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

• Published in: Pediatric blood & cancer Vol. 63; no. 1; pp. 39 - 46
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.01.2016; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; brain tumors; Child; Child, Preschool; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacokinetics; Dacarbazine - toxicity; Female; Hematology; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; medulloblastoma; Medulloblastoma - drug therapy; Neoplasm Recurrence, Local; neuroblastoma; Neuroblastoma - drug therapy; Oncology; pediatric hematology/oncology; Pediatrics; phase I clinical trials; Taxoids - administration & dosage; Taxoids - pharmacokinetics; Taxoids - therapeutic use; Taxoids - toxicity; TPI 287; neuroblastoma; brain tumors; medulloblastoma; pediatric hematology/oncology; TPI 287; phase I clinical trials
• ISSN: 1545-5009; 1545-5017
• DOI: 10.1002/pbc.25687

Background The 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. Procedure Eighteen 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 Cmax, AUC0‐24, t1/2, CL, and Vd 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. Results We determined the MTD of TPI 287 alone and in combination with temozolomide to be 125 mg/m2. The non‐dose‐limiting toxicities at this dose were mainly anorexia and pain. The dose‐limiting toxicities (DLTs) of two patients at 135 mg/m2 were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy. Conclusions Overall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle. Pediatr Blood Cancer 2015; 9999:1–8 © 2015 Wiley Periodicals, Inc.