Pazopanib in Treating Patients With Recurrent Glioblastoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00459381
• Collaborator: (none)
• Enrollment: 35
• Locations: 9
• Arm: 1
• Duration (Months): 19.1
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor	Drug: pazopanib hydrochloride; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the therapeutic efficacy of pazopanib hydrochloride, as measured by 6-month progression-free survival (PFS), in patients with recurrent glioblastoma.

2. Determine the safety profile of this drug in these patients.

SECONDARY OBJECTIVES:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of GW786034 (Pazopanib) in Patients With Recurrent Glioblastoma
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: pazopanib hydrochloride; Given orally; Other Names: GW786034B Votrient ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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.

2. 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

3. 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

4. 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

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles	Los Angeles	California	United States	90095
2	University of California San Francisco	San Francisco	California	United States	94115
3	National Cancer Institute Neuro-Oncology Branch	Bethesda	Maryland	United States	20814
4	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
5	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
6	Duke University	Durham	North Carolina	United States	27710
7	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15232
8	MD Anderson Cancer Center	Houston	Texas	United States	77030
9	University of Wisconsin	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Howard Fine, MD, North American Brain Tumor Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00459381
• Other Study ID Numbers: NCI-2012-02710; NABTC-0602; U01CA062399; CDR0000538083
• First Posted: Apr 11, 2007
• Last Update Posted: Mar 15, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Recurrence

Study Results

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

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Period Title: Overall Study
STARTED	35
COMPLETED	35
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Overall Participants	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	13 37.1%
Male	22 62.9%
Karnofsky Performance Status Scale (participants) [Number]
90-100	26 74.3%
60-80	9 25.7%
Prior Radiotherapy (participants) [Number]
Number [participants]	35 100%
Time from Radiotherapy to study enrollment (months) [Median (Full Range) ]
Median (Full Range) [months]	10
Number of Prior chemotherapy reginmens (participants) [Number]
1	24 68.6%
2	9 25.7%
3	2 5.7%
Surgery for recurrence for current progression prior to enrollment (participants) [Number]
Yes	8 22.9%
No	27 77.1%

Outcome Measures

1. Primary Outcome

Title	6 Months Progression-free Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	35
Number (95% Confidence Interval) [percent]	3

2. Primary Outcome

Title	Number of Participants Discontinuing Treatment Due to Toxicity
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	35
thrombotic/embolic	3 8.6%
CNS hemorrhage	1 2.9%

3. Secondary Outcome

Title	Most Common Toxicities Experienced After at Least One Dose of Pazopanib
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	35
hypertension	37 105.7%
fatigue	34 97.1%
elevated ALT	40 114.3%

4. Secondary Outcome

Title	Overall Radiographic Response (ORR) Rate
Description	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

Outcome Measure Data

Analysis Population Description

34 pts had follow-up scans and wee evaluable for objective radiographic response (ORR)

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	34
Number (95% Confidence Interval) [percent]	5.9

5. Secondary Outcome

Title	Best Radiographic Response
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	34
Progressive Disease	32 91.4%
Stable Disease	62 177.1%
Partial Response	6 17.1%

6. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

All 35 patients were included in an intent to treat analysis for PFS and OS.

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	35
Median (95% Confidence Interval) [weeks]	35

7. Secondary Outcome

Title	Time to Progression or Progression Free Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
Measure Participants	35
Median (95% Confidence Interval) [weeks]	12

Adverse Events

Time Frame	2 years
Arm/Group Title	Treatment (Pazopanib Hydrochloride)
Arm/Group Description	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
All Cause Mortality
	Treatment (Pazopanib Hydrochloride)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Pazopanib Hydrochloride)
	Affected / at Risk (%)	# Events
Total	0/35 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Pazopanib Hydrochloride)
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
anemia	5/35 (14.3%)	5
Leukopenia	7/35 (20%)	7
lymphopenia	12/35 (34.3%)	12
neutropenia	5/35 (14.3%)	5
Gastrointestinal disorders
constipation	2/35 (5.7%)	2
diarrhea	5/35 (14.3%)	5
abdominal distension	2/35 (5.7%)	2
flatulence	3/35 (8.6%)	3
dyspepsia	4/35 (11.4%)	4
abdominal pain	2/35 (5.7%)	2
General disorders
fatigue	12/35 (34.3%)	12
Investigations
Thrombocytopenia	9/35 (25.7%)	9
weight loss	2/35 (5.7%)	2
elevated ALT	14/35 (40%)	14
elevated AST	8/35 (22.9%)	8
hyperbilirubinemia	7/35 (20%)	7
Metabolism and nutrition disorders
anorexia	2/35 (5.7%)	2
hypermagnesemia	3/35 (8.6%)	3
hypoalbuminemia	3/35 (8.6%)	3
hypophosphatemia	3/35 (8.6%)	3
proteinuria	2/35 (5.7%)	2
Musculoskeletal and connective tissue disorders
pain in extremity	4/35 (11.4%)	4
Nervous system disorders
Intracranial hemorrhage	3/35 (8.6%)	3
Respiratory, thoracic and mediastinal disorders
epistaxis	4/35 (11.4%)	4
Vascular disorders
arterial hypertension	13/35 (37.1%)	13
thromboembolic event	2/35 (5.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.