Phase II Trial of Pazopanib (GW786034) in Pre-Treated and Untreated Metastatic Melanoma Patients
18 Years
N/A
Both
Recurrent Melanoma, Stage IV Melanoma
Trial Information
Phase II Trial of Pazopanib (GW786034) in Pre-Treated and Untreated Metastatic Melanoma Patients
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
- 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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Tumor response rate defined as the number of eligible patients whose disease status meets the RECIST criteria for CR or PR
Outcome Description:
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.
Outcome Time Frame:
Up to 5 years
Safety Issue:
No
Principal Investigator
Amy Weise
Investigator Role:
Principal Investigator
Investigator Affiliation:
Mayo Clinic
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-01163
NCT ID:
NCT00861913
Start Date:
April 2009
Completion Date:
Related Keywords:
- Recurrent Melanoma
- Stage IV Melanoma
- Melanoma
Name | Location |
|---|---|
| Mayo Clinic | Rochester, Minnesota 55905 |
| University of Wisconsin Hospital and Clinics | Madison, Wisconsin 53792-0001 |
