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

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

Author information

1
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
2
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
3
A. Alfred Taubman Research Institute, University of Michigan, Ann Arbor, Michigan.

Abstract

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

PMID:
28436582
DOI:
10.1002/pbc.26563
[Indexed for MEDLINE]

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