Phase II Trial of Pazopanib (GW786034) in Pre-Treated and Untreated Metastatic Melanoma Patients
Phase II Trial of Pazopanib (GW786034) in Pre-Treated and Untreated Metastatic Melanoma Patients
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.
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.
Inclusion Criteria:
Histologically confirmed unresectable malignant melanoma
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
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
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
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