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Published on: October 3, 2010
Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor
Amar Gajjar1, Clinton F Stewart, David W Ellison
1Authors' Affiliations: Departments of Oncology, Pharmaceutical Sciences, Pathology, Radiological Sciences, Biostatistics, and Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee; Center for Neuroscience Research, Children's National Medical Center, Washington, DC; Division of Hematology-Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; Department of Pediatrics, Texas Children's Hospital, Houston, Texas; Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; and Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Purpose:
To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma.
Experimental Design:
Initially, vismodegib was administered daily at 85 mg/m(2) and escalated to 170 mg/m(2). The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with small body surface area (BSA, 0.67-1.32 m(2)) or 300 mg for those who were larger (BSA, 1.33-2.20 m(2)). Pharmacokinetics were performed during the first course of therapy, and the right knees of all patients were imaged to monitor bone toxicity. Immunohistochemical analysis was done to identify patients with Sonic Hedgehog (SHH)-subtype medulloblastoma.
Results:
Thirteen eligible patients were enrolled in the initial study: 6 received 85 mg/m(2) vismodegib, and 7 received 170 mg/m(2). Twenty eligible patients were enrolled in the flat-dosing part of the study: 10 at each dosage level. Three dose-limiting toxicities were observed, but no drug-related bone toxicity was documented. The median (range) vismodegib penetration in the cerebrospinal fluid (CSF) was 0.53 (0.26-0.78), when expressed as a ratio of the concentration of vismodegib in the CSF to that of the unbound drug in plasma. Antitumor activity was seen in 1 of 3 patients with SHH-subtype disease whose tumors were evaluable, and in none of the patients in the other subgroups.
Conclusions:
Vismodegib was well tolerated in children with recurrent or refractory medulloblastoma; only two dose-limiting toxicities were observed with flat dosing. The recommended phase II study dose is 150 or 300 mg, depending on the patient's BSA. Clin Cancer Res; 19(22); 6305-12. ©2013 AACR.
Insights
Vismodegib is safe and well-tolerated in children with medulloblastoma, with recommended flat doses of 150 or 300 mg based on body surface area. This smoothened inhibitor showed some antitumor activity in the Sonic Hedgehog subtype.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Molecular Targeted Therapy
Background:
- Medulloblastoma is a common pediatric brain tumor with limited treatment options for refractory or relapsed cases.
- Vismodegib, a smoothened inhibitor, targets the Sonic Hedgehog signaling pathway implicated in medulloblastoma development.
Purpose of the Study:
- To evaluate the safety, tolerability, and pharmacokinetics of vismodegib in pediatric patients with refractory or relapsed medulloblastoma.
- To determine the recommended dose for Phase II studies based on observed toxicities and drug exposure.
Main Methods:
- A dose-escalation study followed by a flat-dosing schedule (150 mg or 300 mg based on body surface area [BSA]).
- Pharmacokinetic analyses were conducted, and bone toxicity was monitored via knee imaging.
- Immunohistochemistry was used to identify Sonic Hedgehog (SHH)-subtype medulloblastoma.
Main Results:
- Vismodegib was generally well-tolerated, with only two dose-limiting toxicities observed during flat dosing.
- No drug-related bone toxicity was documented.
- Cerebrospinal fluid (CSF) penetration of vismodegib was observed (median ratio 0.53).
- Antitumor activity was noted in one evaluable patient with SHH-subtype medulloblastoma.
Conclusions:
- Vismodegib demonstrates an acceptable safety profile in children with recurrent or refractory medulloblastoma.
- The recommended Phase II dose is 150 mg or 300 mg, adjusted for patient BSA.
- Further investigation into vismodegib's efficacy, particularly in SHH-subtype medulloblastoma, is warranted.
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