Pazopanib in Treating Patients With Recurrent Glioblastoma

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying the side effects and how well pazopanib works in treating patients with recurrent glioblastoma. Pazopanib 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. Determine the therapeutic efficacy of pazopanib hydrochloride, as measured by 6-month progression-free survival (PFS), in patients with recurrent glioblastoma. II. Determine the safety profile of this drug in these patients. SECONDARY OBJECTIVES: I. Determine the efficacy of this drug, as measured by radiographic response, time to progression, and overall survival, in these patients. OUTLINE: This is a multicenter study. Patients receive oral pazopanib hydrochloride daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for at least 2 years.

Official Title
-----------------
A Phase II Trial of GW786034 (Pazopanib) in Patients With Recurrent Glioblastoma

Conditions
-----------------
Recurrent Adult Brain Tumor, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
-----------------
* Drug: pazopanib hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed glioblastoma multiforme, including gliosarcoma Recurrent disease Must have unequivocal radiographic evidence of tumor progression by MRI, as defined by any of the following: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline Clear worsening of any evaluable disease Appearance of any new lesions or site Clear clinical worsening Must have failed prior radiotherapy that was completed ≥ 42 days ago Patients who received prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease, rather than radiation necrosis, based on positron emission tomography (PET) scan, thallium scanning, magnetic resonance spectroscopy, or surgical documentation of disease Treatment for no more than 2 prior relapses allowed Relapse is defined as progression following initial therapy (i.e., radiotherapy with or without chemotherapy, if that was used as initial therapy; therefore no more than 3 prior therapies [initial therapy and therapy for 2 relapses] allowed) If the patient had a surgical resection for relapsed disease and no anticancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse For patients who had prior therapy for a low-grade glioma, the surgical diagnosis of a glioblastoma multiforme will be considered the first relapse Karnofsky performance status 60-100% Life expectancy > 8 weeks WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Hemoglobin ≥ 10 g/dL (may be reached by transfusion) Platelet count ≥ 100,000/mm^3 PT/INR/PTT ≤ 1.2 times upper limit of normal (ULN) SGOT < 2.5 times ULN Bilirubin < 2.5 times ULN Creatinine < 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min Urine protein:creatinine ratio > 1 OR urine protein < 1,000 mg by 24-hour urine collection OR proteinuria < 1+ Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-barrier contraception during study therapy OR practice abstinence from sexual intercourse for 14 days prior to, during, and for ≥ 21 days after study therapy Systolic blood pressure (BP) ≤ 140 mm Hg and diastolic BP ≤ 90 mm Hg Prior initiation or adjustment of BP medication allowed provided the average of 3 BP readings is ≤ 140/90 mm Hg No uncontrolled significant medical illnesses that would preclude study therapy No other conditions, including any of the following: Serious or nonhealing wound, ulcer, or bone fracture Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days Cerebrovascular accident (CVA) within the past 6 months Myocardial infarction, cardiac arrhythmia, admission for unstable angina, cardiac angioplasty, or stenting within the past 84 days Venous thrombosis within the past 84 days New York Heart Association (NYHA) class III or IV heart failure Asymptomatic NYHA class II heart failure while on treatment allowed No other cancer except for nonmelanoma skin cancer or carcinoma in situ of the cervix unless in complete remission and off of all therapy for that disease for ≥ 3 years No disease that would obscure toxicity or dangerously alter drug metabolism No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or other agents No QTc prolongation (i.e., QTc interval ≥ 500 msecs) or other significant ECG abnormalities No condition that impairs 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 See Disease Characteristics Recovered from prior therapy At least 28 days since prior resection of recurrent or progressive tumor and recovered Residual disease after resection of recurrent glioblastoma is not mandated for eligibility into the study More than 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin) Radiosensitizers allowed More than 14 days since prior investigational agents More than 14 days since prior vincristine More than 21 days since prior procarbazine More than 28 days since prior cytotoxic therapy More than 42 days since prior nitrosoureas No prior bevacizumab No prior sorafenib tosylate or sunitinib malate No prior pazopanib hydrochloride No concurrent CYP2C9 substrates, including any of the following: Anticoagulants (e.g., warfarin [therapeutic doses only]) Oral hypoglycemics (e.g., glipizide, glyburide, tolbutamide, glimepiride, or nateglinide) Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, or methylergonovine) Neuroleptics (e.g., pimozide) Erectile dysfunction agents (e.g., sildenafil, tadalafil, or vardenafil) Antiarrhythmics (e.g., bepridil, flecainide, lidocaine, mexilitine, amiodarone, quinidine, or propafenone) Immune modulators (e.g., cyclosporine, tacrolimus, or sirolimus) Miscellaneous drugs (e.g., theophylline, quetiapine, risperidone, tacrine, clozapine, or atomoxetine) No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy (including chemotherapy, radiotherapy, hormonal treatment, or immunotherapy) or investigational drugs No concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) Non-EIAEDs allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 oral pazopanib hydrochloride daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Other: laboratory biomarker analysis | Drug: pazopanib hydrochloride<br>* Given orally<br>* Other names: Votrient;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Months Progression-free Survival | Calculated from study registration till 6month time point. Progression defined by Macdonald criteria Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration | 6 months | 
| Number of Participants Discontinuing Treatment Due to Toxicity | Use NCI Common toxicity Criteria Adverse Event Version 3.0 to grade toxicities. Any patient who received at least one dose of pazopanib was evaluable for toxicity. Calculated the number of participants who had an event that was related to pazopanib that caused the patient to stop treatment due to this event. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Most Common Toxicities Experienced After at Least One Dose of Pazopanib | NCI Common Toxicity Criteria (CTCAE) version 3.0. All patients that received at least one dose of pazopanib were evaluable. All events recorded that were related to drug were calculated per patient. | Up to 2 years | 
| Overall Radiographic Response (ORR) Rate | The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (MRI) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration | 2 years | 
| Best Radiographic Response | Using the Macdonald criteria, the best MRI image response while the patient was on active treatment. 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration | 3 years | 
| Overall Survival | calculated from study registration until date of death or patient censored at the last date known alive | From date of registration to date of death due to any cause, assessed up to 2 years | 
| Time to Progression or Progression Free Survival | PFS for patients who died on treatment or within 30 days of the end of treatment w/out progression date, was date of death. All other pts without documented progression were censored at the date of last follow-up prior to start new treatment. All 35 patients were included in an intent to treat analysis for PFS and OS. 3 pts censored for PFS, all less than 2 wks after study registration. | 1 year |