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A phase I study of zoledronic acid and low‐dose cyclophosphamide in recurrent/refractory neuroblastoma: A new approaches to neuroblastoma therapy (NANT) study
Author(s) -
Russell Heidi V.,
Groshen Susan G.,
Ara Tasnim,
DeClerck Yves A.,
Hawkins Randy,
Jackson Hollie A.,
DaldrupLink Heike E.,
Marachelian Araz,
Skerjanec Andrej,
Park Julie R.,
Katzenstein Howard,
Matthay Katherine K.,
Blaney Susan M.,
Villablanca Judith G.
Publication year - 2011
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.22821
Subject(s) - zoledronic acid , medicine , bisphosphonate , neuroblastoma , cyclophosphamide , hypophosphatemia , gastroenterology , oncology , urology , chemotherapy , osteoporosis , biology , genetics , cell culture
Background Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. Procedure Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m 2 /day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL‐6, and sIL‐6R were evaluated. Results Twenty‐one patients, median age 7.5 (range 0.8–25.6) years were treated with 2 mg/m 2 (n = 4), 3 mg/m 2 (n = 3), or 4 mg/m 2 (n = 14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1–18) courses was given. Two dose limiting toxicities (grade 3 hypophosphatemia) occurred at 4 mg/m 2 zoledronic acid. Other grades 3–4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 1), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3–18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL‐6 levels decreased with therapy. Conclusions Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m 2 every 28 days. Pediatr Blood Cancer 2011; 57: 275–282. © 2010 Wiley‐Liss, Inc.