Clinical trial NCT00861913: Pazopanib Hydrochloride in Treating Patients With Metastatic Melanoma That Cannot be Removed by Surgery
Official title: Phase II Trial of Pazopanib (GW786034) in Pre-Treated and Untreated Metastatic Melanoma Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent Melanoma
Stage IV Cutaneous Melanoma AJCC v6 and v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-03-16
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Tumor Response Rate
timeFrame: Up to 5 years
measure: Toxicity
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall Survival
timeFrame: From registration to death due to any cause, assessed up to 5 years
measure: Progression Free Survival
timeFrame: From registration to documentation of disease progression, assessed up to 5 years
measure: Duration of Response
timeFrame: From time of documented response to the date progression is documented, assessed up to 5 years.
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Amy Weise
role: PRINCIPAL_INVESTIGATOR
References: