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

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.

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