PBTC-002 Abstract for Health Professionals

Study Title: A Phase I Study of SU5416 in Pediatric Patients With Recurrent or Progressive Poor Prognosis Brain Tumors

Description:

This is a phase I trial for patients 21 years of age or less, with recurrent or progressive brain tumors. It is a collaborative study of the Pediatric Brain Tumor Consortium.

Patients will receive intravenous SU5416 twice weekly for up to two years. Cohorts of 3 to 6 patients will receive escalating doses of SU5416 until the maximum tolerated dose (MTD) is established.

SU5416 Dose Escalation Table

Dose Level

Patients not on enzyme-inducing anticonvulsant drugs

Dose (mg/m2)

Patients taking enzyme-inducing anticonvulsant drugs

Dose (mg/m2)

1

110

48

2

145

65

3

190

85

4

250

110

5

330

145

6

-

190

7

-

250

8

-

330

Pharmacokinetic analysis and biological activity studies will be conducted using standard pharmacokinetic tests and in vitro endothelial proliferation and inhibition assays and sera from patients pre-drug and post-drug. Standard 3-D MRI, multi-voxel MRS, rapid perfusion/diffusion MRI and PET (where available) imaging will be obtained.

Objectives:

  1. To determine the maximum-tolerated dose (MTD) and toxicity profile of SU5416 in pediatric patients with refractory brain tumors, stratified by concurrent use of enzyme-inducing anticonvulsant drugs.
  1. To obtain preliminary information about the efficacy of SU5416 and investigate the relation among tumor imaging characteristics, surrogate markers of tumor angiogenesis, and reported toxicities.

Rationale:

The traditional role of chemotherapy has been to directly disrupt the division of cancerous cells; however, tumor cells with high mutation rates quickly develop resistance to the therapy so that further treatment by the same agent no longer slows the growth of the tumor. One alternative to targeting tumor cells themselves is disrupting the supply of blood (and therefore oxygen and nutrients) to the malignancy.

This study utilizes SU5416 (Semoxind), which may inhibit the proliferation of cancerous cells indirectly by interfering with the activity of tyrosine kinase receptors on the surfaces of endothelial cells, which help to support blood flow to the tumor. SU5416 inhibits endothelial cell proliferation in vitro but does not inhibit normal or tumor cell growth, proliferation, or differentiation, which are targets of standard chemotherapy. SU5416 has been tested on numerous mouse and human tumors in a murine in vivo system and has shown regression of some tumors. Extensive testing of this agent in mice, and preliminary toxicity data in adults has shown limited drug induced toxicity, even when used at high doses.

Eligibility Criteria:

Contact:

Study Chair Study Co-Chair

Kieran, Mark W., MD, PhD
Dana-Farber Cancer Institute
Department of Pediatrics
44 Binney Street
Boston, MA  02115

MacDonald, Tobey, MD
Children's National Medical Center
Neuro-Oncology Program
111 Michigan Avenue, NW
Washington, DC  20010


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