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Targeted molecular therapy GDC-0449 well-tolerated in phase 1 trial of pediatric medulloblastoma
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ASCO 2010 Annual Meeting
CHICAGO — Results from the phase-1 Pediatric Brain Tumor Consortium Study – or PBTC 25 – showed that the novel targeted molecular therapy GDC-0449 appeared to be safe for children with drug-resistant medulloblastoma.
GDC-0449 targets aberrant signaling in the sonic hedgehog pathway, which has been shown to be responsible for 20% of medulloblastomas.
Twelve of 13 children with recurrent or refractory medulloblastoma have tolerated the drug well without significant adverse effects, including one patient who carries an activated sonic hedgehog pathway who was on the drug for more than a year without disease progression.
Amar J. Gajjar, MD, co-chair of the department of oncology at St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the results at the 2010 ASCO Annual Meeting. Although it is very early in the evaluation process, Gajjar said that results are promising for a disease that desperately needs new treatment options.
“Medulloblastoma accounts for 400 to 500 diagnoses in children annually in this country,” he said. “These children are treated with radiation and chemotherapy, and though we can cure a lot of these children, they have a lot of long-term side effects. If we can develop treatments that are targeted specifically to molecular subtypes, we can cure these children with much less toxic therapies.”
Researchers administered either 85 mg/m2 GDC-0449 or 170 mg/m2 GDC-0449 once daily for 28 days. They performed pharmacokinetic analysis during the first 28-day course and obtained steady-state concentrations before each subsequent course of therapy (day 21). Physicians then took MRI scans of patients’ knees at baseline and at three months to assess abnormalities in bone development.
One patient assigned 170 mg/m2 GDC-0449 experienced dose-limiting toxicity, grade-3 gamma-Glutamyl transpeptidase. No patient experienced grade-4 toxicities.
The median steady-state day 21 concentration with the 85 mg/m2 dose was 10.15 mcM (9.10 mcM – 18.99 mcM) and 14.50 mcM (14.43 mcM –14.57 mcM) at the 170 mg/m2 dose.
Gajjar said researchers are planning a phase 2 trial in children with relapsed medulloblastoma. A positive result in that trial could mean that GDC-0449 is the first targeted agent in pediatric medulloblastoma aimed at a specific signaling pathway, rather than functioning as broad chemotherapeutic agent.
“Our next steps are to embark on a phase 2 trial and treat sonic hedgehog patients with this drug,” he said. “We are also currently conducting an adult phase 2 trial, again stratifying on the basis of whether they have sonic hedgehog disease or not, and treating them with this targeted molecular therapy. This study is already underway and preliminary analysis has shown a benefit for these patients.” – by Jason Harris
There’s not a lot of data on follow-up, but this is an amazing proof of principal, and this pathway looks to be very relevant in a number of cancers.
– Lynn Schuchter, MD
Professor of
Medicine, Abramson Cancer Center, University of Pennsylvania
For more information:
- Gajjar AJ. #CRA 9501. Presented at: the 2010 ASCO Annual Meeting; June 4-8; Chicago.
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