Sorafenib in Newly Diagnosed High Grade Glioma
Sorafenib in Newly Diagnosed High Grade Glioma
This is a phase I study to evaluate the safety and tolerability of Sorafenib in combination
 with Temodar and radiation therapy in patients with newly diagnosed high grade glioma
 (glioblastoma, gliosarcoma, anaplastic astrocytoma and anaplastic oligodendroglioma or
 oligoastrocytoma). The mechanism of action of sorafenib, an oral multikinase inhibitor, makes
 it an interesting drug to investigate in the treatment of patients with high grade glioma as
 this agent has anti-angiogenic activity and inhibits other pathways such as Ras,
 Platelet-derived growth factor (PDGF) and fms-like tyrosine kinase receptor-3 (Flt-3), which
 are potential targets against gliomas.
Up to 18 patients will be included in this phase I study. The primary goal of this study will
 be to establish the maximum tolerated dose of sorafenib when used in combination with
 temozolomide and radiation therapy. Secondary goals of this study include: response rate,
 time to treatment failure, 6 month progression-free survival, event free survival and overall
 survival. A correlative study will investigate the pharmacokinetics of sorafenib used in
 combination with radiation therapy and temozolomide.
Inclusion Criteria:

 -  Histological documentation of newly diagnosed malignant glioma

 -  ECOG performance status of 0 or 1

 -  Age ≥18

 -  Life expectancy of at least 12 weeks

 -  Hemoglobin ≥ 9.0 g/dl

 -  Granulocyte count ≥1.5 X 10^9/L

 -  Platelet count ≥100 X 10^9/L

 -  SGOT ≤ 2.5X upper limit of normal (ULN)

 -  SGPT ≤ 2.5X upper limit of normal (ULN)

 -  Alkaline phosphatase ≤4x ULN

 -  Serum creatinine ≤1.5X ULN

 -  Bilirubin ≤1.5X ULN

 -  Spontaneous PT-INR/PTT < 1.5x upper limit of normal (patients on therapeutic
 anticoagulation will be allowed to participate.

 -  Patients must be on a stable or decreasing dose of corticosteroids for at least 2
 weeks

 -  Patient for whom a first line treatment with temozolomide and radiotherapy is adequate

 -  Prophylactic anti-emetic, pentamidine inhalation / co-trimoxazole and anticonvulsants
 are allowed

 -  All patients must sign written informed consent.

 Exclusion Criteria:

 -  Prior treatment for high grade glioma

 -  Previous exposure to Ras pathway inhibitors

 -  Other concurrent active malignancy (with the exception of cervical carcinoma in situ
 or non melanoma carcinoma of the skin, superficial bladder tumor [Ta, Tis & T1] or any
 cancer curatively treated > 3 years prior to study entry).

 -  Serious medical or psychiatric illness that would, in the opinion of the investigator,
 interfere with the prescribed treatment, including but not limited to: Congestive
 heart failure > NYHA class 2, active CAD, cardiac arrythmias requiring anti-arrythmic
 therapy or uncontrolled hypertension within the last 12 months

 -  Any condition limiting the patient's judgment capacity

 -  History of HIV infection, chronic hepatitis C or B as well as clinically active
 infections (> grade 2 NCI-CTC version 3.0)

 -  History of organ allograft

 -  Renal dialysis

 -  Evidence or history of bleeding diathesis

 -  Major surgery within 4 weeks of start of study treatment, except for neurosurgical
 resection

 -  Autologous bone marrow transplant or stem cell rescue within 4 months of study

 -  Substance abuse, medical, psychological or social conditions that may interfere with
 the patient's participation in the study or evaluation of study results.

 -  Medical condition that prevents the patient from swallowing pills

 -  Use of biologic response modifiers, such as G-CSF within 3 week of study entry.

 -  Pregnant or breast-feeding women.

 -  Refusal to use effective contraception. Women of childbearing potential must have a
 negative pregnancy test performed within 7 days of the start of treatment. Both men
 and women enrolled in this trial must use adequate barrier birth control measures
 during the course of the trial and for at least 3 months after administration of study
 medication.

 -  Known or suspected allergy to the investigational agent or any agent given in
 association with this trial.