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

April 12, 2018 updated by: City of Hope Medical Center

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Duarte, California, United States, 91010-3000
        • City of Hope Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Cohort 1
Patients do not receive temsirolimus.
Other: cytokine levels
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
EXPERIMENTAL: Cohort 2
48 hours after surgery, patients receive one 200 mg dose of temsirolimus IV.
Other: cytokine levels
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
Drug: temsirolimus
Receive temsirolimus IV
Other: pharmacological study
Plasma levels of temsirolimus and sirolimus will be evaluated in serial blood samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Feasibility of using a microdialysis catheter to assess the neuropharmacodynamics (nPD) of temsirolimus
Time Frame: Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately
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
Time Frame: Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately
Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately

Secondary Outcome Measures

Outcome Measure
Time Frame
Relationship between temsirolimus dose and changes in intracerebral levels of VEGF, IL-1ß, and other cytokines
Time Frame: Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately
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
Time Frame: 30 days after placement of the microdialysis catheter.
30 days after placement of the microdialysis catheter.
Relationship between changes in intracerebral cytokine levels after treatment with temsirolimus
Time Frame: Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately
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.
Time Frame: Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately
Every 6 hours for 96 hours after confirmation that the microdialysis catheter is placed appropriately

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

City of Hope Medical Center

Collaborators

National Cancer Institute (NCI)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2008

Primary Completion (ACTUAL)

November 1, 2010

Study Completion (ACTUAL)

November 1, 2010

Study Registration Dates

First Submitted

November 1, 2008

First Submitted That Met QC Criteria

November 1, 2008

First Posted (ESTIMATE)

November 4, 2008

Study Record Updates

Last Update Posted (ACTUAL)

April 17, 2018

Last Update Submitted That Met QC Criteria

April 12, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 07064
  • P30CA033572 (U.S. NIH Grant/Contract)
  • CHNMC-07064
  • CDR0000617019 (REGISTRY: NCI PDQ)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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