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

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
following:

- 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
hemorrhage

- 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
recovered

- 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
corticosteroids)

- 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)