Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias

Pediatr Blood Cancer. 2012 Dec 15;59(7):1252-8. doi: 10.1002/pbc.24264. Epub 2012 Aug 8.

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.

Procedure: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adenine Nucleotides / administration & dosage*
  • Adenine Nucleotides / adverse effects
  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Arabinonucleosides / administration & dosage*
  • Arabinonucleosides / adverse effects
  • Child
  • Child, Preschool
  • Clofarabine
  • Cyclophosphamide / administration & dosage*
  • Cyclophosphamide / adverse effects
  • DNA Damage / drug effects
  • Drug Administration Schedule
  • Female
  • Humans
  • Leukemia / drug therapy*
  • Leukemia, Myeloid, Acute / drug therapy
  • Male
  • Maximum Tolerated Dose
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Recurrence
  • Young Adult

Substances

  • Adenine Nucleotides
  • Arabinonucleosides
  • Clofarabine
  • Cyclophosphamide