Pazopanib Hydrochloride in Treating Patients With Metastatic Melanoma That Cannot be Removed by Surgery

Study Overview
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Brief Summary
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This phase II trial is studying the side effects of pazopanib hydrochloride and to see how well it works in treating patients with metastatic melanoma that cannot be removed by surgery. 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.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the anti-tumor activity and safety profile of single agent Pazopanib (pazopanib hydrochloride). SECONDARY OBJECTIVES: I. To assess the impact of Pazopanib on circulating levels of vascular endothelial growth factor (VEGF). II. To examine the association between tumor response and B-Raf and N-Ras mutations. III. To examine pre/post-treatment expression levels of VEGF, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and Ki67. IV. To correlate baseline and changes in p-ERK levels in the tumor with response. V. To determine pazopanib steady-state trough plasma concentrations (Css,min) and the relationships between Css,min and the PD effects and toxicities of pazopanib. VI. To examine the associations of common polymorphisms in CYP1A2, CYP2C8, UGT1A1, ABCB1, and ABCG2 with the PK and PD of pazopanib. VII. To Assess Progression Free Survival. VIII. To Assess Overall Survival. OUTLINE: This is a multicenter study. Patients receive oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor tissue biopsy at baseline and blood sample collection at baseline and on days 14, 28, and 42 for research studies. Tumor tissue samples are analyzed by DNA sequencing, ELISA, western blotting, and immunoperoxidase staining. Blood samples are analyzed for pharmacodynamics, pharmacokinetics, and pharmacogenetics by high-performance liquid chromatography with tandem mass spectrometry. After completion of study treatment, patients are followed periodically for up to 5 years.

Official Title
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Phase II Trial of Pazopanib (GW786034) in Pre-Treated and Untreated Metastatic Melanoma Patients

Conditions
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Recurrent Melanoma, Stage IV Cutaneous Melanoma AJCC v6 and v7

Intervention / Treatment
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* 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 confirmed unresectable malignant melanoma Radiographic or clinical evidence of metastatic disease Measurable disease with ≥ 1 lesion whose longest diameter can be measured as ≥ 2.0 cm by CT or MRI scans or ≥ 1.0 cm by spiral CT scan Disease that is measurable by physical examination only is not allowed No known intraluminal metastatic lesion(s) with suspected bleeding No brain metastases by MRI or CT scan ECOG performance status 0-2 Life expectancy > 12 weeks WBC ≥ 3,000/μL Hemoglobin ≥ 9 g/dL Absolute neutrophil count ≥ 1,500/μL Platelets ≥ 100,000/μL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Creatinine ≤ 1.5 times ULN Serum troponin normal Urine protein ≤ 1+ (≤ 30 mg/dL) on 2 consecutive dipstick or other urine assessments taken ≥ 1 week apart QTc interval < 480 msec Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No significant ECG abnormalities (e.g., frequent ventricular ectopy, evidence of ongoing myocardial ischemia) No serious nonhealing wound, ulcer, or bone fracture No history of abdominal fistula, gastrointestinal perforation, active diverticulitis, intra-abdominal abscess, or gastrointestinal tract bleeding within the past 28 days No history of myocardial infarction, cardiac arrhythmia within the past 6 months No NYHA class III-IV heart failure Patients with a history of class II heart failure and who are asymptomatic on treatment may be eligible No history of bleeding disorder, including hemophilia, disseminated intravascular coagulation, or any other abnormality of coagulation potentially predisposing patients to bleeding No uncontrolled infection No evidence of active bleeding or bleeding diathesis No hemoptysis within 6 weeks of first dose of study drug No active peptic ulcer disease No inflammatory bowel disease No ulcerative colitis or other gastrointestinal conditions with increased risk of perforation No history of cerebrovascular accident, including transient ischemic attack, pulmonary embolism, or untreated deep venous thrombosis within the past 6 months Patients with recent deep vein thrombosis who have been treated with therapeutic anticoagulating agents within the past 6 weeks are eligible No known endobronchial lesions or involvement of large pulmonary vessels by tumor No current active hepatic or biliary disease, except Gilbert syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 140 mm Hg and diastolic BP > 90 mm Hg) No condition that impairs ability to swallow and retain pazopanib hydrochloride (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or other agents used in the study No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would or might reasonably be expected to limit compliance with study requirements No admission for unstable angina, cardiac angioplasty, or stenting within the past 6 months More than 6 weeks since prior major surgery More than 4 weeks since prior and no concurrent radiotherapy At least 14 days or 5 half-lives and no concurrent CYP interactive medications No prior radiotherapy to ≥ 25% of bone marrow No prior therapy with a VEGFR tyrosine-kinase inhibitor No concurrent antiretroviral therapy for HIV-positive patients No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib hydrochloride No concurrent chemotherapy No other concurrent investigational agents No other concurrent anticancer agents or therapies No concurrent medications that are associated with a risk of QTc prolongation and/or Torsades de Pointes

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pazopanib hydrochloride)<br>Patients receive oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pazopanib Hydrochloride<br>* Given orally<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 |
| --- | --- | --- |
| Tumor Response Rate | Tumor response rate is defined as the number of eligible patients whose disease status meets the Response Evaluation Criteria In Solid Tumors (RECIST) criteria for compete response (CR) or partial response (PR) divided by the number of evaluable patients. A ninety percent confidence interval for the true response proportion will be calculated assuming that the number of confirmed tumor responses follows a binomial distribution and using the Duffy-Santner approach. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the largest dimension (LD) of target lesions taking as reference the baseline sum LD. | Up to 5 years | 
| Toxicity | Toxicity is defined as any grade 3 or higher adverse event as assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and at least possibly related to treatment. The maximum grade for each type of toxicity will be recorded for each patient. We report the number of patients experiencing a grade 3 or higher adverse event at least possibly related to treatment. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival time is defined as the time from registration to the time of death due to any cause. Estimated using the method of Kaplan-Meier. | From registration to death due to any cause, assessed up to 5 years | 
| Progression Free Survival | Progression free survival is defined as the time from registration to the time of progression or death, whichever occurs first. Estimated using the method of Kaplan-Meier. | From registration to documentation of disease progression, assessed up to 5 years | 
| Duration of Response | The date at which the objective status is first noted to be either a Complete Response (CR) or Partial Response (PR) to the date progression is documented, assessed up to 5 years. | From time of documented response to the date progression is documented, assessed up to 5 years. |