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Clinical Trial
. 2011 Aug 20;29(24):3293-300.
doi: 10.1200/JCO.2011.34.7427. Epub 2011 Jul 18.

Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia

Hiroto Inaba  1 , Jeffrey E Rubnitz, Elaine Coustan-Smith, Lie Li, Brian D Furmanski, Gerard P Mascara, Kenneth M Heym, Robbin Christensen, Mihaela Onciu, Sheila A Shurtleff, Stanley B Pounds, Ching-Hon Pui, Raul C Ribeiro, Dario Campana, Sharyn D Baker
Affiliations
Clinical Trial

Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia

Hiroto Inaba et al. J Clin Oncol. .

Abstract

Purpose: To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.

Patients and methods: Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.

Results: At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.

Conclusion: Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Activity of sorafenib and sorafenib N-oxide in a human kinase screen and acute myeloid leukemia (AML) cell lines. (A) Kinase interaction maps of sorafenib and sorafenib N-oxide evaluated at 10 μmol/L across panel of 442 kinases by active-site competitive binding assay. Binding inhibition is shown as percentage of kinase that remained bound compared with that in dimethyl sulfoxide (DMSO)–treated control. Larger red circles indicate higher-affinity binding. (B) FMS-like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) binding constants of sorafenib and sorafenib N-oxide. Quantity of kinase measured by quantitative real-time polymerase chain reaction (qPCR) signal is plotted against corresponding drug concentration in log10 scale. Binding constants (Kd) were calculated in duplicate experiments by using Hill equation. (C) Activity of sorafenib and sorafenib N-oxide in AML cells in MTT assay. Cells were treated for 72 hours with increasing concentrations of sorafenib N-oxide or indicated mixtures of sorafenib and sorafenib N-oxide. Drug concentration in log scale is plotted against mean percentage of drug-treated cells in relation to DMSO-treated cells. Data points represent two to three independent experiments with six to eight replicates for each drug concentration.
Fig 2.
Fig 2.
Clinical course and bone marrow response in patient 2. (A) Patient achieved complete remission with persistence of minimal residual disease after receiving sorafenib with clofarabine (Clo) and cytarabine (Ara-C); acute myeloid leukemia recurred during respiratory syncytial virus (RSV) infection. Single-agent sorafenib induced third complete remission, and RSV infection cleared. Five weeks later, after sorafenib was interrupted because of thrombocytopenia, blast cells increased to 74%; there was no response to readministration of sorafenib. Gold bars represent percentage of bone marrow blast cells. (B) Bone marrow response to initial 7-day treatment with single-agent sorafenib. Magnification ×10 (panels A, C); ×40 (panels B, D).
Fig A1.
Fig A1.
Mean steady-state sorafenib and sorafenib N-oxide plasma concentrations. Sorafenib (A) 200 mg/m2 or (B) 150 mg/m2 was administered twice daily, and serial pharmacokinetic sampling was performed on day 7. Dashed line indicates sorafenib concentration of 10 μmol/L (4.65 mg/L).
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