Bevacizumab and Irinotecan or Temozolomide in Treating Patients With Recurrent or Refractory Glioblastoma Multiforme or Gliosarcoma

Adult Glioblastoma Clinical Trial

Official title:

A Randomized Phase II Trial of Bevacizumab With Irinotecan or Bevacizumab With Temozolomide in Recurrent Glioblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00433381
• Other study ID #: NCI-2009-00743
• Secondary ID: NCI-2009-00743RT
• Status: Completed
• Phase: Phase 2
• Start date: March 1, 2007
• Est. completion date: February 16, 2011

Study information

• Verified date: August 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial is studying the side effects and how well giving bevacizumab together with irinotecan or temozolomide works in treating patients with recurrent or refractory glioblastoma multiforme or gliosarcoma. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan or temozolomide may kill more tumor cells.

Description:

PRIMARY OBJECTIVES:

I. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of 6-month progression-free survival rate, in patients with recurrent or refractory intracranial glioblastoma multiforme or gliosarcoma.

II. Determine the adverse event profile and tolerability of bevacizumab and temozolomide in these patients.

SECONDARY OBJECTIVES:

I. Determine the efficacy of bevacizumab and temozolomide, in terms of 6-month progression-free survival rate, in patients previously treated with temozolomide.

II. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of objective response, in patients with measurable disease.

III. Determine the efficacy of bevacizumab and temozolomide, in terms of objective response, in patients with measurable disease who were previously treated with temozolomide.

IV. Determine the toxicity profile and tolerability of bevacizumab and irinotecan hydrochloride in these patients.

TERTIARY OBJECTIVES:

I. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as an early indicator of response to therapy after 2 weeks of treatment with bevacizumab.

II. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as a prognostic indicator based on images taken at baseline, at 2 weeks, and after 2 courses of study treatment.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (< 50 vs >= 50 years of age) and Karnofsky performance status (70-80% vs 90-100%). Patients are randomized to 1 of 2 treatment arms with a 2:1 ratio (arm I:arm II).

ARM I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21.

ARM II: Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.

In both arms, treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. All patients undergo MRI at baseline and at every 2 courses (no 2-week MRI) per standard of care until progression or discontinuation of treatment to assess areas of breakdown of the blood-brain barrier. Patients undergo an additional MRI after study therapy. Consenting patients also undergo diffusion and perfusion MRI and magnetic resonance spectroscopic imaging for correlative studies.

After completion of study therapy, patients are followed up for at least 1 month.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 123
• Est. completion date: February 16, 2011
• Est. primary completion date: January 21, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma

• Original histology of low-grade glioma with subsequent histological diagnosis of GBM or gliosarcoma allowed

• Recurrent or refractory disease, meeting all of the following criteria:

• Must have received prior temozolomide

• Pathologic or imaging confirmation of tumor progression or regrowth required

• Confirmation of true progressive disease (rather than radiation necrosis) by positron emission tomography, thallium scanning, MRI spectroscopy, or surgical documentation required for patients who received prior interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery

• Unequivocal radiographic evidence of tumor progression by MRI within the past 14 days (while on a stable dose of steroids for ? 5 days)

• No acute intratumoral hemorrhage on MRI

• Patients with MRI demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) are eligible

• Karnofsky performance status 70-100%

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for at least 6 months after completion of bevacizumab therapy

• Systolic blood pressure ? 160 mm Hg or diastolic blood pressure ? 90 mm Hg (antihypertensive medication allowed)

• Able to undergo brain MRI scans with intravenous gadolinium

• Absolute neutrophil count ? 1,500 cells/mm?

• Platelet count ? 100,000 cells/mm?

• Hemoglobin ? 10 g/dL (transfusion or other intervention allowed)

• WBC ? 3,000 cells/mm?

• AST < 2 times upper limit of normal

• Bilirubin ? 1.6 mg/dL

• Creatinine < 1.5 mg/dL

• Urine protein:creatinine ratio ? 0.5 by urinalysis OR total urinary protein < 1,000 mg by 24-hour urine collection

• INR < 1.4 (for patients not on warfarin)

• No patients with severely impaired renal function (i.e., estimated glomerular filtration rate < 30 mL/min or on dialysis)

• No other prior invasive malignancy, except nonmelanomatous skin cancer or carcinoma in situ of the cervix, unless the patient has been disease free and off therapy for that disease for ? 3 years

• No severe, active comorbidity, defined as any of the following:

• Transmural myocardial infarction or unstable angina within the past 6 months

• Evidence of recent myocardial infarction or ischemia manifested as ST elevation of ? 2 mm by EKG performed within the past 14 days

• New York Heart Association class II-IV congestive heart failure requiring hospitalization within the past 12 months

• History of stroke or transient ischemic attack within the past 6 months

• Cerebrovascular accident within the past 6 months

• Serious and inadequately controlled cardiac arrhythmia

• Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)

• Clinically significant peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Serious or nonhealing wound, ulcer, or bone fracture

• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 14 days

• Acquired immune deficiency syndrome (AIDS)

• No significant traumatic injury within the past 28 days

• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication; requirement for IV alimentation; prior surgical procedures affecting absorption; or active peptic ulcer disease)

• No disease that would obscure toxicity or dangerously alter drug metabolism

• No concurrent major surgical procedures

• Recovered from prior therapy

• Recent resection of recurrent or progressive tumor allowed provided the following criteria are met:

• Failed prior radiotherapy that was completed ? 42 days ago

• Residual disease after resection of recurrent glioblastoma is not mandated

• More than 28 days since prior surgery or open biopsy

• More than 7 days since prior core or needle biopsy

• At least 28 days since prior investigational agents

• At least 14 days since prior vincristine

• At least 42 days since prior nitrosoureas

• At least 21 days since prior procarbazine

• At least 28 days since other prior cytotoxic therapy

• At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin [except radiosensitizers])

• At least 14 days since prior enzyme-inducing antiepileptic drugs (EIAEDs)

• Concurrent non-hepatic EIAEDs allowed

• No other concurrent CYP3A4 inducers, such as rifampin or Hypericum perforatum (St. John's wort)

• Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin) allowed provided all of the following criteria are met:

• No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

• In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulants or on a stable dose of low molecular weight heparin

• No concurrent highly active antiretroviral therapy

• No concurrent prophylactic use of growth factors

Related Conditions & MeSH terms

• Adult Glioblastoma
• Adult Gliosarcoma
• Brain Neoplasms
• Glioblastoma
• Gliosarcoma
• Recurrent Adult Brain Neoplasm

Intervention

Biological:
• Bevacizumab
Given IV

Drug:
• Irinotecan Hydrochloride
Given IV
• Temozolomide
Given orally

Locations

Country	Name	City	State
United States	Akron General Medical Center	Akron	Ohio
United States	New Mexico Oncology Hematology Consultants	Albuquerque	New Mexico
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Saint Vincent Anderson Regional Hospital/Cancer Center	Anderson	Indiana
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Franciscan Saint Francis Health-Beech Grove	Beech Grove	Indiana
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Northern Rockies Radiation Oncology Center	Billings	Montana
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Mills-Peninsula Medical Center	Burlingame	California
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	John Muir Medical Center-Concord Campus	Concord	California
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Dayton NCI Community Oncology Research Program	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Veteran Affairs Medical Center	Dayton	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	John F Kennedy Medical Center	Edison	New Jersey
United States	Fairbanks Memorial Hospital	Fairbanks	Alaska
United States	Saint Francis Hospital	Federal Way	Washington
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Unity Hospital	Fridley	Minnesota
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Marin General Hospital	Greenbrae	California
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	M D Anderson Cancer Center	Houston	Texas
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Cheshire Medical Center-Dartmouth-Hitchcock Keene	Keene	New Hampshire
United States	Kettering Medical Center	Kettering	Ohio
United States	EvergreenHealth Medical Center	Kirkland	Washington
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Providence Milwaukie Hospital	Milwaukie	Oregon
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Mobile Infirmary Medical Center	Mobile	Alabama
United States	Cottonwood Hospital Medical Center	Murray	Utah
United States	Intermountain Medical Center	Murray	Utah
United States	Yale University	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Sutter Cancer Research Consortium	Novato	California
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	Radiation Therapy Oncology Group	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Adventist Medical Center	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Reid Health	Richmond	Indiana
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Highland Hospital	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Dixie Medical Center Regional Cancer Center	Saint George	Utah
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Intermountain Health Care	Salt Lake City	Utah
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	University of Washington Medical Center	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Upper Valley Medical Center	Troy	Ohio
United States	Legacy Meridian Park Hospital	Tualatin	Oregon
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Greene Memorial Hospital	Xenia	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	American College of Radiology Imaging Network, Radiation Therapy Oncology Group

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Irinotecan Hydrochloride Arm	Progression defined as = 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased. Percentage is calculated by taking the number of patients who have survived 6 months without progression of study disease after study registration in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who were lost to follow-up after less than 6 months.	From randomization to six months.
Primary	Count/Percentage of Patients Discontinuing Treatment Due to Treatment-related Medical Complications(Bevacizumab and Temozolomide Arm)	This endpoint determines tolerability of this treatment arm. If tolerable, then the secondary endpoint of treatment efficacy for this arm occurs. Percentage is calculated by taking the number of patients who did not stop bevacizumab and temozolomide treatment due to medical complications in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who did not begin treatment.	From randomization to end of treatment (treatment can continue up to 24 months for patients with stable or responding tumor).
Primary	Number of Participants With Predicted Progression-free Survival at 6 Months (PFS-6)	Magnetic Resonance Imaging with Spectroscopy (MRS or MRSI) metabolic tumor ratios will be used to predict 6-month progression-free survival (PFS-6) over all study participants. Ratios of NAA/Cho, Cho/Cr, NAA/Cr measured at 2 weeks and 8 weeks and every 2 months until 96wks were used to predict survival, and time to progression, evaluated at 96wks, is the determinate of PFS at 6months (PFS-6). Subjects will not be analyzed by arm.	2 and 8 weeks posttreatment, and every 2 months until 96wks
Primary	Number of Participants With Predicted Overall Survival (OS) at 12 Months	Magnetic Resonance Imaging with Spectroscopy (MRS or MRSI) metabolic tumor ratios will be used to predict 12-month overall survival (OS).; Ratios of NAA/Cho, Cho/Cr, NAA/Cr measured at 2 weeks and 8 weeks and every 2 months until 96wks were used to predict survival, and time to death, evaluated at 96wks, is the determinate of OS at 12 months. Subjects will not be analyzed by arm.	2 and 8 weeks posttreatment, and every 2 months until 96wks
Secondary	Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Temozolomide Arm	Progression defined as = 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased. Percentage is calculated by taking the number of patients who have survived 6 months without progression of study disease after study registration in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who were lost to follow-up after less than 6 months.	From randomization to six months.
Secondary	Patients' Best Objective Response (Complete Response, Partial Response, Stable Disease, Progression)	Tumor size measured in millimeters and is the largest crosssectional area using perpendicular measurements of contrast enhancing abnormality. Complete response (CR): Complete disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off corticosteroids, and neurologically stable or improved. Partial response (PR): = 50% decrease in size of enhancing tumor on consecutive MRI scans at least 1 month apart, corticosteroids stable or reduced, and neurologically stable or improved. Progressive disease (PD): = 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased. Stable disease (SD): Does not qualify for CR, PR, or PD.	From randomization to death or last follow-up. Patients were followed up to 62.9 months.
Secondary	Agreement Between Local Interpretation and Central Interpretation of Standard MRI	Local and central interpretations of the standard MRI were assessed for progression and survival at all available imaging (baseline visit, week 2, and after every 2 cycles of treatment, and at termination of treatment). Patients who suffer clinical progression without radiographic confirmation of progression were considered to have progressive disease in determination of PFS-6. Subjects participated in the MR substudies regardless of therapeutic intervention	baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment
Secondary	Accuracy of Local PFS 6-mo Interpretation Using Central Review PFS-6 as the Reference Standard	Local reads were treated as the test and central reads were treated as the reference standard. Thus, a participant meeting the definition of progression on any standard MRI central interpretation (baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment) was considered positive for PFS-6. Therefore, a true positive is defined as a positive local interpretation for a subject with a positive central read.	baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment
Secondary	Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to N-acetylaspartate (NAA) (Lac/NAA) Ratio	Aim not included in final (February 10, 2009) protocol (removed from section 2).	2 weeks following initiation of protocol treatment (T1) and at 8 weeks following chemotherapy with bevacizumab (T2)
Secondary	Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response	Aim not included in final (February 10, 2009) protocol (removed from section 2)	2 weeks following initiation of protocol treatment (T1)
Secondary	Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival	Aim not included in final (February 10, 2009) protocol (removed from section 2)	2 weeks following initiation of protocol treatment (T1)
Secondary	Change in Perfusion MRI Markers at Week 2 as Predictors of 12mo Overall Survival (OS)	To assess the potential role of perfusion MRI as a prognostic indicator for 12-month OS based on the change in MRI markers evaluated before treatment and 2 weeks following initiation of protocol treatment. Percent change in mean tumor relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI normalized to white matter (nRCBV) and standardized rCBV (sRCBV) between baseline and week 2 are the prognostic indicators.	Baseline and 2 Weeks
Secondary	Change in Perfusion MRI Markers at Week 8 as Predictors of 12mo Overall Survival (OS)	To assess the potential role of perfusion MRI as a prognostic indicator for 12-month OS based on the change in MRI markers evaluated before treatment and 8 weeks following initiation of protocol treatment. Percent change in mean tumor relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI normalized to white matter (nRCBV) and standardized rCBV (sRCBV) between baseline and week 8 are the prognostic indicators.	Baseline and 8 weeks
Secondary	Change in Perfusion MRI Markers at Week 16 as Predictors of 12mo Overall Survival (OS)	To assess the potential role of perfusion MRI as a prognostic indicator for 12-month OS based on the change in MRI markers evaluated before treatment and 16 weeks following initiation of protocol treatment. Percent change in mean tumor relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI normalized to white matter (nRCBV) and standardized rCBV (sRCBV) between baseline and week 16 are the prognostic indicators.	Baseline and 16 Weeks