Inclusion Criteria:
1. Patients must have a histologically confirmed diagnosis of a recurrent/progressive
WHO Gr.4 malignant glioma (glioblastoma multiforme or gliosarcoma) or WHO Gr.3
malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma or anaplastic
mixed glioma). Recurrence will be defined based on the modified MacDonald criteria
or based on histopathologic confirmation of tissue obtained via surgical
intervention. Patients with prior low-grade glioma are eligible if histologic
assessment demonstrates transformation to WHO Gr.III or IV malignant glioma;
2. > or = to 18 y/o;
3. KPS . or = to 60%;
4. Patients must be presenting in 1st, 2nd or 3rd relapse. Relapse is defined as
progression following anti-cancer therapy other than surgery, including non-surgical
therapies that are considered standard treatment for high-grade glioma if
administered to patients with prior low-grade glioma. Prior therapy must have
included external beam radiotherapy;
5. Adequate bone marrow, liver and renal function as assessed by the following:
Hematocrit > or = to 29%, ANC > or = to 1,500/mm3, Platelet count > or = to
125,000/mm3, Total bilirubin < or = to 1.5 x ULN, ALT and AST < or = to 2.5 x the
ULN ( < or = to 5 x ULN for patients with liver involvement), INR < 1.5 or a PT/PTT
within normal limits (unless on therapeutic anti-coagulation). Patients receiving
anti-coagulation treatment with a low-molecular weight heparin will be allowed to
participate, however oral warfarin is not permitted except for low-dose warfarin
(1mg po DAILY), Creatinine < 1.5 x ULN, Serum Na, K+, Mg2+, Phosphate and Ca2+ > or
= to Lower Limit of Normal (LLN);
6. An interval of at least 2 weeks between prior surgical resection (1 week for biopsy)
and initiation of study regimen;
7. An interval of at least 12 weeks from completion of standard, daily XRT, unless one
of the following occurs: a) new area of enhancement on MRI imaging that is outside
the XRT field; b) biopsy proven recurrent tumor; c) radiographic evidence of
progressive tumor on 2 consecutive scans at least 4 weeks apart;
8. An interval of at least 4 weeks from prior chemotherapy (except nitrosoureas which
require 6 weeks) unless there is unequivocal evidence of tumor progression and the
patient has recovered from all anticipated toxicities from prior therapy;
9. An interval of a least 14 days from exposure to investigational agents, unless there
is unequivocal evidence of tumor progression and the patients has recovered from all
anticipated toxicities from prior therapy;
10. Signed written informed consent including HIPAA according to institutional
guidelines. A signed informed consent must be obtained prior to any study specific
procedures;
11. If sexually active, patients will take contraceptive measures for the duration of
the treatments and for 3 months following discontinuation of dasatinib and TMZ;
12. Women of childbearing potential must have a negative serum or urine pregnancy test
(sensitivity < or = to 25IU HCG/L) within 72 hours prior to the start of study drug
administration.
Exclusion Criteria:
1. Prior dasatinib. Imatinib mesylate in the prior three months;
2. Grade 3 or greater toxicity related to prior TMZ therapy;
3. Prior progression on protracted daily TMZ;
4. Pregnancy or breast feeding;
5. History of significant concurrent illness;
6. More than 3 prior episodes of progressive disease;
7. Significant cardiac disease including any of the following:
1. congestive heart failure > class II NYHA;
2. unstable angina (anginal symptoms at rest);
3. new onset angina (began within the last 3 months);
4. myocardial infarction within the past 6 months;
5. any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
6. uncontrolled congestive heart failure; diagnosed congenital long QT syndrome;
prolonged QTc interval on pre-entry electrocardiogram (> 450 msec);
8. Excessive risk of bleeding as defined by stroke within the prior 6 months, history
of CNS or intraocular bleed, or septic endocarditis;
9. Female patients who are pregnant or breastfeeding, or adults of reproductive
potential not employing an effective method of birth control. (Women of childbearing
potential must have a negative serum pregnancy test within 72 hours prior to
administration of study regimen). Sexually active women of childbearing potential
(WOCBP) must use an effective method of birth control during the course of the
study, in a manner such that risk of failure is minimized. Prior to study
enrollment, women of childbearing potential must be advised of the importance of
avoiding pregnancy during trial participation and the potential risk factors for an
unintentional pregnancy;
10. Concurrent severe and/or uncontrolled medical disease that could compromise
participation in the study such as pleural or pericardial effusion of any grade,
uncontrolled diabetes, uncontrolled hypertension (defined as systolic blood pressure
> 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management),
active clinically serious infection > CTCAE Gr.2, history of clinically significant
bleeding diathesis or coagulopathy including platelet function disorder (e.g. known
von Willebrand's disease) or acquired bleeding disorder within one year (e.g.,
acquired anti-factor VIII antibodies), impairment of GI function or GI disease that
may significantly alter the absorption of the study regimen (i.e. ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel
obstruction, or inability to swallow the tablets), ongoing or recent (< or = to 3
months) significant gastrointestinal bleeding;
11. Thrombolic or embolic events such as cerebrovascular accident including transient
ischemic attacks within the past 6 months;
12. Any hemorrhage/bleeding event > CTCAE Gr.3 within 4 weeks of 1st dose of study drug;
13. Serious non-healing wound, ulcer, or bone fracture;
14. Major surgery, open biopsy or significant traumatic injury within 4 weeks of 1st
study drug;
15. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C;
16. Patient is < 3 years free of another primary malignancy except: if the other primary
malignancy is not currently clinically significant or requiring active intervention,
or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma
in situ. Existence of any other malignant disease is not allowed;
17. Patient unwilling to or unable to comply with the protocol including ability to
swallow whole pills or presence of any malabsorption syndrome;
18. Concurrent administration of warfarin, rifampin or St. John's Wort, except for
low-dose warfarin (1mg po DAILY);
19. Clinically serious infection requiring active intervention (CTCAE Gr.2 or greater);
20. Hypokalemia or hypomagnesemia if it cannot be corrected;
21. Concomitant Medications, consider the following prohibitions:
1. Drugs that are generally accepted to have a risk of causing Torsades de Pointes
including: (Patients must discontinue drug 7 days prior to starting dasatinib)
1. quinidine, procainamide, disopyramide. 2. amiodarone, sotalol, ibutilide, dofetilide. 3. erythromycin, clarithromycin. 4. chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide. 5. cisapride, bepridil, droperidol, methadone, arsenic, chloroquine,
domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,
lidoflazine.
2. Drugs that reduce dasatinib exposure such as H2 blockers or proton-pump
inhibitors (eg famotidine and omeprazole), which can cause long-term
suppression of gastric acid secretion. The concomitant use of H2 blockers or
proton pump inhibitors with dasatinib is in general not recommended and
antacids should be considered in place of H2 blockers or proton pump inhibitors
in patients receiving dasatinib therapy. However, given that nearly all
recurrent malignant brain tumor patients are on dexamethasone for increased
intracranial pressure, such patients must also receive effective medical
therapy to prevent complications related to increased gastric acid secretion
due to chronic dexamethasone therapy. Therefore all patients enrolled on the
current protocol will receive standard H2 blocker (preferred) or proton pump
inhibitor (PPI) therapy to be administered on a daily basis each evening.
Dasatinib will be administered each morning in order to maximize the time
interval from administered H2 blocker (preferred) or proton pump inhibitor
(PPI).
3. Drugs that cause hypocalcemia (i.e. IV bisphosphonates will be withheld for the
first 8 weeks of dasatinib therapy due to risk of hypocalcemia).
4. Any prohibited CYP3A4 inhibitors; 22. Prisoners or subjects who are
compulsorily detained (involuntarily incarcerated) for treatment of either a
psychiatric or physical (e.g., infectious) illness.
