Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study.
OBJECTIVE
To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma.


METHODS
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.
Authors' 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.
Amar
A
Gajjar
Clinton F
CF
Stewart
David W
DW
Ellison
Sue
S
Kaste
Larry E
LE
Kun
Roger J
RJ
Packer
Stewart
S
Goldman
Murali
M
Chintagumpala
Dana
D
Wallace
Naoko
N
Takebe
James M
JM
Boyett
Richard J
RJ
Gilbertson
Tom
T
Curran
D000293:Adolescent; D000813:Anilides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008527:Medulloblastoma / Q000188:drug therapy*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D000072086:Smoothened Receptor; D016896:Treatment Outcome; D055815:Young Adult
D000813:Anilides; D000970:Antineoplastic Agents; C538724:HhAntag691; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor