A Pediatric Brain Tumor Consortium (PBTC) Phase I study of a novel targeted agent for children with drug-resistant medulloblastoma, the most common malignant brain tumor in children, has shown early indications of therapeutic benefit, in addition to being well tolerated.

The drug, GDC-0449 is an orally active agent that binds to the SMO receptor and prevents downstream signaling through GLI and targets aberrant signaling in the ?sonic hedgehog pathway,? (SHH pathway) which has been shown to be responsible for 20% of medulloblastomas, as well as other cancers.

In this is study, 12 of 13 children with recurrent or drug-resistant medulloblastoma have tolerated the drug well without significant side effects, with one patient who carries an activated sonic hedgehog pathway remaining on the drug for more than a year without disease progression.

A previous case report in a young adult with medulloblastoma that had an activated sonic hedgehog pathway demonstrated a similar promising response.

?This group of drug-resistant patients urgently needs new treatments,? said Amar Gajjar, MD, director of the Neuro-Oncology Division in the Department of Oncology at St. Jude Children?s Research Hospital in Memphis, Tenn., and principal investigator of the PBTC Phase I trial ?Some patients have remained on this trial for extended periods of time, and our early results are positive and encouraging. The trend in treating children with these cancers is toward targeted therapies like this one, which block key signaling pathways and disable the cancer?s ability to function or reproduce.?

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Study method
GDC 0449 was administered once daily for 28 days dose levels of (1) 85 mg/m /dose and (2) 170 mg/m/dose. A course was defined as 28 days in duration. PK analysis was performed during the first course and steady-state concentrations were obtained prior to each subsequent course (day 21). MRI scans of the knees were obtained at baseline and 3 mos to assess abnormalities in bone development.

Further trials
The researchers will further test this drug in a planned PBTC Phase II trial in children with relapsed medulloblastoma. If the Phase II trial finds an appropriate number of positive responses, Dr. Gajjar said, then the drug may represent the first targeted agent in pediatric medulloblastoma aimed at a specific signaling pathway, rather than a broadly acting chemotherapeutic agent. The drug would be an important advance because fewer than 5 percent of children with recurrent medulloblastoma are long-term survivors.

Previous early-stage studies have suggested this drug may also be effective against basal cell carcinoma in adults, and there is currently a Phase II trial being conducted for adults with recurrent medulloblastoma.

Clinical Science Symposium: Signalling in Pediatric Cancer Comes to the Clinic
Lead Author: Amar J. Gajjar, MD, St. Jude’s Research Hospital, Memphis, TN

Date: Saturday, June 5, 2010, 4:45-5:00 PM CDT .
Location: Room S504
Abstract: CRA 9501
Title: A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent or refractory medulloblastoma: A Pediatric Brain Tumor Consortium study (PBTC 25).
Authors: A. J. Gajjar, C. F. Stewart, D. W. Ellison, T. Curran, P. Phillips, S. Goldman, R. Packer, L. E. Kun, J. M. Boyett, R. J. Gilbertson.

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