Pazopanib Hydrochloride in Treating Patients With Stage IV or Recurrent Nasopharyngeal Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well pazopanib hydrochloride works in treating patients with stage IV or recurrent nasopharyngeal cancer. 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. Determine the efficacy of pazopanib hydrochloride in patients with stage IV or recurrent nasopharyngeal carcinoma. II. Determine the progression-free survival of patients treated with this drug. III. Determine the toxicity of this drug in these patients. IV. Determine the effect of this drug on angiogenesis inhibition using dynamic contrast-enhanced computed tomography (CT) scan. V. Determine the pharmacokinetic profile of this drug in these patients. VI. Correlate the effect of this drug on angiogenesis inhibition with the clinical benefit rate and pharmacokinetics. OUTLINE: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 12 months.

Official Title
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A Phase 2 Study of GW786034 (Pazopanib) in Asian Patients With Recurrent/Metastatic Nasopharyngeal Carcinoma

Conditions
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Recurrent Lymphoepithelioma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Stage IV Lymphoepithelioma of the Nasopharynx, Stage IV Squamous Cell Carcinoma of the Nasopharynx

Intervention / Treatment
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* Drug: pazopanib hydrochloride
* Other: pharmacological study
* Procedure: computed tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed nasopharyngeal carcinoma, meeting the following criteria: World Health Organization (WHO) type II-III disease Stage IV or recurrent disease Must have failed at least 1 prior line of chemotherapy for metastatic or recurrent disease Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques OR >= 10 mm by spiral CT scan No known brain metastases Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 or Karnofsky PS 70-100% Life expectancy > 3 months WBC >= 3,000/mm³ Absolute neutrophil count >= 1,500/mm³ Platelet count >= 100,000/mm³ Bilirubin normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (ULN) Creatinine normal OR creatinine clearance >= 60 mL/min Proteinuria =< 1+ on 2 consecutive dipsticks taken >= 1 week apart Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) =< 1.2 times ULN Systolic blood pressure (BP) =< 140 mm Hg and diastolic BP =< 90 mm Hg Initiation or adjustment of BP medication allowed provided the average of 3 BP readings are < 140/90 mm Hg prior to study entry No history of allergic reaction attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or to other study agents No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No cerebrovascular accident within the past 6 months No history of any of the following diseases within the past 12 weeks: Myocardial infarction Cardiac arrhythmia Admission for unstable angina Cardiac angioplasty or stenting Venous thrombosis No New York Heart Association (NYHA) class III-IV heart failure Patients with a history of NYHA class II heart failure are eligible provided they are asymptomatic on treatment No significant electrocardiogram (ECG) abnormalities, including QTc prolongation (i.e., QTc >= 500 msec) No serious or non-healing wound, ulcer, or bone fracture No condition that would impair the ability to swallow and retain pazopanib hydrochloride, including any of the following: Gastrointestinal tract disease resulting in an inability to take oral medication Requirement for IV alimentation Prior surgical procedures affecting absorption Active peptic ulcer disease No concurrent uncontrolled illness including, but not limited to, the following: Coagulopathy Ongoing or active infection Psychiatric illness or social situation that would preclude study compliance No known allergy to CT contrast agents Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered More than 4 weeks since prior radiotherapy At least 4 weeks since prior surgery No prior antiangiogenesis therapy No other concurrent investigational agents No other concurrent anticancer therapy No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib hydrochloride, as determined by the Principal Investigator No concurrent medications that have the potential to interact with the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4 No concurrent therapeutic warfarin Low molecular weight heparin or prophylactic low-dose warfarin allowed No concurrent antiretroviral therapy for human immunodeficiency virus (HIV)-positive patients

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 pazopanib hydrochloride PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Pharmacological study will be done on Day 1 and Day 28. Computed tomography will be done at baseline and day 28. | Drug: pazopanib hydrochloride<br>* Given PO<br>* Other names: Votrient;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: computed tomography<br>* Correlative studies<br>* Other names: tomography, computed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate | Clinical benefit rate (CBR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST ver 1.0) and assessed by CT or MRI. CBR includes 1) Complete response (CR): disappearance of all lesions; 2) partial response (PR): >=30% decrease in the sum of the longest diameter of target lesions and 3) stable disease (SD): non-PR and non progressive disease. | 12 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (PR) | Per response evaluation criteria in solid tumors (RECIST v1.0) and assessed by MRI or CT: Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions and non-PD (PD: progressive disease) of non-target lesions. | 12 weeks of treatment | 
| Progression-free Survival | Progression will be evaluated in this study using the new international criteria proposed by RECIST Committee. The sample proportion and associated 95% confidence interval will be reported. | From the date of enrollment to the date of first documented progression or death, whichever occurs first, or to the date when the patient was last known to be alive, up to 3 years. | 
| Overall Survival |  | From date of enrollment to the study to the date of death from any cause or to the date when the patient was last known to be alive, up to 3 years. | 
| Toxicity Profile: Percentage of Participants With Significant (Grade 3/4) Related Adverse Event (AE) | The frequencies of grade 3/4 related toxicities were recorded among all participants, and the percentage of participants who experienced significant AEs were reported. | From the time of first treatment with pazopanib hydrochloride to up to 30days after completion of treatment | 
| Pharmacodynamic Study: Tumor Blood Flow at Baseline | Dynamic-contrast enhanced computed tomography (DCE-CT) was performed at baseline and Day 28, tumor blood flow was measured.19 of 33 patients had evaluable DCE-CT data. | Pretreatment | 
| Pharmacodynamic Study: Tumor Blood Flow on Day 28 | DCE-CT was performed on Day 28 and tumor blood flow was measured. 19 of 33 patients had evaluable DCE-CT data. | 28 days post treatment | 
| Pharmacokinetic Study: Percentage of Participants With Trough Concentration at Steady State (Day 28) Above 15 µg/mL | Pazopanib pharmacokinetic parameters were estimated on Day 1 and Day 28 (steady state). Trough concentration of pazopanib was measured on Day 28 with blood sampling at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after Day 28 dose. | Day 28 of treatment | 
| Pharmacokinetic Study: AUC0-24h/Dose on Day 1 | AUC 0-24h/dose were measured on day 1 for 26 evaluable participants. Blood sampling is done at zero (pre-dose), 0.5 hr, 1, 2, 3, 4, 5, 6 and 8 hrs after the first dose. | Day 1 of treatment | 
| Pharmacokinetic Study: Area Under Curve (AUC) 0-24h/Dose on Day 28 | AUC 0-24h/dose were measured on day 28 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after day 28 dose. | Day 28 of treatment | 
| Pharmacokinetic Study: Volume of Distribution (Vd/F/Dose) on Day 1 | Volume of distribution (Vd/F/dose) were measured on day 1 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 hrs after first dose. | Day 1 of treatment | 
| Pharmacokinetic Study: Volume of Distribution at Steady State (Vss/F/Dose) on Day 28 | Volume of distribution at steady state (Vss/F/Dose) were measured on day 28 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after day 28 dose. | Day 28 of treatment |