A phase I trial of TPI-287 as a single agent and its combination with temozolomide in relapsed neuroblastoma or medulloblastoma.

Abstract

TPS329 Background: Neuroblastoma is the most common extracranial solid tumor and medulloblastoma is the most common brain tumor in children. The prognosis for infants with neuroblastoma is good, while only 30% of children diagnosed after 12-15 months of age survive despite aggressive multimodal therapies. Therapies for children with relapsed medulloblastoma are associated with severe long-term toxicities with <15% survival. Thus, development of new therapies, especially ones with favorable toxicity profiles, would improve the treatment of these diseases. A novel anti- microtubule agent, TPI 287, is synthetically manufactured from naturally occurring taxanes extracted from yew starting material. The synthesis involves modifications of the side chain to make the drug more lipophilic, and modification of the baccatin ring structure which circumvents multidrug resistance (MDR)-based resistance and allows for binding to mutant tubulin. Selection was also made on the basis of the very high potency of this drug ...