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Phase I Study of Dasatinib Plus Protracted Temozolomide in Recurrent Malignant Glioma

Phase 1
18 Years
Not Enrolling
Glioblastoma Multiforme, Gliosarcoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Glioma

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Trial Information

Phase I Study of Dasatinib Plus Protracted Temozolomide in Recurrent Malignant Glioma

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

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

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

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,

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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity assessed using CTCAE v.3.0

Outcome Time Frame:


Safety Issue:


Principal Investigator

Annick Desjardins, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

June 2009

Completion Date:

June 2012

Related Keywords:

  • Glioblastoma Multiforme
  • Gliosarcoma
  • Anaplastic Astrocytoma
  • Anaplastic Oligodendroglioma
  • Glioma
  • Dasatinib
  • Sprycel
  • Temozolomide
  • Temodar
  • Recurrent Malignant Glioma
  • Malignant Glioma
  • glioblastoma multiforme
  • gliosarcoma
  • anaplastic astrocytoma
  • anaplastic oligodendroglioma
  • anaplastic mixed glioma
  • glioma
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma



Duke University Medical Center Durham, North Carolina  27710