Pazopanib Hydrochloride With or Without Bicalutamide in Treating Patients With Prostate Cancer That Did Not Respond to Hormone Therapy

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well giving pazopanib with or without bicalutamide works in treating patients with prostate cancer that did not respond to hormone therapy. Pazopanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as bicalutamide, may lessen the amount of androgens made by the body. Giving pazopanib hydrochloride together with bicalutamide may be an effective treatment for prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the therapeutic activity of GW786034 (pazopanib hydrochloride) with and without bicalutamide in the treatment of hormone-refractory prostate cancer using prostate specific antigen (PSA)-response rate. SECONDARY OBJECTIVES: I. To estimate objective tumor response in patients with measurable disease. II. To estimate the median time to progression. III. To investigate the safety and tolerability of GW786034 with and without bicalutamide. IV. To estimate the median duration of PSA-response. V. To determine the steady state levels of GW786034 with and without bicalutamide. VI. To investigate the correlation between prior exposure to bicalutamide and non-steroidal anti-androgens with response and survival outcomes. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. ARM II: Patients receive pazopanib hydrochloride PO QD on days 1-28. Patients also receive bicalutamide PO QD on days 8-28 of course 1 and on days 1-28 in all subsequent courses. Courses in both arms repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 weeks for 12 weeks.

Official Title
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A Phase 2 Study of GW786034 (Pazopanib) With or Without Bicalutamide in Hormone Refractory Prostate Cancer

Conditions
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Hormone-Resistant Prostate Cancer, Recurrent Prostate Carcinoma

Intervention / Treatment
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* Drug: Bicalutamide
* Other: Laboratory Biomarker Analysis
* Drug: Pazopanib Hydrochloride
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed prostate cancer Must have received prior hormonal therapy, including either medical (luteinizing hormone-releasing hormone [LHRH] agonist) or surgical (orchiectomy) castration Castrate level of testosterone (< 50 ng/dL) Patients treated with LHRH agonists must continue or restart this therapy Must have radiological documentation of either measurable or non-measurable disease Must show documented progression of prostate cancer while on hormonal therapy as indicated by PSA increase Rising PSA is defined as ≤ 2 consecutive rises in PSA taken ≥ 1 week and ≤ 2 months apart PSA >= 5 ng/mL No known brain metastases Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 OR Karnofsky PS 60-100% Life expectancy > 3 months White blood cell (WBC) >= 3,000/mm^3 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 International normalized ratio (INR) =< 1.2 Activated partial thromboplastin time (PTT) =< 1.2 times upper limit of normal (ULN) Bilirubin normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 times ULN Creatinine normal OR creatinine clearance >= 60 mL/min Fertile patients must use effective contraception No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or bicalutamide Proteinuria =< 1+ on 2 consecutive dipsticks taken >= 1 week apart QTc < 480 msec No significant electrocardiogram (ECG) abnormalities No poorly controlled hypertension (systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg) No condition (e.g., gastrointestinal [GI] tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation; prior surgical procedures affecting absorption; or active peptic ulcer disease) that impairs the ability to swallow and retain pazopanib hydrochloride tablets No serious or nonhealing wound, ulcer, or bone fracture No abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within the past 28 days No cerebrovascular accident within the past 6 months No myocardial infarction, cardiac arrhythmia, admission for unstable angina, cardiac angioplasty, or stenting within the past 12 weeks No venous thrombosis within the past 12 weeks No New York Heart Association (NYHA) class III-IV heart failure Patients with a history of NYHA class II heart failure who are asymptomatic on treatment are eligible No concurrent uncontrolled illness, including, but not limited to, ongoing or active infection No psychiatric illness or social situation that would preclude study compliance Recovered from all prior therapy Prior neoadjuvant or adjuvant chemotherapy allowed More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy At least 4 weeks since prior antiandrogens At least 4 weeks since prior surgery No prior bicalutamide therapy lasting > 3 months in duration Concurrent steroids allowed if no change in steroid dosage within the past 4 weeks No other concurrent investigational agents No concurrent therapeutic warfarin Concurrent low molecular weight heparin or prophylactic low-dose warfarin allowed No concurrent combination antiretroviral therapy for human immunodeficiency virus (HIV)-positive patients

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: Arm A (pazopanib hydrochloride)<br>Patients receive pazopanib hydrochloride PO QD on days 1-28. . | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pazopanib Hydrochloride<br>* Given PO<br>* Other names: Votrient;Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Arm B (pazopanib hydrochloride, bicalutamide)<br>Patients receive pazopanib hydrochloride PO QD on days 1-28. Patients also receive bicalutamide PO QD on days 8-28 of course 1 and on days 1-28 in all subsequent courses. | Drug: Bicalutamide<br>* Given PO<br>* Other names: ICI 176334;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pazopanib Hydrochloride<br>* Given PO<br>* Other names: Votrient;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response Rate | Prostate-specific antigen (PSA) response rate (defined as a confirmed > / = 50% decline (minimum 5ng/ml) in PSA from baseline maintained for >4 weeks, and without other evidence of disease progression documented at time of confirmatory values). | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response Rate as Assessed by RECIST Criteria | RECIST PR defined as - At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Time from start of treatment to time criteria are met for disease progression or death from any cause, whichever came first, assessed up to 5 years | 
| Progression-free Survival | PFS is defined as the time from treatment initiation to disease progression or death from any cause, whichever came first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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 | From time of treatment initiation to disease progression or death from any cause, whichever came first, assessed up to 5 years | 
| Median Duration of PSA-Response | Definition of PSA response: >= 50% fall (minimum 5 ng/ml) in PSA from baseline maintained for >4 weeks, and without other evidence of disease progression documented at time of confirmatory values. PSA response duration will commence on the date of the first >=50% decline in PSA. The response duration ends when PSA progression criteria are met with the second increasing PSA value. PSA progression in PSA responders: rise in PSA of 50% (minimum 5ng/ml) above nadir value and confirmed by a second increasing value at least 1 week later. | From time PSA response criteria are met until time PSA progression criteria are met or death from any cause, whichever came first, up to 5 years | 
| Stable Disease Rate as Assessed by RECIST Criteria | RECIST Stable defined as - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Measured from the start of the treatment until the criteria for progression are met or death from any cause, whichever came first, assessed up to 5 years | 
| Time to Disease Progression | Earliest date on which disease progression was determined by any of the methods listed: PSA progression, objective disease progression (Response Evaluation Criteria in Solid Tumors [RECIST] criteria) or cancer-related symptomatic progression. | Time from start of treatment to time criteria are met for disease progression or death from any cause, whichever came first, assessed up to 5 years | 
| Toxicity | Patients who came off treatment due to toxicity. | Assessed up to 5 years |