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

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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.


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.


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.

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