Sorafenib Tosylate and Temsirolimus in Treating Patients With Recurrent Glioblastoma

Primary Objective -

Phase I (closed to accrual as of 01/11/2008):

To establish a maximum tolerable dose of temsirolimus in combination with sorafenib in
patients with recurrent glioblastoma not receiving enzyme-inducing anticonvulsants (EIACs).

Phase II (closed to accrual as of 12/07/2012):

To assess the efficacy of temsirolimus and sorafenib in the treatment of recurrent
glioblastoma in non-EIAC patients as measured by progression-free survival status at six
months (PFS6).

Secondary Objectives -

Phase I (closed to accrual as of 01/11/2008):

I. To define the safety profile of temsirolimus and sorafenib in non-EIAC patients.

II. To assess the evidence of antitumor activity.

Phase II (closed to accrual as of 12/07/2012):

I. To assess the safety and toxicities of temsirolimus and sorafenib in the above-noted
patient populations.

Outline: This is a multicenter, phase I, dose-escalation study followed by a phase II study.

Phase I (Arm A): 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. 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 (Arm B): Patients receive sorafenib and temsirolimus as in phase I at the MTD.
(patients not undergoing surgery)

Group 2 (Arm C): 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 at the
MTD.

Group 3 (Arm D): Patient receive sorafenib and temsirolimus as in phase I 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:

- Central pathology review submission; this review is mandatory prior to registration to
confirm eligibility; it should be initiated as soon after surgery as possible

- =< 2 prior systemic chemotherapy regimens

- Histological confirmation of a grade 4 astrocytoma (glioblastoma) or gliosarcoma, at
primary diagnosis or recurrence by World Health Organization (WHO) criteria; central
pathology review is mandatory prior to study entry to confirm eligibility

- Evidence of tumor progression by magnetic resonance imaging (MRI) or computed
tomography (CT) scan following radiation therapy (RT) or following the most recent
anti-tumor therapy

- Bidimensionally measurable or evaluable disease by MRI or CT scan

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

- >= 12 weeks since the completion of RT

- Fixed or decreasing dose of corticosteroids (or no corticosteroids) >= 1 week prior to
registration

- >= 1 week from minor surgery other than venous line placement and > 3 weeks from major
surgery (except for patients undergoing tumor tissue acquisition)

- >= 4 weeks since prior cytotoxic chemotherapy (>= 6 weeks for nitrosoureas)

- >= 2 weeks from cytostatic chemotherapy such as tamoxifen, cis-retinoic acid, or
thalidomide (address questions regarding such agents to study chair)

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

- Absolute neutrophil count (ANC) >= 1,500/mm^3

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

- Hemoglobin (Hgb) >= 10 gm/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

- Willingness to provide the biologic specimens as required by the protocol; (please
note that the willingness to participate pertains only to the patient and does not
factor in the institution?s ability to participate in any part of the translational
component)

Exclusion Criteria:

- Prior intratumoral chemotherapy (e.g., Gliadel or IL13-PE38QQR), stereotactic
radiosurgery, or interstitial brachytherapy unless there is a separate lesion on MRI
which is not part of the previous treatment field or there is proof of recurrent
disease based on biopsy, MRI spectroscopy, or positron emission tomography (PET) scan

- Prior CCI-779, sorafenib, or other agents specifically targeting mammalian target of
rapamycin (mTOR) or raf; patients receiving prior agents inhibiting VEGF or VEGF
receptor (R) (prior anti-VEGF group) are eligible but: 1) must be at least four weeks
from last treatment with the agent(s); and 2) must have recovered from any clinically
relevant toxicities attributable to this agent(s)

- Evidence of bleeding diathesis or coagulopathy

- Note: Patients on prophylactic anticoagulation therapy (e.g., low-dose warfarin)
are eligible provided their coagulation parameter levels are as follows:
prothrombin time (International Normalized Ratio [INR] of prothrombin time) < 1.1
x institutional upper limit of normal

- Note: Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided
that both of the following criteria are met: a) the patient has an in-range INR
(usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable
dose of low molecular weight heparin, and b) the patient has no active bleeding
or pathological condition that carries a high risk of bleeding (e.g., tumor
involving major vessels or known varices)

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

- Receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, fosphenytoin,
carbamazepine, phenobarbital, or primidone) or any other potent cytochrome P450,
family 3, subfamily A, polypeptide 4 (CYP3A4) inducer, such as rifampin or St. John?s
wort

- Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
oral medication or a requirement for IV alimentation, prior surgical procedures
affecting absorption, or active peptic ulcer disease) that impairs their ability to
swallow pills

- Hypertension with systolic blood pressure of > 140 mmHg or diastolic pressure > 90
mmHg; however, patients with well-controlled hypertension are eligible

- Uncontrolled infection

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- Known hypersensitivity to any of the components of CCI-779 or sorafenib

- Other active malignancy

- Uncontrolled intercurrent illness, including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, psychiatric illness/social situation that would preclude study compliance
with study requirements

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive;
HIV-positive patients on combination antiretroviral therapy are ineligible

- Receiving any investigational agents other than CCI-779 and sorafenib

- Significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline MRI or
CT, or other history of significant intratumoral, intracerebral, or subarachnoid
hemorrhage