Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
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.
Interventions
DRUGpazopanib hydrochloride
Given orally
OTHERlaboratory biomarker analysis
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Months Progression-free Survival | 6 months | 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 |
| Number of Participants Discontinuing Treatment Due to Toxicity | 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Radiographic Response | 3 years | 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 |
| Most Common Toxicities Experienced After at Least One Dose of Pazopanib | Up to 2 years | 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. |
| Time to Progression or Progression Free Survival | 1 year | 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. |
| Overall Survival | From date of registration to date of death due to any cause, assessed up to 2 years | calculated from study registration until date of death or patient censored at the last date known alive |
| Overall Radiographic Response (ORR) Rate | 2 years | 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 |
Countries
United States
Participant flow
Recruitment details
Subjects accrued between June 2007 to January 2008 at 4 NABTC Cancer Centers using their outpatient facilities. Survival follow-up extended to June 2009
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Pazopanib Hydrochloride) 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
pazopanib hydrochloride: Given orally
laboratory biomarker analysis: Correlative studies | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | Treatment (Pazopanib Hydrochloride) |
|---|---|
| Age, Continuous | 53 years |
| Karnofsky Performance Status Scale 60-80 | 9 participants |
| Karnofsky Performance Status Scale 90-100 | 26 participants |
| Number of Prior chemotherapy reginmens 1 | 24 participants |
| Number of Prior chemotherapy reginmens 2 | 9 participants |
| Number of Prior chemotherapy reginmens 3 | 2 participants |
| Prior Radiotherapy | 35 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 22 Participants |
| Surgery for recurrence for current progression prior to enrollment No | 27 participants |
| Surgery for recurrence for current progression prior to enrollment Yes | 8 participants |
| Time from Radiotherapy to study enrollment | 10 months |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 35 |
| serious Total, serious adverse events | 0 / 35 |
Outcome results
Primary
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
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | 6 Months Progression-free Survival | 3 percent |
Primary
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.
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Number of Participants Discontinuing Treatment Due to Toxicity | thrombotic/embolic | 3 Participants |
| Treatment (Pazopanib Hydrochloride) | Number of Participants Discontinuing Treatment Due to Toxicity | CNS hemorrhage | 1 Participants |
Secondary
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
Time frame: 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Best Radiographic Response | Progressive Disease | 32 percentage of participants |
| Treatment (Pazopanib Hydrochloride) | Best Radiographic Response | Stable Disease | 62 percentage of participants |
| Treatment (Pazopanib Hydrochloride) | Best Radiographic Response | Partial Response | 6 percentage of participants |
Secondary
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.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Most Common Toxicities Experienced After at Least One Dose of Pazopanib | hypertension | 37 percentage of participants |
| Treatment (Pazopanib Hydrochloride) | Most Common Toxicities Experienced After at Least One Dose of Pazopanib | fatigue | 34 percentage of participants |
| Treatment (Pazopanib Hydrochloride) | Most Common Toxicities Experienced After at Least One Dose of Pazopanib | elevated ALT | 40 percentage of participants |
Secondary
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
Time frame: 2 years
Population: 34 pts had follow-up scans and wee evaluable for objective radiographic response (ORR)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Overall Radiographic Response (ORR) Rate | 5.9 percent |
Secondary
Overall Survival
calculated from study registration until date of death or patient censored at the last date known alive
Time frame: From date of registration to date of death due to any cause, assessed up to 2 years
Population: All 35 patients were included in an intent to treat analysis for PFS and OS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Overall Survival | 35 weeks |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Time to Progression or Progression Free Survival | 12 weeks |