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Phase 2 Study of Sorafenib Plus Protracted Temozolomide in Recurrent Glioblastoma Multiforme

Phase 2
18 Years
Not Enrolling
Recurrent Glioblastoma Multiforme

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Trial Information

Phase 2 Study of Sorafenib Plus Protracted Temozolomide in Recurrent Glioblastoma Multiforme


This is an open-label, non-randomized, single center phase 2 trial. A treatment cycle will
consist of 4 weeks of therapy.

Sorafenib will be administered at a set dose of 400 mg (2 x 200 mg tablets) twice daily,
without food (at least 1 hour before or 2 hours after eating). Temozolomide will be
administered at a set dose of 50 mg/m2 once daily without food (at least 1 hour before or 2
hours after eating).

Thirty-two (32) patients will be enrolled in this single-stage study.


After 16 patients with recurrent GBM are treated, an interim analysis will be conducted. If
6 or more patients have experienced unacceptable toxicity, accrual of patients in this
patient group will be terminated. Otherwise, patient accrual will continue. If 9 or more of
the total 32 patients experience unacceptable toxicity, the treatment regimen will be
considered to have an unacceptable toxicity profile. The type I and II error rates
associated with this testing are 0.053 and 0.053, respectively.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- 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
swallow tablets).

- 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
study drug.

- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of 1st dose of
study drug.

- Serious non-healing wound, ulcer, or bone fracture.

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of 1st
study drug.

- 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

Type of Study:


Study Design:

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

Outcome Measure:

6 Month Progression Free Survival (PFS)

Outcome Description:

Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

David A Reardon, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Institutional Review Board

Study ID:




Start Date:

September 2007

Completion Date:

December 2010

Related Keywords:

  • Recurrent Glioblastoma Multiforme
  • Recurrent Glioblastoma Multiforme
  • GBM
  • Glioblastoma
  • Sorafenib
  • Temozolomide
  • Brain Tumor
  • Recurrent GBM
  • Temodar
  • Gliosarcoma
  • Glioma
  • Nexavar
  • Glioblastoma



Duke University Health SystemDurham, North Carolina  27705