title: A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA. hmrussel@txccc.org
authors.forename: Heidi V
authors.initials: HV
authors.lastname: Russell
authors.forename: Susan G
authors.initials: SG
authors.lastname: Groshen
authors.forename: Tasnim
authors.initials: T
authors.lastname: Ara
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerck
authors.forename: Randy
authors.initials: R
authors.lastname: Hawkins
authors.forename: Hollie A
authors.initials: HA
authors.lastname: Jackson
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
authors.forename: Araz
authors.initials: A
authors.lastname: Marachelian
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Howard
authors.initials: H
authors.lastname: Katzenstein
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D003520:Cyclophosphamide