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

Condition(s) targeted: Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor

Intervention: irinotecan hydrochloride (Drug); bevacizumab (Biological); temozolomide (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Mark Gilbert, Principal Investigator, Affiliation: Radiation Therapy Oncology Group

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.

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

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Six-month Progression-free Survival (PFS) for Bevacizumab and Irinotecan Hydrochloride Arm

Rate of Treatment Discontinuation Due to Treatment-related Medical Complications(Bevacizumab and Temozolomide Arm)

Secondary outcome:

Six-month Progression-free Survival (Bevacizumab and Temozolomide Arm)

Best Objective Response Rate (Complete Response, Partial Response, Stable Disease, Progression) in Both Arms

Agreement Between Local Interpretation and Central Interpretation of the Standard MRI on the 6-month Progression-free Survival

Accuracy of Local Interpretation on the 6-month Progression-free Survival Using Central Review as the Reference Standard

Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to N-acetylaspartate (NAA) (Lac/NAA) Ratio

Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response

Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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/mm³

- Platelet count ≥ 100,000 cells/mm³

- Hemoglobin ≥ 10 g/dL (transfusion or other intervention allowed)

- WBC ≥ 3,000 cells/mm³

- 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

Mobile Infirmary Medical Center, Mobile, Alabama 36607, United States

Fairbanks Memorial Hospital, Fairbanks, Alaska 99701, United States

Sutter Solano Medical Center, Vallejo, California 94589, United States

Yale University, New Haven, Connecticut 06520, United States

Boca Raton Regional Hospital, Boca Raton, Florida 33486, United States

University of Chicago, Chicago, Illinois 60637, United States

Saint Francis Hospital and Health Centers, Beech Grove, Indiana 46107, United States

Reid Hospital and Health Care Services, Richmond, Indiana 47374, United States

University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, United States

Henry Ford Hospital, Detroit, Michigan 48202, United States

William Beaumont Hospital-Royal Oak, Royal Oak, Michigan 48073, United States

Washington University School of Medicine, Saint Louis, Missouri 63110, United States

Northern Rockies Radiation Oncology Center, Billings, Montana 59101, United States

Cheshire Medical Center-Dartmouth-Hitchcock Keene, Keene, New Hampshire 03431, United States

Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States

John F Kennedy Medical Center, Edison, New Jersey 08818, United States

Highland Hospital, Rochester, New York 14620, United States

University of Rochester, Rochester, New York 14642, United States

Mission Hospital-Memorial Campus, Asheville, North Carolina 28801, United States

Carolinas Medical Center, Charlotte, North Carolina 28203, United States

Dayton CCOP, Dayton, Ohio 45420, United States

Good Samaritan Hospital - Dayton, Dayton, Ohio 45406, United States

Grandview Hospital, Dayton, Ohio 45405, United States

Miami Valley Hospital, Dayton, Ohio 45409, United States

Samaritan North Health Center, Dayton, Ohio 45415, United States

Veteran Affairs Medical Center, Dayton, Ohio 45428, United States

Blanchard Valley Hospital, Findlay, Ohio 45840, United States

Atrium Medical Center-Middletown Regional Hospital, Franklin, Ohio 45005-1066, United States

Kettering Medical Center, Kettering, Ohio 45429, United States

Upper Valley Medical Center, Troy, Ohio 45373, United States

Greene Memorial Hospital, Xenia, Ohio 45385, United States

Adventist Medical Center, Portland, Oregon 97216, United States

Radiation Therapy Oncology Group, Philadelphia, Pennsylvania 19103, United States

M D Anderson Cancer Center, Houston, Texas 77030, United States

American Fork Hospital, American Fork, Utah 84003, United States

Sandra L Maxwell Cancer Center, Cedar City, Utah 84720, United States

Cottonwood Hospital Medical Center, Murray, Utah 84107, United States

Intermountain Medical Center, Murray, Utah 84157, United States

McKay-Dee Hospital Center, Ogden, Utah 84403, United States

Utah Valley Regional Medical Center, Provo, Utah 84604-3337, United States

Dixie Medical Center Regional Cancer Center, Saint George, Utah 84770, United States

Intermountain Health Care, Salt Lake City, Utah 84103, United States

LDS Hospital, Salt Lake City, Utah 84143, United States

Utah Cancer Specialists-Salt Lake City, Salt Lake City, Utah 84106, United States

Norris Cotton Cancer Center-North, Saint Johnsbury, Vermont 05819, United States

Saint Francis Hospital, Federal Way, Washington 98003, United States

Evergreen Hospital Medical Center, Kirkland, Washington 98033, United States

University of Washington Medical Center, Seattle, Washington 98195, United States

Virginia Mason CCOP, Seattle, Washington 98101, United States

University of Wisconsin Hospital and Clinics, Madison, Wisconsin 53792, United States

Froedtert and the Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States

Starting date: March 2007
Last updated: May 7, 2014