A Feasibility, Dose-Escalation Study Using Intracerebral Microdialysis to Assess the Neuropharmacodynamics of Temsirolimus in Patients With Primary or Metastatic Brain Tumors

OBJECTIVES:

Primary

- Determine the feasibility of using a microdialysis catheter with a high cut-off
membrane to perform neuropharmacodynamics (nPD) assessment of targeted therapy with a
mammalian target of rapamycin (mTOR) inhibitor, where nPD is defined as changes in
intracerebral levels of vascular endothelial growth factor (VEGF), interleukin-1ß
(IL-1ß), and other cytokines.

Secondary

- Assess the relationship between temsirolimus dose and changes in intracerebral levels
of VEGF, IL-1ß, and other cytokines.

- Compare changes in intracerebral cytokine levels to changes in systemic cytokine
levels.

- Assess the relationship between the degree of microvascular proliferation and the
tensin homologue deleted on chromosome 10 (PTEN) status in tumor tissue.

- Assess the relationship between changes in intracerebral cytokine levels after
treatment with temsirolimus.

OUTLINE: Two cohorts of 6 patients will be enrolled in this study. All patients undergo
debulking craniotomy or stereotactic biopsy and a placement of a intracerebral CMA 71
microdialysis (ICMD) catheter. Patients then are assigned to 1 of 2 treatment cohorts.

- Cohort 1: Patients do not receive temsirolimus. Dialysate samples will be collected at
regular intervals during the 96 hours following placement of the catheter as well as
serial blood samples to measure levels of cytokines, chemokines and growth factors that
occur after neurosurgery.

- Cohort 2: Beginning 48 hours after surgery, patients receive a single 200 mg dose of
temsirolimus IV. Dialysate samples will be collected at regular intervals during the 96
hours following placement of the catheter as well as serial blood samples to measure
levels of cytokines, chemokines and growth factors that occur after neurosurgery.
Plasma levels of temsirolimus and sirolimus will also be measured from the serial blood
samples.

After completion of study therapy and removal of ICMD catheter, patients are followed for 30
days.

Inclusion Criteria

Patients must be at least 18 years of age.

Patients must have either a primary or metastatic brain tumor(s).

Patients must be in need of a surgical debulking or a stereotactic biopsy for the purpose
of diagnosis or differentiating between tumor progression and treatment-induced effects
following radiation therapy + or - chemotherapy.

For patients in cohort 2, treatment with temsirolimus must not be contraindicated.

Patients in cohort 2 must not be taking any hepatic enzyme-inducing anticonvulsants
(phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine).

Patients who are taking strong CYP3A4 inducers or inhibitors such as clarithromycin,
itraconazole, ketoconazole, nefazodone, telithromycin, rifampin, rifabutin, rifampacin, or
St. John's Wort must discontinue the medication beginning at least one week prior to
surgery and lasting for the duration of the study. The only exception will be
dexamethasone which can be used post-operatively as indicated.

Patients must have a Karnofsky Performance Status >= 60% or an ECOG/Zubrod score of<= 2.

Patients must have recovered from any toxicity of any prior therapy.

Patients must have adequate bone marrow function (defined as an absolute neutrophil count
of >= 1500 cells/mm3 and platelet count ≥ 100,000 cells/mm3), liver function with total
bilirubin <= 2.0 mg/dl and AST (SGOT) <= 4 times the institutional upper limit of normal,
and serum creatinine <=1.5 x the institutional upper limit of normal.

Patients must be able to understand and be willing to sign a written informed consent
document.

The effects of temsirolimus on a developing fetus are unknown. Therefore, female patients
of childbearing potential and sexually-active male patients must agree to use an effective
method of contraception while participating in this study. Women of childbearing potential
must have a negative pregnancy test <=2 weeks prior to registration.

Exclusion Criteria

Patients must not be planning to receive radiation, other chemotherapy or participate in
another clinical trial from the time of surgery until the microdialysis catheters is
removed.

Patients allergic to temsirolimus, sirolimus (rapamycin), or Dextran.

Patients with a coagulopathy, increased susceptibility to infection or bleeding disorders.

Patients on anticoagulant drug therapy.

Patients with uncontrolled diabetes.

Patients who have a serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with the completion of treatment according
to this protocol.

Female patients who are pregnant or breast-feeding.

HIV-positive patients receiving anti-retroviral therapy are excluded from the study due to
the possibility of PK interactions with temsirolimus; however, patients will not be
routinely screened for HIV.