Pazopanib as Second Line Therapy in Patients With Metastatic Prostate Cancer Refractory to Total Androgen Blockade
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Pazopanib (GW786034)
Intervention description: Pazopanib 800 mg daily x 12 weeks
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: Male
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No

Summary:

      A growing body of literature supports the role of angiogenesis in the development and spread
      of a variety of human cancers including prostate cancer.

        -  Vascular endothelial growth factor (VEGF) expression is low in normal prostate tissue,
           but markedly increased in tumor tissues, and has a positive association with tumor stage
           and grade

        -  Plasma VEGF levels are significantly elevated in patients with hormone refractory
           prostate cancer (HRPC) compared to those patients with localized disease and have been
           associated with disease progression in other cancer patient population.

        -  The Cancer and Leukemic Group-B demonstrated that VEGF levels correlate with survival.

      Pazopanib is a potent multi-target receptor tyrosine kinase inhibitor of vascular endothelial
      growth factor receptors.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosis of adenocarcinoma of the prostate histology, currently on total androgen
             blockage with a bicalutamide.

          2. Subjects must provide written informed consent prior to administration of pazopanib or
             the performance of any study-specific procedures or assessments, and must be willing
             to comply with treatment and follow up. Procedures conducted as part of the subject's
             routine clinical management (e.g., blood count, imaging study) and obtained prior to
             signing of informed consent may be utilized for screening or baseline purposes
             provided these procedures are conducted as specified in the protocol. Note: It is not
             necessary that informed consent be obtained within the protocol-specified screening
             window.

          3. Received no prior second line hormone therapy or any chemotherapy. No prior
             bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI) for advanced or
             metastatic prostate cancer.

          4. Must have metastatic diagnosis, meaning disease beyond the prostate gland.

          5. A progressing PSA of ≥ 3, the PSA will be measured in ≥ 14 days.

          6. KPS of ≥ 70

          7. Age ≥ 18 years old

          8. Adequate organ system functions:

               -  Absolute neutrophil count (ANC) ≥ 1.5 X 109/L

               -  Hemoglobin ≥ 9 g/dL

               -  Platelets ≥ 100 X 109/L

               -  International normalized ratio (INR) ≤ 1.2 X upper limit of normal (ULN)

               -  Partial thromboplastin time (PTT) ≤ 1.2 X ULN

               -  Total bilirubin ≤ 1.5 X ULN

               -  AST and ALT ≤ 2.5 X ULN

               -  Calculated creatinine clearance ≥ 30 mL/min

               -  Urine Protein to Creatinine Ratio (UPC)2 < 1

               -  Total serum calcium concentration < 12.0mg/dL

                    -  Subjects may not have had a transfusion within 7 days of screening
                       assessment.

                    -  If UPC ≥ 1, then a 24-hour urine protein must be assessed. Subjects must
                       have a 24-hour urine protein value < 1 g to be eligible.

          9. Left ventricular ejection fraction (LVEF) ≥ 55% as assessed by echocardiography or
             multigated acquisition (MUGA) scan. The same modality used at baseline must be applied
             for subsequent evaluations.

        Exclusion Criteria:

        Subjects meeting any of the following criteria must not be enrolled in the study:

          1. History of another malignancy.

             Note: Subjects who have had another malignancy and have been disease-free for 3 years,
             or subjects with a history of completely resected non-melanomatous skin carcinoma or
             successfully treated in situ carcinoma are eligible.

          2. History or clinical evidence of central nervous system (CNS) metastases.

             Note: Subjects who have previously-treated CNS metastases (surgery ± radiotherapy,
             radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

               -  Are asymptomatic and,

               -  Have had no evidence of active CNS metastases for ≥ 6 months prior to enrollment
                  and,

               -  Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC).

          3. Clinically significant gastrointestinal abnormalities including, but not limited to:

               -  Malabsorption syndrome,

               -  Major resection of the stomach or small bowel that could affect the absorption of
                  study drug,

               -  Active peptic ulcer disease,

               -  Inflammatory bowel disease,

               -  Ulcerative colitis, or other gastrointestinal conditions with increased risk of
                  perforation,

               -  History of abdominal fistula, gastrointestinal perforation, or intra abdominal
                  abscess within 28 days prior to beginning study treatment.

          4. Presence of uncontrolled infection.

          5. Prolongation of corrected QT interval (QTc) > 480 milliseconds (msecs).

          6. History of any one or more of the following cardiovascular conditions within the past
             12 months:

               -  Cardiac angioplasty or stenting,

               -  Myocardial infarction,

               -  Unstable angina,

               -  Symptomatic peripheral vascular disease,

               -  Class III or IV congestive heart failure, as defined by the New York Heart
                  Association (NYHA).

          7. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA).

          8. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the
             past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic
             anticoagulating agents for at least 6 weeks are eligible.

          9. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150mmHg
             or diastolic blood pressure (DBP) of ≥ 90 mmHg].

             Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
             study entry. Blood pressure must be re-assessed on two occasions that are separated by
             a minimum of 24 hours. The mean SBP/DBP values from each blood pressure assessment
             must be < 150/90mmHg in order for a subject to be eligible for the study. See Section
             6.3.2 for instruction on blood pressure measurement and obtaining mean blood pressure
             values.

         10. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
             presence of any non-healing wound, fracture, or ulcer.

         11. Evidence of active bleeding or bleeding diathesis

         12. Hemoptysis within 6 weeks of first dose of study drug.

         13. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions
             that could interfere with subject's safety, obtaining informed consent or compliance
             to the study.

         14. Prohibited medications within 28 days unless the half-life of the medication is longer
             than 28 days, will not be permitted.

         15. Use of an investigational agent, including an investigational anti-cancer agent,
             within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study
             drug.

         16. Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors
             (e.g., bevacizumab, sunitinib, sorafenib, etc), or are mTOR inhibitors (eg.
             temsirolimus, everolimus, etc).

         17. Is now undergoing and/or has undergone in the last 4 weeks immediately prior to first
             dose of study drug, (surgery, tumor embolization, chemotherapy, radiation therapy,
             immunotherapy, or biological therapy)

         18. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
             progressing in severity.

         19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to pazopanib.