutes on day 1 and oral prednisone twice daily on days 1-21. In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: mitoxantrone hydrochloride<br>* Given IV<br>* Other names: Novantrone;Drug: prednisone<br>* Given orally<br>* Other names: Deltra;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to the randomized treatment as determined by > 50% PSA response as measured by RECIST criteria | The frequency of response with 95% confidence limits for a binomial outcome will be calculated. | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of any toxicity by grade |  | Up to 3 months | 
| Response duration | Will be estimated using the Kaplan-Meier product limit method. | From the date PR or CR is first determined until the first evidence of progressive disease, assessed up to 3 months | 
| Time to progressive disease | Will be estimated using the Kaplan-Meier product limit method. | From the date protocol therapy is started until the first evidence of progressive disease, assessed up to 3 months | 
| Frequency of response to third-line (crossover) therapy | Estimates of response to third line treatment along with 95% confidence intervals will be calculated. | Up to 3 months |