Pazopanib Hydrochloride After Leuprolide Acetate or Goserelin Acetate in Treating Patients With Relapsed Prostate Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well pazopanib hydrochloride works after leuprolide or goserelin in treating patients with relapsed prostate cancer. Pazopanib hydrochloride 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 leuprolide acetate or goserelin acetate, may lessen the amount of androgens made by the body. Giving pazopanib after leuprolide or goserelin may be an effective treatment for prostate cancer

Detailed Description
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PRIMARY OBJECTIVES: I. Determine if pazopanib hydrochloride is able to increase time to progression, as measured by prostate-specific antigen (PSA), after 6 months of limited gonadotropin-releasing hormone (GnRH) agonist therapy comprising leuprolide acetate or goserelin in patients with androgen-sensitive relapsed stage D0 prostate cancer. SECONDARY OBJECTIVES: I. Determine the adverse events in patients treated with this regimen. II. To monitor for changes in testosterone in relationship to pazopanib therapy versus observation. OUTLINE: Patients receive androgen blockade comprising GnRH agonist therapy (e.g., leuprolide acetate or goserelin acetate) for 6 months. Patients who develop metastases or have PSA progression while on GnRH agonist therapy are removed from the study and placed on total androgen blockade. The remaining patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo observation. After completion of study treatment, patients are followed up periodically for up to 12 months.

Official Title
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A Randomized, Phase II Study of GW786034 (Pazopanib) in Stage D0 Relapsed Androgen Sensitive Prostate Cancer Following Limited GnRH Agonist Therapy

Conditions
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Recurrent Prostate Cancer

Intervention / Treatment
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* Drug: pazopanib hydrochloride
* Drug: leuprolide acetate
* Drug: goserelin acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed prostate cancer Stage D0 Must have undergone some definitive local therapy for prostate cancer Must be free of macrometastatic disease, as evidenced by computed tomography (CT) scan and bone scan, if serum PSA ≥ 10 ng/mL prior to GnRH agonist therapy Progressive disease meeting the following criteria: NOTE: Patients who have undergone a prostatectomy and have two detectable, rising serum PSA levels are eligible Two consecutive rises in PSA above nadir recorded after definite local therapy Serum PSA concentrations must have absolute value of > 0.5 ng/mL (separated by ≥ 2 weeks) prior to beginning GnRH agonist therapy PSA < 0.5 ng/mL Testosterone < 30 ng/mL No measurable disease No brain metastases requiring steroid or anticonvulsant therapy Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 OR Karnofsky PS 60- 100% Prothrombin time (PT)/international normalization ratio (INR)/partial thromboplastin time (PTT) ≤ 1.2 times upper limit of normal (ULN) Bilirubin normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN Creatinine ≤ 1.5 times ULN OR creatinine clearance > 50 mL/min Proteinuria ≤ 1+ on 2 consecutive dipsticks > 1 week apart Urine protein: creatinine ratio < 1 OR urine protein < 1.0 g/24 hours Fertile patients must use effective double-barrier contraception during study therapy OR completely abstain from sexual intercourse 14 days prior to, during, and for ≥ 21 days after completion of study therapy No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or to other agents used in the study No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situations that would preclude compliance with study requirements No human immunodeficiency virus (HIV) positivity No condition that impairs the ability to swallow and retain pazopanib hydrochloride tablets, including any of the following: Gastrointestinal tract disease resulting in an inability to take oral medication Requirement for intravenous (IV) alimentation Prior surgical procedures affecting absorption Active peptic ulcer disease No other conditions, including any of the following: Serious or nonhealing wound, ulcer, or bone fracture Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days Cerebrovascular accident within the past 6 months Myocardial infarction, admission for unstable angina, cardiac angioplasty, or stenting within the past 6 months Venous thrombosis within the past 12 weeks New York Heart Association (NYHA) class III or IV heart failure History of currently treated asymptomatic NYHA class II heart failure allowed Systolic blood pressure (BP) ≤ 140 mm Hg and diastolic BP ≤ 90 mm Hg Prior initiation or adjustment of BP medication allowed provided that the average of 3 BP readings at a visit prior to enrollment is < 140/90 mm Hg More than 3 months since prior antiandrogen More than 4 months since prior orchiectomy or implantable luteinizing LHRH agonist No prior GnRH agonists except for neoadjuvant or adjuvant therapy associated with local therapy Patients who have started a GnRH agonist for micrometastatic disease after local therapy allowed provided the following criteria are met: Progressive disease Willing to discontinue therapy before 6 months have elapsed Have signed consent prior to completing 6 months of the initial hormone therapy Are within 4 months of initiating GnRH agonist therapy No prior or concurrent GnRH antagonist therapy No concurrent ketoconazole No concurrent cytochrome P450 2C9 (CYP2C9) substrates, including any of the following: Anticoagulants (e.g., warfarin [therapeutic doses only]) Low molecular weight heparin or prophylactic low-dose warfarin allowed Oral hypoglycemics (e.g., glipizide, glyburide, tolbutamide, glimepiride, or nateglinide) Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, or methylergonovine) Neuroleptics (e.g., pimozide) Erectile dysfunction agents (e.g., sildenafil, tadalafil, or vardenafil) Antiarrhythmics (e.g., bepridil, flecainide, lidocaine, mexiletin, amiodarone, quinidine, or propafenone) Immune modulators (e.g., cyclosporine, tacrolimus, or sirolimus) Miscellaneous medications (e.g., theophylline, quetiapine, risperidone, tacrine, clozapine, or atomoxetine) No concurrent medications associated with the risk of QTc prolongation and/or Torsades de Pointes Replacement of drugs that do not carry these risks allowed No other concurrent non-Food and Drug Administration (FDA)-approved agents

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: Pazopanib<br>Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: pazopanib hydrochloride<br>* Given PO<br>* Other names: Votrient;Drug: leuprolide acetate<br> <br> * Other names: Lupron Depot;Drug: goserelin acetate<br> <br> * Other names: Zoladex;|
| Active Comparator: Observation<br>Patients undergo observation after treatment with leuprolide acetate and goserelin acetate. | Drug: leuprolide acetate<br> <br> * Other names: Lupron Depot;Drug: goserelin acetate<br> <br> * Other names: Zoladex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to PSA Progression | The median time to disease progression for the therapy and observation groups will be estimated using the Kaplan-Meier estimate and compared using the log-rank test. | Baseline, every 4 weeks during treatment, and up to 12 months after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median PSA Progression-free Survival | Kaplan-Meier estimates for PSA progression-free survival will be computed for the pazopanib and active surveillance groups and compared using the log rank test. The outcome measure is median PSA progression-free survival time. | Time from randomization to PSA progression or death from any cause |