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Dasatinib and Bevacizumab in ...

Dasatinib and Bevacizumab in Treating Patients With Recurrent or Progressive High-Grade Glioma or Glioblastoma Multiforme

Last Updated: 2019-10-21

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

144 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-10-31

Study Completion Date

2019-07-01

Brief Summary

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RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 block the growth of the tumor by blocking blood flow to the tumor. It is not yet known whether bevacizumab together with dasatinib are more effective than a placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.

PURPOSE: This randomized phase I/II trial (Phase I completed) is studying the side effects and best dose of dasatinib when given together with bevacizumab and to see how well it works compared to placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.

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Detailed Description

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OUTLINE: This is a multicenter, phase I, dose-escalation study (Phase I completed) of dasatinib followed by a phase II randomized study. Patients are grouped according to study (1 vs 2). Patients in the phase II portion are stratified according to age (\> 70 years of age vs ≤ 70 years of age), and ECOG performance status (0 vs 1 or 2).

Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oral dasatinib once or twice daily on days 1-14 until the maximum-tolerated dose (MTD) is determined. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. (Phase I completed) Please see the Arms section for the Phase II treatment regimens.

OBJECTIVES:

PRIMARY OBJECTIVES:

1. Determine the maximum tolerated dose (MTD) of dasatinib in combination with bevacizumab in high grade glioma patients. (Phase I)
2. To assess the safety and adverse events of the dasatinib in combination with bevacizumab in this patient population. (Phase I)
3. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by progression free survival at six months and compare it with the efficacy of bevacizumab alone. (Phase II)

SECONDARY OBJECTIVES:

1. To describe the overall toxicity associated with the dasatinib/bevacizumab combination. (Phase I)
2. To describe any preliminary evidence of antitumor activity. (Phase I)
3. To assess the time to disease progression. (Phase II)
4. To assess the safety and toxicity of the bevacizumab combination with dasatinib in this patient population. (Phase II)
5. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by overall survival time and compare it with the efficacy of bevacizumab alone. (Phase II)
6. To assess the impact of the treatment on the patient's quality of life (QOL) using the overall score from the FACT-Br (Phase II)

Conditions

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Glioblastoma Multiforme

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Arm I

Patients receive bevacizumab on Day 1 and dasatinib on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

bevacizumab

Intervention Type BIOLOGICAL

Given intravenously

dasatinib

Intervention Type DRUG

Given orally

Arm II

Patients receive bevacizumab on Day 1 and placebo on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Group Type ACTIVE_COMPARATOR

bevacizumab

Intervention Type BIOLOGICAL

Given intravenously

placebo

Intervention Type OTHER

Given orally

Interventions

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bevacizumab

Given intravenously

Intervention Type BIOLOGICAL

dasatinib

Given orally

Intervention Type DRUG

placebo

Given orally

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

1. ≥18 years of age
2. Study 1: Histologic confirmation of grade 3 or 4 glioma, including astrocytoma, oligodendroglioma, and mixed gliomas, as determined by pre-registration central pathology review.
3. Study 2: Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as determined by pre-registration central pathology review. NOTE: Variant gliosarcomas are eligible
4. Evidence of tumor progression by MRI or CT scan following RT or following the most recent anti-tumor therapy. Patients who had surgical treatment at recurrence are eligible if there is imaging evidence of disease progression as compared to the first postoperative scan.
5. Bidimensionally measurable or evaluable disease by MRI or CT scan.
6. ECOG Performance Status (PS) 0, 1, or 2.
7. Patient willing to discontinue use of aspirin or medications that inhibit platelet function ≥ 1 week prior to registration.
8. Previous RT and ≥12 weeks since the completion of RT prior to registration.
9. The following laboratory values obtained ≤ 21 days prior to registration.

* ANC ≥1500
* PLT ≥100,000
* Hgb \>9.0 g/dL
* T. bili ≤1.5 x ULN
* SGOT (AST) ≤ 3 x ULN
* Creatinine ≤ ULN
10. UPC ratio \<1. NOTE: Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio ≥1.0, 24-hour urine protein must be obtained and the level should be \<1000 mg
11. Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.
12. Ability to complete questionnaire(s) by themselves or with assistance.
13. Provide informed written consent
14. Willingness to return to enrolling institution for follow-up.
15. Patient willing to provide mandatory tissue samples for research purposes
16. Study 1: Any number of prior chemotherapy regimens for recurrent disease. Study 2: Up to 2 prior chemotherapy regimens with ≤1 regimen for recurrent disease.

Exclusion Criteria

1. Pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception during this study and for up to 6 months after bevacizumab treatment has ended. NOTE: bevacizumab and dasatinib are investigational agents whose genotoxic effects on the developing fetus and newborn are unknown.
2. Prior intratumoral therapy, stereotactic radiosurgery, or interstitial brachytherapy.

EXCEPTION: Separate lesion on MRI which is not part of the previous treatment field, or convincing evidence of recurrent disease, based on biopsy, MRI spectroscopy, or PET scan.
3. Prior treatment with bevacizumab or VEGF-Trap (Aflibercept).
4. Inadequately controlled hypertension (systolic blood pressure of \>150 mmHg or diastolic pressure \>100 mmHg on anti-hypertensive medications).

NOTE: Patients with well-controlled hypertension are eligible.
5. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
6. Immunocompromised patients (other than that related to the use of corticosteroids). NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this study.
7. Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, or prior surgical procedures affecting absorption) that impairs ability to swallow pills.
8. Receiving therapeutic anticoagulation with Warfarin. NOTE: Prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices is allowed, provided that INR \<1.5. Therapeutic anti-coagulation with low molecular weight heparin is allowed at time of registration.
9. Evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation).
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
11. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
12. Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma in-situ of the cervix. Note: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer.
13. History of myocardial infarction or unstable angina ≤6 months prior to registration.
14. New York Heart Association (NYHA) classification II, III or IV congestive heart failure.
15. Core biopsy or other minor surgical procedures ≤7 days prior to registration. Note: Placement of a vascular access device is allowed.
16. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to registration or anticipation of need for major surgical procedure during the course of the study.
17. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis ≤6 months prior to registration.
18. History of hypertensive crisis or hypertensive encephalopathy.
19. Known hypersensitivity to any of the components of dasatinib or bevacizumab.
20. Serious, non-healing wound, active ulcer, or untreated bone fracture
21. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤6 months prior to registration.
22. Active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤30 days prior to registration.
23. History of stroke or transient ischemic attack (TIA) ≤6 months prior to registration.
24. Any evidence of CNS hemorrhage on baseline CT or MRI
25. Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes ≤7 days prior to registration (patients must discontinue drug 7 days prior to starting dasatinib)

* Quinidine, procainamide, disopyramide
* Amiodarone, sotalol, ibutilide, dofetilide
* Erythromycin, clarithromycin
* Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
* Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
* Prochlorperazine
26. Diagnosed congenital long QT syndrome
27. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)
28. Prolonged QTc interval on pre-entry electrocardiogram (\>450 msec)
29. Patients may not have any clinically significant cardiovascular disease including the following:

* Myocardial infarction or ventricular tachyarrhythmia within 6 months.
* Prolonged QTc ≥ 480 msec (Fridericia correction)
* Ejection fraction less than institutional normal
* Major conduction abnormality (unless a cardiac pacemaker is present)

Note: Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (ECG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study.
30. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration
31. Known pleural or pericardial effusion of any grade
32. Concomitant use of H2 blockers or proton pump inhibitors that cannot be discontinued or switched to locally acting agents (i.e. famotidine or omeprazole.)
33. Use of the following Enzyme Inducing Anti-Convulsive (EIAC) medications is prohibited ≤ 7 days prior to registration: carbamazepine (Tegretol®, Tegretol XR®, Carbatrol®), phenytoin (Dilantin®, Phenytek®), fosphenytoin (Cerebyx®), phenobarbital, pentobarbital and primidone (Mysoline®). Note: Many antiepileptic drugs induce hepatic enzymes. Because dasatinib is metabolized by hepatic enzymes, patients taking antiepileptic medications that induce hepatic enzymes (EIACs) are ineligible for this trial. To be eligible for this trial, patients taking EIACs must be switched to non-EIACs ≥ 7 days prior to registration. The following agents are not known to affect dasatinib metabolism and are acceptable for use: valproic acid (Depakote®, Depacon®), gabapentin (Neurontin®), lamotrigine (Lamictal®), topiramate (Topamax®), tiagabine (Gabitril®), zonisamide (Zonegran®), levetiracetam (Keppra®), clonazepam (Klonopin®) and clobazam (Frisium®).

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Evanthia Galanis, MD

Role: STUDY_CHAIR

Mayo Clinic

Locations

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Mayo Clinic Scottsdale

Scottsdale, Arizona, United States

Site Status

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, United States

Site Status

Palchak David MD

Pismo Beach, California, United States

Site Status

Aurora Presbyterian Hospital

Aurora, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Penrose Cancer Center at Penrose Hospital

Colorado Springs, Colorado, United States

Site Status

St. Anthony Central Hospital

Denver, Colorado, United States

Site Status

Porter Adventist Hospital

Denver, Colorado, United States

Site Status

Presbyterian - St. Luke's Medical Center

Denver, Colorado, United States

Site Status

St. Joseph Hospital

Denver, Colorado, United States

Site Status

Rose Medical Center

Denver, Colorado, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

North Colorado Medical Center

Greeley, Colorado, United States

Site Status

Sky Ridge Medical Center

Lone Tree, Colorado, United States

Site Status

Hope Cancer Care Center at Longmont United Hospital

Longmont, Colorado, United States

Site Status

McKee Medical Center

Loveland, Colorado, United States

Site Status

St. Mary - Corwin Regional Medical Center

Pueblo, Colorado, United States

Site Status

Exempla Lutheran Medical Center

Wheat Ridge, Colorado, United States

Site Status

Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center

Hartford, Connecticut, United States

Site Status

Beebe Medical Center

Lewes, Delaware, United States

Site Status

Tunnell Cancer Center at Beebe Medical Center

Lewes, Delaware, United States

Site Status

CCOP - Christiana Care Health Services

Newark, Delaware, United States

Site Status

Lombardi Comprehensive Cancer Center at Georgetown University Medical Center

Washington D.C., District of Columbia, United States

Site Status

Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital

Fort Lauderdale, Florida, United States

Site Status

Memorial Cancer Institute at Memorial Regional Hospital

Hollywood, Florida, United States

Site Status

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Hollywood, Florida, United States

Site Status

Mayo Clinic - Jacksonville

Jacksonville, Florida, United States

Site Status

Ella Milbank Foshay Cancer Center at Jupiter Medical Center

Jupiter, Florida, United States

Site Status

CCOP - Mount Sinai Medical Center

Miami Beach, Florida, United States

Site Status

Florida Hospital Cancer Institute at Florida Hospital Orlando

Orlando, Florida, United States

Site Status