Ph. I Dasatinib/Protracted Temozolomide in Recurrent Malignant Glioma
Ph. I Dasatinib/Protracted Temozolomide in Recurrent Malignant Glioma
The primary objective of this study is to determine the maximum tolerated dose (MTD) and dose
 limiting toxicity (DLT) of dasatinib when combined with protracted, daily temozolomide (TMZ).
 Secondary objectives are: To further evaluate the safety and tolerability of dasatinib plus
 protracted, daily TMZ; 2. To evaluate the pharmacokinetics of dasatinib when administered
 with protracted, daily TMZ among recurrent malignant glioma patients who are on and not on
 CYP-3A enzyme inducing anti-epileptic drugs (EIAEDs); 3. To evaluate for anti-tumor activity
 with this regimen in this patient population.
This is an open-label, single center, one-arm phase I dose-escalation study of dasatinib plus
 protracted , daily TMZ administered orally on a continuous daily dosing schedule among adult
 patients with recurrent or relapsing malignant glioma. The study format includes a classical
 "3+3" dose escalation design to determine the MTD and DLT of dasatinib plus protracted, daily
 TMZ among recurrent malignant glioma patients. Patients will be stratified based on whether
 they are receiving EIAED and each stratum will independently dose escalate. Additionally, the
 study will characterize the safety, tolerability, biologic activity, and pharmacokinetic
 profile of dasatinib when used in combination with protracted, daily TMZ.

 Patients will start treatment on day 1 of cycle 1 with dasatinib. For patients undergoing
 dasatinib pharmacokinetic (PK) analysis, dasatinib will be administered alone until initial
 PK assessments are collected. Protracted TMZ will be initiated after initial dasatinib PK
 assessments are collected and will continue to be administered with dasatinib on a continuous
 daily dosing schedule. The initial dasatinib PK assessments will be collected over 24 hours
 between days 3-7 of cycle 1. Patients not undergoing dasatinib PK collections will begin both
 dasatinib and protracted, daily TMZ together on day 1, cycle 1.

 The protracted, daily TMZ dose will be 50 mg/m² daily for all patients. The dose level of
 dasatinib will be increased in successive cohorts. Cohorts of 3-6 patients will accrue at
 each dose level until MTD is defined. Each cohort will consist of a minimum of 3 newly
 enrolled patients. Intra-patient dose escalation is not permitted. It is estimated that this
 study will enroll a minimum of 30 patients (up to 4 dose levels/stratum; 3 patients/dose
 level for levels 1-3 and 6 patients at level 4) and a maximum of 48 patients (6 patients/dose
 level; 4 dose levels/stratum). Cohorts may be expanded at any dose level for further
 elaboration of safety and pharmacokinetic parameters as required.

 The primary safety and efficacy analysis will be conducted on all patient data at the time
 all patients who are still receiving study drug will have completed at least 4 cycles of
 treatment. The additional data for any patients continuing to receive study drug past this
 time, as allowed by the protocol, will be further summarized in a report once these patients
 either completed or discontinued the study. Prior to the primary analysis, an additional
 safety report may be prepared.

 The most common side effects include vomiting, diarrhea, anorexia (loss of appetite), fluid
 retention, fatigue, headache, rash, hypocalcemia (low calcium level), and decreases in blood
 counts. Other possible side effects may include nausea, joint pain, muscle aches, generalized
 pain, abdominal pain, and fever. Rare side effects may include QTc prolongation (heart beat
 changes), pulmonary edema (fluid around the lungs), difficulty breathing, cough, hemorrhage,
 gastrointestinal bleeding, pneumonia, cardiac effusion (fluid in the sac surrounding the
 heart), and cardiac failure. Temodar has been well tolerated by both adults and children with
 the most common toxicity being mild myelosuppression. Other, less likely, potential
 toxicities include nausea and vomiting, constipation, headache, alopecia, rash, burning
 sensation of skin, esophagitis, pain, diarrhea, lethargy, hepatotoxicity, anorexia, fatigue
 and hyperglycemia. As in the case with many anti-cancer drugs, Temodar may be carcinogenic.
 Rats given Temodar have developed breast cancer.
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.