title: Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias.
abstract: BACKGROUND
  By inhibiting DNA repair, clofarabine (CLO) may augment cyclophosphamide (CY)-induced DNA damage and apoptosis. We performed a Phase I study for refractory and/or relapsed (R/R) leukemia in children to determine maximum-tolerated dose (MTD) of time-sequential CLO followed by CY.
  
  
  METHODS
  Thirteen patients with (R/R) ALL (n = 8) and AML (N = 5), median age 9 years (range: 2-12 years), were treated with escalating doses of CLO on days 1, 2, 3 and 8, 9, 10 and CY 200 mg/m(2) /day on days 0 and 1 then 400 mg/m(2) /day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20 mg/m(2) /day) and three patients at DL2 (CLO 30 mg/m(2) /day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2 hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2 hours after CLO followed by CY on day 1.
  
  
  RESULTS
  Two patients at DL2 had dose-limiting toxicities (DLTs) that included hypotension with cardio-respiratory failure (1) and hepato-renal failure (1). Complete remission (CR) was achieved in 2/11 (18.2%) and partial remission (PR) in 2/11 (18.2%) for an overall response (OR) of 36.4%. The use of CLO before CY augmented CY-induced DNA damage in leukemic blasts compared to CY alone.
  
  
  CONCLUSIONS
  In pediatric patients with R/R leukemia, 20 mg/m(2) /day is the MTD for CLO in timed sequential combination with CY. Increased DNA damage with the use of this combination suggests a mechanism for the sequential timing of these two chemotherapeutic agents.
authors.affiliation: Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting & Blaustein Cancer Research Building, Baltimore, MD 21231, USA.
authors.forename: Abeer
authors.initials: A
authors.lastname: Abd Elmoneim
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Ricklis
authors.forename: Jessica
authors.initials: J
authors.lastname: Boklan
authors.forename: Todd
authors.initials: T
authors.lastname: Cooper
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.forename: Katherine
authors.initials: K
authors.lastname: Rolla
authors.forename: Tammy
authors.initials: T
authors.lastname: Scott
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
mesh_terms: D000208:Acute Disease; D000227:Adenine Nucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D004249:DNA Damage / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012008:Recurrence; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine; D003520:Cyclophosphamide