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Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high‐risk neuroblastoma
Author(s) -
Mody Rajen,
Zhao Lili,
Yanik Gregory Anthony,
Opipari Valerie
Publication year - 2017
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.26563
Subject(s) - medicine , irinotecan , refractory (planetary science) , bortezomib , toxicity , gastroenterology , neuroblastoma , progressive disease , chemotherapy , surgery , oncology , cancer , multiple myeloma , colorectal cancer , physics , astrobiology , biology , genetics , cell culture
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/m 2 /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/m 2 /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.