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

Study Overview
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Brief Summary
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RATIONALE: Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Studying samples of blood and tumor tissue from patients with cancer in the laboratory may help doctors learn more about how this treatment is used by the body. PURPOSE: The purpose of this study is to evaluate the feasibility of using a microdialysis catheter to see what effect temsirolimus has on various biological substances associated with brain tumors over time.

Detailed Description
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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.

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

Conditions
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Brain and Central Nervous System Tumors, Metastatic Cancer

Intervention / Treatment
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* Drug: temsirolimus
* Other: pharmacological study
* Other: cytokine levels


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1<br>Patients do not receive temsirolimus. | Other: cytokine levels<br>* Dialysate samples are collected at regular intervals during the 96 hours following placement of the catheter to measure changes in levels of cytokines, chemokines and growth factors<br>|
| Experimental: Cohort 2<br>48 hours after surgery, patients receive one 200 mg dose of temsirolimus IV. | Drug: temsirolimus<br>* Receive temsirolimus IV<br>Other: pharmacological study<br>* Plasma levels of temsirolimus and sirolimus will be evaluated in serial blood samples.<br>Other: cytokine levels<br>* Dialysate samples are collected at regular intervals during the 96 hours following placement of the catheter to measure changes in levels of cytokines, chemokines and growth factors<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of using a microdialysis catheter to assess the neuropharmacodynamics (nPD) of temsirolimus |  | Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately | 
| Changes in intracerebral levels of vascular endothelial growth factor (VEGF), interleukin-1ß (IL-1ß), and other cytokines |  | Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between temsirolimus dose and changes in intracerebral levels of VEGF, IL-1ß, and other cytokines |  | Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately | 
| Relationship between the degree of microvascular proliferation and the tensin homologue deleted on chromosome 10 (PTEN) status in tumor tissue |  | 30 days after placement of the microdialysis catheter. | 
| Relationship between changes in intracerebral cytokine levels after treatment with temsirolimus |  | Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately | 
| Compare changes in intracerebral cytokine levels to changes in systemic cytokine levels. |  | Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult anaplastic astrocytoma, adult diffuse astrocytoma, adult craniopharyngioma, adult choroid plexus tumor, adult brain stem glioma, tumors metastatic to brain, recurrent adult brain tumor, adult gliosarcoma, adult giant cell glioblastoma, adult ependymoblastoma, adult medulloblastoma, adult supratentorial primitive neuroectodermal tumor (PNET), adult anaplastic ependymoma, adult ependymoma, adult myxopapillary ependymoma, adult subependymoma, adult mixed glioma, meningeal melanocytoma, adult meningeal hemangiopericytoma, adult grade I meningioma, adult grade II meningioma, adult grade III meningioma, adult anaplastic oligodendroglioma, adult oligodendroglioma, adult pineoblastoma, adult pineocytoma