Phase 2 Study of Sorafenib Plus Protracted Temozolomide in Recurrent Glioblastoma Multiforme
- Patients must have histologically confirmed diagnosis of recurrent/progressive GBM.
Recurrence will be distinguished from "pseudoprogression" following XRT/Temodar as
outlined in inclusion criteria 4.6 (below). Pts with recurrent disease whose
diagnostic pathology confirmed glioblastoma multiforme will not need re-biopsy. Pts
with prior low-grade glioma or WHO grade III malignant glioma are eligible if
histologic assessment demonstrates transformation to GBM.
- Age > 18 years.
- Pts must be presenting in 1st, 2nd or 3rd relapse. Prior therapy must have included
external beam radiotherapy.
- Adequate bone marrow, liver and renal function as assessed by following:
- Hemoglobin > 9.0 g/dl
- Absolute neutrophil ct (ANC) > 1,500/mm3
- Platelet ct > 100,000/mm3
- Total bilirubin < 1.5 x ULN
- ALT & AST < 2.5 x ULN ( < 5 x ULN for pts with liver involvement)
- INR < 1.5 or PT/PTT within normal limits (unless on therapeutic
anti-coagulation). Pts receiving anti-coagulation treatment with agent such as
warfarin or heparin may be allowed to participate. For pts on warfarin, INR
should be measured prior to initiation of sorafenib and monitored at least
weekly, or as defined by local standard of care, until INR is stable.
- Creatinine < 1.5 x ULN
- An interval of at least 2 weeks between prior surgical resection (1 week for biopsy)&
initiation of study regimen;
- An interval of at least 12 weeks from completion of standard, daily XRT, unless 1 of
the following occurs: 1) new area of enhancement on MRI imaging that is outside XRT
field; 2) biopsy proven recurrent tumor; 3) radiographic evidence of progressive
tumor on 2 consecutive scans at least 4 weeks apart.
- 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 pts
has recovered from all anticipated toxicities from prior therapy.
- Karnofsky performance score > 60%.
- Ability to understand and willingness to sign written informed consent. A signed
informed consent must be obtained prior to any study specific procedures.
- If sexually active, patients will take contraceptive measures (barrier method of
birth control) for duration of treatments and for 3 months following discontinuation
of sorafenib & temozolomide.
- Pts who have had prior bevacizumab are eligible however interval of at least 6 weeks
must have elapsed since their last dose.
- Prior treatment with sorafenib.
- Significant cardiac disease including any of following: a) congestive heart failure >
class II NYHA; b) unstable angina (anginal symptoms at rest); c) new onset angina
(within last 3 months); d) myocardial infarction within past 6 months; e) cardiac
ventricular arrhythmias requiring anti-arrhythmic therapy.
- Known severe hypersensitivity to sorafenib or any of excipients or temozolomide.
- Excessive risk of bleeding as defined by stroke within prior 6 months, history of CNS
or intraocular bleed, or septic endocarditis.
- Female pts who are pregnant/breast feeding, or adults of reproductive potential not
employing effective method of birth control.
- Concurrent severe and/or uncontrolled medical disease that could compromise
participation in study such as uncontrolled diabetes, uncontrolled hypertension,
active clinically serious infection > CTCAE Grade 2, history of bleeding diathesis or
coagulopathy, impairment of GI function or GI disease that may significantly alter
absorption of the study regimen (i.e. ulcerative disease, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to
- Thrombolic or embolic events such as cerebrovascular accident including transient
ischemic attacks within past 6 months
- Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of 1st dose of
- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of 1st dose of
- Serious non-healing wound, ulcer, or bone fracture.
- Major surgery, open biopsy or significant traumatic injury within 4 weeks of 1st
- Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
- Pt is < 3 years free of another primary malignancy except: if other primary
malignancy is not currently clinically significant or requiring active intervention,
or if other primary malignancy is basal cell skin cancer or cervical carcinoma in
situ. Existence of any other malignant disease is not allowed.
- Pts unwilling or unable to comply with protocol including ability to swallow whole
pills or presence of any malabsorption syndrome.
- Concurrent administration of St. John's Wort.
- Clinically serious infection requiring active intervention (CTCAE grade 2 or