Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk neuroblastoma

Pediatr Blood Cancer. 2017 Nov;64(11). doi: 10.1002/pbc.26563. Epub 2017 Apr 24.


Purpose: Prognosis for relapsed/refractory high-risk neuroblastoma (HR-NBL) remains poor. Bortezomib, a proteasome inhibitor, has shown preclinical activity against NBL as a single agent and in combination with cytotoxic chemotherapy including irinotecan.

Patients and methods: Eighteen HR-NBL patients with primary refractory (n = 8) or relapsed (n = 10) disease were enrolled in a Phase I study using modified Time To Event Continual Reassessment Method. Bortezomib (1.2 mg/m2 /day) was administered on days 1, 4, 8, and 11 intravenously (IV) and irinotecan was given IV on days 1-5 (35, 40, or 45 mg/m2 /day, on dose levels [DL] 1-3, respectively). The maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and response rate were examined.

Results: Eighteen NBL patients were evaluable for toxicity; 17 were evaluable for response assessment. A total of 142 courses were delivered (mean 8.2, median 2, range 1-48), with two patients receiving more than 40 courses of therapy. Two DLTs were reported, including a grade 4 thrombocytopenia (DL2) and a grade 3 irritability (DL3). MTD was estimated as DL3. Two of 17 (12%) evaluable patients showed objective responses (ORs) lasting more than 40 courses, including 1 partial remission and 1 complete remission. Four patients (23%) had prolonged stable disease (SD) lasting six or more courses, with a total of 35% study patients demonstrating clinical benefit in the form of prolonged OR or SD.

Conclusion: The combination of bortezomib and irinotecan was well tolerated by patients with relapsed/refractory NBL with favorable toxicity profile. It also showed modest but promising clinical activity and merits further testing in Phase II studies.

Keywords: irinotecan; proteasome inhibitor; relapsed/refractory high-risk neuroblastoma.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bortezomib / administration & dosage
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Child
  • Child, Preschool
  • Cohort Studies
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Irinotecan
  • Male
  • Maximum Tolerated Dose
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Prognosis
  • Salvage Therapy*
  • Survival Rate
  • Young Adult


  • Bortezomib
  • Irinotecan
  • Camptothecin