Recurrent Melanoma, Stage IV Cutaneous Melanoma AJCC v6 and v7
Conditions
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPazopanib Hydrochloride
Given orally
OTHERPharmacological Study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate | Up to 5 years | 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. |
| Toxicity | Up to 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From registration to death due to any cause, assessed up to 5 years | 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. |
| Progression Free Survival | From registration to documentation of disease progression, assessed up to 5 years | 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. |
| Duration of Response | From time of documented response to the date progression is documented, assessed up to 5 years. | 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. |
Countries
United States
Participant flow
Recruitment details
From April 2009 to July 2009, 13 participants were registered.
Pre-assignment details
All participants were evaluable for all endpoints and toxicity.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Pazopanib Hydrochloride) Patients receive 800 mg oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Treatment (Pazopanib Hydrochloride) |
|---|---|
| Age, Continuous | 64 years |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 5 / 13 |
Outcome results
Primary
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.
Time frame: Up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Toxicity | Grade 3 | 8 participants |
| Treatment (Pazopanib Hydrochloride) | Toxicity | Grade 4 or higher | 0 participants |
Primary
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.
Time frame: Up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Tumor Response Rate | 7.7 percentage of patients |
Secondary
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.
Time frame: From time of documented response to the date progression is documented, assessed up to 5 years.
Population: There was one response and therefore median duration of response was not analyzed.
Secondary
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.
Time frame: From registration to death due to any cause, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Overall Survival | 13.6 months |
Secondary
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.
Time frame: From registration to documentation of disease progression, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Progression Free Survival | 3.9 months |