A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma

作者：Mitchell Deanna; Bergendahl Genevieve; Ferguson William; Roberts William; Higgins Timothy; Ashikaga Takamaru; DeSarno Mike; Kaplan Joel; Kraveka Jacqueline; Eslin Don; Werff Alyssa Vander; Hanna Gina K; Sholler Giselle L Saulnier^*

来源：Pediatric Blood and Cancer, 2016, 63(1): 39-46.

DOI：10.1002/pbc.25687

• brain tumors
• medulloblastoma
• neuroblastoma
• pediatric hematology
• oncology
• phase I clinical trials
• TPI 287

BackgroundThe primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses.
ProcedureEighteen patients were enrolled to a phase I dose escalation trial of weekly intravenous infusion of TPI 287 for two 28-day cycles with toxicity monitoring to determine the MTD, followed by two cycles of TPI 287 in combination with TMZ. Samples were collected to determine the pharmacokinetic parameters C-max, AUC(0-24), t(1/2), CL, and V-d on day 1 of cycles 1 (TPI 287 alone) and 3 (TPI 287+TMZ) following TPI 287 infusion. Treatment response was evaluated by radiographic (CT or MRI) and radionuclide (MIBG) imaging for neuroblastoma.
ResultsWe determined the MTD of TPI 287 alone and in combination with temozolomide to be 125mg/m(2). The non-dose-limiting toxicities at this dose were mainly anorexia and pain. The dose-limiting toxicities (DLTs) of two patients at 135mg/m(2) were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy.
ConclusionsOverall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125mg/m(2) IV on days 1, 8, and 15 of a 28 day cycle.

• 出版日期2016-1