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A Phase I/II Trial of Sorafenib and CCI-779 in Patients With Recurrent Glioblastoma

Phase 1/Phase 2
18 Years
Open (Enrolling)
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

A Phase I/II Trial of Sorafenib and CCI-779 in Patients With Recurrent Glioblastoma


I. Establish a maximum tolerable dose of temsirolimus in combination with sorafenib in
patients with recurrent glioblastoma not receiving enzyme-inducing anticonvulsants (EIACs).
(Phase I [closed to accrual as of 11/21/07]) II. Define the safety profile of temsirolimus
and sorafenib in these patients. (Phase I [closed to accrual as of 11/21/07]) III. Assess
the evidence of antitumor activity. (Phase I [closed to accrual as of 11/21/07])Assess the
efficacy, as measured by progression-free survival, of temsirolimus and sorafenib in
patients with recurrent glioblastoma not receiving EIACs. (Phase II) IV. Assess the safety
and toxicities of this regimen in these patients. (Phase II)


I. Correlate tumor and blood biomarkers with clinical outcome of patients treated with
temsirolimus and sorafenib.

II. Evaluate tumor tissue specimens for evidence of bioactivity of these agents.

OUTLINE: This is a multicenter, phase I (closed to accrual as of 11/21/07), dose-escalation
study of temsirolimus followed by a phase II open-label study.

PHASE I: Patients receive sorafenib orally (PO) twice daily (BID) on days 1-28 and
temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22. (closed to accrual
as of 11/21/07) Treatment repeats every 28 days in the absence of disease progression or
unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of temsirolimus
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients are assigned to 1 of 3 treatment groups.

GROUP 1: Patients receive sorafenib and temsirolimus as in phase I (closed to accrual as of
11/21/07) at the MTD. (patients not undergoing surgery)

GROUP 2: Patients receive sorafenib PO BID on days 1-8 (15 doses) and temsirolimus IV at the
MTD on day 1. Patients undergo surgery on day 8. (patients undergoing surgery) After
recovering from surgery, patients receive sorafenib and temsirolimus as in phase I (closed
to accrual as of 11/21/07) at the MTD.

GROUP 3: Patient receive sorafenib and temsirolimus as in phase I (closed to accrual as of
11/21/07) at the MTD. (patients who have received prior anti-vascular endothelial growth
factor [VEGF] therapy and are not undergoing surgery)

Biopsy or resected tissue and blood are collected prior to treatment (usually at diagnosis)
and analyzed for biomarkers. After completion of study treatment, patients are followed
every 6 months for 5 years and then annually thereafter.

Inclusion Criteria:

- Histologically confirmed grade IV astrocytoma (glioblastoma) or gliosarcoma

- Evidence of tumor progression by magnetic resonance imaging (MRI) or computed
tomography (CT) scan after prior radiotherapy or most recent antitumor therapy

- Bidimensionally measurable or evaluable disease by MRI or CT scan

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

- White blood cells (WBC) >= 3,000/mm^3

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 10 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
2.5 x ULN

- Creatinine =< 2.0 x ULN

- Serum cholesterol =< 350 mg/dL

- Serum triglycerides =< 400 mg/dL

- International normalized ration (INR) > 1.5 (unless on full-dose warfarin)

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for 6 months after
completion of study therapy

- No human immunodeficiency virus (HIV) positivity

- No evidence of bleeding diathesis or coagulopathy

- No condition (e.g., gastrointestinal tract disease resulting in an inability to take
oral medication, requirement for IV alimentation, or active peptic ulcer disease)
that would impair the ability to swallow pills

- No uncontrolled hypertension with systolic blood pressure (BP) > 140 mm Hg or
diastolic BP pressure> 90 mm Hg

- No uncontrolled infection

- No known hypersensitivity to any of the components of temsirolimus or sorafenib

- No immunocompromised patients (other than that related to the use of corticosteroids)

- No other active malignancy

- No uncontrolled intercurrent illness, including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude study compliance

- No significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline
MRI or CT scan

- No other history of significant intratumoral, intracerebral, or subarachnoid

- Concurrent full-dose anticoagulants (e.g., warfarin) allowed provided all of the
following criteria are met:

- In-range INR(between 2 and 3) on a stable dose of oral anticoagulant or on a
stabledose of low molecular weight heparin

- No active bleedingor pathological condition that carries a high risk of bleeding
(e.g., tumorinvolving major vessels or known varices)

- At least 12 weeks since prior radiotherapy

- At least 4 weeks since prior temsirolimus, sorafenib, or other agents specifically
targeting mTOR, raf, or vascular endothelial growth factor (VEGF)/VEGF receptors and

- At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas)

- At least 2 weeks since prior cytostatic chemotherapy (e.g., tamoxifen, isotretinoin,
or thalidomide)

- At least 1 week since prior fixed or decreasing dose of corticosteroids (or no

- At least 1 week since prior minor surgery other than venous line placement (3 weeks
for major surgery)

- No more than 2 prior systemic chemotherapy regimens

- No prior surgical procedures affecting absorption

- No prior intratumoral chemotherapy (e.g., polifeprosan 20 with carmustine implant or
cintredekin besudotox), stereotactic radiosurgery, or interstitial brachytherapy
unless there is a separate lesion on MRI that is not part of the previous treatment
field or there is proof of recurrent disease based on biopsy, MRI spectroscopy, or
positron emission tomography scan

- No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin,fosphenytoin,
carbamazepine, phenobarbital, or primidone) or any other potent CYP3A4 inducer, such
as rifampin or Hypericum perforatum (St. John's wort)

- No other concurrent investigational agents

- No concurrent prophylactic hematopoietic colony-stimulating factors

- No other concurrent anticancer agents or therapies

- Concurrent prophylactic anticoagulation therapy (e.g., low-dosewarfarin) allowed
provided coagulation parameter levels (prothrombin time [INR]) < 1.1 times upper
limit of normal (ULN)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Description:

The âsuccessâ probability, i.e., 6-month progression-free survival percentage, for each of group 1 and group 3 will be estimated as the number of evaluable patients still alive at 6 months divided by the total number of evaluable patients followed for at least 6 months. Ninety percent confidence intervals for the âsuccessâ probability will be calculated according to the approach of Duffy and Santner.

Outcome Time Frame:

At 6 months

Safety Issue:


Principal Investigator

Kurt Jaeckle

Investigator Role:

Principal Investigator

Investigator Affiliation:

North Central Cancer Treatment Group


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Gliosarcoma



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