Dasatinib in Treating Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma

National Cancer Institute (NCI)

Status and phase

Completed

Phase 2

Conditions

Adult Glioblastoma

Adult Giant Cell Glioblastoma

Recurrent Adult Brain Neoplasm

Adult Gliosarcoma

Treatments

Other: Pharmacological Study

Drug: Dasatinib

Study type

Interventional

Funder types

Other

NETWORK

NIH

Identifiers

NCT00423735

RTOG-0627 (Other Identifier)

U10CA180868 (U.S. NIH Grant/Contract)

NCI-2009-00744 (Registry Identifier)

RTOG 0627 (Other Identifier)

CDR0000526070

U10CA021661 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This phase II trial studies how well dasatinib works in treating patients with glioblastoma multiforme or gliosarcoma that has come back. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Full description

PRIMARY OBJECTIVES:

I. To determine the therapeutic efficacy of dasatinib in all patients (i.e., stages 1B and 2 combined) with recurrent/progressive glioblastoma (GBM) as measured by 6-month progression-free survival.

SECONDARY OBJECTIVES:

I. To determine the therapeutic efficacy of dasatinib for stage 1B patients with recurrent/progressive GBM as measured by a hybrid endpoint of 6-month progression-free survival OR objective response of (complete response [CR] or partial response [PR]) rate.

II. To determine patient overall survival. III. To determine the toxicity of dasatinib in the treatment of patients with GBM.

IV. To determine radiographic response rate to treatment. V. To determine patient progression-free survival. VI. To explore molecular correlates of clinical outcome. VII. To explore pharmacokinetic correlates of dosing, toxicity, and efficacy.

OUTLINE:

Patients receive dasatinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.

After the completion of study treatment, patients are followed up periodically.

Enrollment

64 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Histologically proven diagnosis of GBM; gliosarcoma is also an eligible diagnosis
The patient must consent to submission of tissue for central pathology review
Patients who have already undergone central pathology review through their enrollment on another Radiation Therapy Oncology Group (RTOG) GBM trial do not need to consent to having their material re-reviewed by the central pathologist for this study
All patients must consent to molecular analysis of pre-dasatinib tumor tissue
Patients accrued to stage I (closed to accrual) or stage IB (opened to accrual May 5, 2009) must have tumors overexpressing at least 2 known dasatinib targets (i.e., SRC proto-oncogene, non-receptor tyrosine kinase [SRC], v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog [KIT], platelet-derived growth factor receptor [PDGFR], or ephrin type-A receptor 2 [EPHA2])
Patients accrued to stage II (cohort closed; not currently applicable) do not require overexpression of SRC, KIT, PDGFR, or EPHA2
History and physical examination, including height and weight, within 10 days prior to registration on study
Brain magnetic resonance imaging (MRI) with and without gadolinium within 10 days prior to registration on study
Contrast-enhanced computed tomography (CT) scans are allowed for patients who cannot undergo MRI scanning
Karnofsky performance status >= 60
Absolute neutrophil count (ANC) >= 1,000 cells/mm^3
Platelets >= 75,000 cells/mm^3
Hemoglobin (Hgb) >= 8.0 g/dl; (note: the use of transfusion or other intervention to achieve Hgb >= 8.0 g/dl is acceptable)
Leukocytes >= 3,000 cells/mm^3
Absolute lymphocyte count (ALC) >= 500 cells/mm^3
Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional upper limit of normal
Creatinine =< 3 X institutional upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
All patients must have undergone prior treatment with radiotherapy and temozolomide; no other prior treatments are allowed
There must be unequivocal radiographic evidence for tumor progression by MRI or CT scan, and the same type of scan (i.e., MRI or CT) must be used throughout the period of protocol treatment for tumor measurement; patients must be on a stable or decreasing dose of corticosteroids for at least 5 days before the baseline MRI/CT is performed
Patients having undergone recent surgery for recurrent/progressive disease are eligible as long as they have recovered from the effects of surgery; patients who recently underwent resection without measurable disease post-operatively are also eligible
Measurable disease is not required for eligibility in patients who recently underwent resection as long as the following conditions are met as applicable:
- Progression of disease led to the surgery
- Gliadel wafers were not placed during the most recent surgery
- Neither convection enhanced delivery nor catheters for infusion of chemotherapy were used during the most recent surgery
- Radioactive seeds were not placed during the most recent surgery
- The histology of the most recent surgery documented recurrent/persistent/progressive malignant glioma
Women of childbearing potential must have a negative beta human chorionic gonadotropin (B HCG) pregnancy test =< 3 days prior to registration
Patient must sign study-specific informed consent prior to study entry

Exclusion criteria

Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
Radiotherapy within 4 weeks or temozolomide within 14 days prior to registration or failure to recover from adverse events of either radiotherapy or temozolomide
Patients may not be receiving any other investigational agents
Severe, active comorbidity, defined as follows:
- Any clinically significant cardiovascular disease including the following:
  - Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
  - Transmural myocardial infarction or ventricular tachyarrhythmia within the past 6 months
  - Prolonged corrected QT interval (QTc) > 480 msec (Fridericia correction)
  - Ejection fraction less than institutional normal
  - Major conduction abnormality (unless a cardiac pacemaker is present)
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; breastfeeding should be discontinued if the mother is treated with dasatinib
History of allergic reactions attributed to compounds of similar chemical or biologic composition to dasatinib
Patients who require concurrent treatment with any medications or substances that are potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible
Patients must not be taking hepatic enzyme inducing antiepileptic drugs (EIAEDs); if patients were previously on EIAEDs that have been discontinued, patients must have been off EIAEDs for >= 2 weeks prior to initiation of dasatinib
Patients who require antacids should use short-acting, locally active agents (e.g., Maalox, Mylanta etc.); however, these agents should not be taken within either 2 hours before or 2 hours after the dasatinib dose
Use of antithrombotic and/or antiplatelet agents (e.g., warfarin, heparin, low molecular weight heparin, aspirin, clopidogrel, ticlopidine, Aggrenox)
Use of ibuprofen or non-steroidal anti-inflammatory drugs (NSAIDs)
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous [IV] alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain dasatinib tablets are excluded
Prior treatment with stereotactic radiosurgery (including Gamma-Knife, Cyberknife, or other variants) or brachytherapy