Treating Patients With Metastatic Prostate Cancer Not Responding to Hormone and Chemotherapy

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial is studying the side effects and best dose of ixabepilone and mitoxantrone hydrochloride when given together with prednisone and to see how well they work in treating patients with metastatic prostate cancer that did not respond to hormone therapy and chemotherapy. Drugs used in chemotherapy, such as ixabepilone, mitoxantrone hydrochloride, and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of the combination of ixabepilone, mitoxantrone hydrochloride, and prednisone in patients with hormone-refractory metastatic prostate cancer that progressed during or after taxane-based chemotherapy. (Phase I) II. Assess the efficacy, as measured by reduction in prostate-specific antigen, of this regimen in these patients. (Phase II) SECONDARY OBJECTIVES: I. Evaluate the overall safety of this regimen as second-line chemotherapy in these patients. II. Evaluate the objective response rate in patients treated with this regimen. OUTLINE: This is a multicenter, phase I, open label, dose-escalation study of mitoxantrone hydrochloride and ixabepilone followed by a phase II study. PHASE I: Patients receive mitoxantrone hydrochloride intravenously (IV) over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of mitoxantrone hydrochloride and ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. PHASE II: Patients receive mitoxantrone hydrochloride and ixabepilone at the MTD determined in phase I and prednisone as in phase I. After completion of study treatment, patients are followed every 3 months.

Official Title
-----------------
Phase I/II Trial of Epothilone Analog BMS-247550 (Ixabepilone), Mitoxantrone, and Prednisone in Hormone Refractory Prostate Cancer (HRPC) Patients Previously Treated With Chemotherapy

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed adenocarcinoma of the prostate Progressive metastatic disease (i.e., positive bone scan or measurable disease) despite castrate levels of testosterone (either from orchiectomy or luteinizing hormone-releasing hormone [LHRH] agonist therapy) Progressive disease after discontinuing hormonal therapy Progressive disease is based on any of the following*: Transaxial imaging Rise in prostate-specific antigen (PSA) Radionuclide bone scan (must show new metastatic lesions) Nonmeasurable or measurable disease For measurable disease, progression is defined by RECIST criteria Positive bone scan and elevated PSA required for nonmeasurable disease PSA evidence of progressive prostate cancer during or after first-line chemotherapy consists of a PSA level ≥ 2 ng/mL that has risen on ≥ 2 successive occasions ≥ 1 week apart Received ≥ 3 prior courses of paclitaxel- or docetaxel-based therapy, with disease progression documented during therapy or after cessation of therapy No more than 1 prior chemotherapy regimen Re-treatment with the same taxane-based regimen allowed Changes in prior chemotherapy regimen (addition of other agents) for disease progression are considered 2 chemotherapy regimens, and are not allowed PSA ≥ 2 ng/mL Testosterone < 50 ng/dL Patients must continue primary androgen deprivation with LHRH analogue if they have not undergone orchiectomy No known active brain metastases ECOG performance status 0-2 Life expectancy ≥ 12 weeks Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 40 mL/min ALT and AST < 2.5 times ULN Granulocyte count ≥ 2,000/mm³ Platelet count ≥ 100,000/mm³ Bilirubin < 1.5 times ULN Ejection fraction normal by MUGA scan or echocardiogram No significant cardiovascular disease, including any of the following: Congestive heart failure (New York Heart Association class III-IV heart disease) Active angina pectoris Myocardial infarction within the past 6 months No serious infections or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by study therapy No psychiatric illness or social situation that would preclude study compliance No pre-existing motor or sensory peripheral neuropathy > grade 1 No known prior severe hypersensitivity reactions to agents containing Cremophor® EL No currently active second malignancy other than nonmelanoma skin cancer Patients are not considered to have a currently active malignancy if they have completed therapy and are considered to be at < 30% risk of relapse Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study treatment See Disease Characteristics No prior mitoxantrone hydrochloride, ixabepilone, or other epothilones At least 4 weeks since prior hormonal therapy (i.e., any dose of megestrol, finasteride, or any herbal product known to decrease PSA levels [e.g., saw palmetto or PC-SPES]) other than LHRH agonist or a stable dose of corticosteroids from a prior chemotherapy regimen More than 4 weeks since other prior systemic therapies for prostate cancer At least 4 weeks since prior radiation therapy More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium) No concurrent moderate to strong CYP3A4 inhibitors No concurrent prophylactic colony-stimulating factors No concurrent radiotherapy

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

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

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion Responding to Treatment With of the Combination of Ixabepilone and Mitoxantrone Hydrochloride With Prednisone in Hormone Refractory Prostate Cancer Patients Who Have Had Prior Taxane Chemotherapy Based Upon a PSA Decline of > 50% (Phase II) | Descriptive statistics will be calculated to characterize the disease and treatment factors including the proportion responding with a 95% confidence interval. If accrual is completed and more than 15 of 58 patients show > 50% Prostate Specific Antigen (PSA) declines after 3 courses, then the null hypothesis of a 20% response proportion will be rejected. PSA declines for individual patients will be plotted in the form of a waterfall diagram of maximal PSA declines. 58 patients were enrolled for phase II, two were ineligible so 56 patients were analyzed. | Every 3 courses until cancer progression/excessive toxicity or death | 
| Safety of the Combination of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I) | This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 for adverse event monitoring and reporting. The cumulative grade 3 or higher adverse events for all dose levels are noted below and in the table of adverse events. | Every 21 days until cancer progression/excessive toxicity or death | 
| Dose Limiting Toxicities for Each Dose Level of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I). | Cohorts of 3 patients will be enrolled at each dose level; if 1 dose limiting toxicity (DLT) is observed then the cohort will be expanded to 6 patients. If a second DLT is observed, the previous dose level will be considered the maximum tolerated dose (MTD). If all observed DLT are due to neuropathy (specific to ixabepilone), then we would consider the previous dose level of Ixabepilone the MTD for that drug, and escalate mitoxantrone hydrochloride as described above to a maximum dose of 12 mg/m^2. Toxicities will be tabulated by grade for each dose cohort and overall for all patients accrued to the phase I study. | Course 1 (first 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (Phase II) | Measured from the start of protocol therapy until RECIST (Response Evaluation Criteria In Solid Tumors Criteria) v1.0 progression. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Every 3 months until cancer progression/excessive toxicity or death |