Clinical trial NCT00433381: Bevacizumab and Irinotecan or Temozolomide in Treating Patients With Recurrent or Refractory Glioblastoma Multiforme or Gliosarcoma
Official title: A Randomized Phase II Trial of Bevacizumab With Irinotecan or Bevacizumab With Temozolomide in Recurrent Glioblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Neoplasm
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: American College of Radiology Imaging Network
name: Radiation Therapy Oncology Group
First posted: 2007-02-12
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Irinotecan Hydrochloride Arm
timeFrame: From randomization to six months.
measure: Count/Percentage of Patients Discontinuing Treatment Due to Treatment-related Medical Complications(Bevacizumab and Temozolomide Arm)
timeFrame: From randomization to end of treatment (treatment can continue up to 24 months for patients with stable or responding tumor).
measure: Number of Participants With Predicted Progression-free Survival at 6 Months (PFS-6)
timeFrame: 2 and 8 weeks posttreatment, and every 2 months until 96wks
measure: Number of Participants With Predicted Overall Survival (OS) at 12 Months
timeFrame: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Secondary outcomes:
measure: Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Temozolomide Arm
timeFrame: From randomization to six months.
measure: Patients' Best Objective Response (Complete Response, Partial Response, Stable Disease, Progression)
timeFrame: From randomization to death or last follow-up. Patients were followed up to 62.9 months.
measure: Agreement Between Local Interpretation and Central Interpretation of Standard MRI
timeFrame: baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment
measure: Accuracy of Local PFS 6-mo Interpretation Using Central Review PFS-6 as the Reference Standard
timeFrame: baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment
measure: Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to N-acetylaspartate (NAA) (Lac/NAA) Ratio
timeFrame: 2 weeks following initiation of protocol treatment (T1) and at 8 weeks following chemotherapy with bevacizumab (T2)
measure: Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response
timeFrame: 2 weeks following initiation of protocol treatment (T1)
measure: Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival
timeFrame: 2 weeks following initiation of protocol treatment (T1)
measure: Change in Perfusion MRI Markers at Week 2 as Predictors of 12mo Overall Survival (OS)
timeFrame: Baseline and 2 Weeks
measure: Change in Perfusion MRI Markers at Week 8 as Predictors of 12mo Overall Survival (OS)
timeFrame: Baseline and 8 weeks
measure: Change in Perfusion MRI Markers at Week 16 as Predictors of 12mo Overall Survival (OS)
timeFrame: Baseline and 16 Weeks
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Mobile Infirmary Medical Center
state: Alabama
city: Fairbanks
country: United States
facility: Fairbanks Memorial Hospital
state: Alaska
city: Scottsdale
country: United States
facility: Arizona Oncology Services Foundation
state: Arizona
city: Berkeley
country: United States
facility: Alta Bates Summit Medical Center-Herrick Campus
state: California
city: Burlingame
country: United States
facility: Mills-Peninsula Medical Center
state: California
city: Concord
country: United States
facility: John Muir Medical Center-Concord Campus
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Greenbrae
country: United States
facility: Marin General Hospital
state: California
city: Novato
country: United States
facility: Sutter Cancer Research Consortium
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center-Pacific Campus
state: California
city: Vallejo
country: United States
facility: Sutter Solano Medical Center/Cancer Center
state: California
city: Walnut Creek
country: United States
facility: John Muir Medical Center-Walnut Creek
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Boise
country: United States
facility: Saint Luke's Mountain States Tumor Institute
state: Idaho
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Anderson
country: United States
facility: Saint Vincent Anderson Regional Hospital/Cancer Center
state: Indiana
city: Beech Grove
country: United States
facility: Franciscan Saint Francis Health-Beech Grove
state: Indiana
city: Indianapolis
country: United States
facility: IU Health Methodist Hospital
state: Indiana
city: Richmond
country: United States
facility: Reid Health
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Annapolis
country: United States
facility: Anne Arundel Medical Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital-Royal Oak
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview-Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott-Northwestern Hospital
state: Minnesota
city: Robbinsdale
country: United States
facility: North Memorial Medical Health Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology PA-Woodbury
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Billings
country: United States
facility: Northern Rockies Radiation Oncology Center
state: Montana
city: Keene
country: United States
facility: Cheshire Medical Center-Dartmouth-Hitchcock Keene
state: New Hampshire
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Edison
country: United States
facility: John F Kennedy Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology Hematology Consultants
state: New Mexico
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: Highland Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheville
country: United States
facility: Mission Hospital-Memorial Campus
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Akron
country: United States
facility: Akron General Medical Center
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital - Dayton
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Health Center
state: Ohio
city: Dayton
country: United States
facility: Dayton NCI Community Oncology Research Program
state: Ohio
city: Dayton
country: United States
facility: Veteran Affairs Medical Center
state: Ohio
city: Findlay
country: United States
facility: Blanchard Valley Hospital
state: Ohio
city: Franklin
country: United States
facility: Atrium Medical Center-Middletown Regional Hospital
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Troy
country: United States
facility: Upper Valley Medical Center
state: Ohio
city: Xenia
country: United States
facility: Greene Memorial Hospital
state: Ohio
city: Gresham
country: United States
facility: Legacy Mount Hood Medical Center
state: Oregon
city: Milwaukie
country: United States
facility: Providence Milwaukie Hospital
state: Oregon
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital and Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Adventist Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Portland
country: United States
facility: Legacy Emanuel Hospital and Health Center
state: Oregon
city: Tualatin
country: United States
facility: Legacy Meridian Park Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Radiation Therapy Oncology Group
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: American Fork
country: United States
facility: American Fork Hospital / Huntsman Intermountain Cancer Center
state: Utah
city: Cedar City
country: United States
facility: Sandra L Maxwell Cancer Center
state: Utah
city: Murray
country: United States
facility: Cottonwood Hospital Medical Center
state: Utah
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital Center
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Saint George
country: United States
facility: Dixie Medical Center Regional Cancer Center
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain Health Care
state: Utah
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists-Salt Lake City
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Saint Johnsbury
country: United States
facility: Norris Cotton Cancer Center-North
state: Vermont
city: Federal Way
country: United States
facility: Saint Francis Hospital
state: Washington
city: Kirkland
country: United States
facility: EvergreenHealth Medical Center
state: Washington
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Vancouver
country: United States
facility: PeaceHealth Southwest Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Radiation Therapy Oncology Group
name: Mark Gilbert
role: PRINCIPAL_INVESTIGATOR
References: