Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

Abstract

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).

Trial registration: ClinicalTrials.gov NCT00827138.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Mean plasma rebastinib concentration-time profile following multiple-dose administration of rebastinib tablets to steady state. Peripheral blood samples were obtained at the indicated times following administration of an oral dose of rebastinib (tablet formulation at doses of 100 mg BID, 150 mg BID, and 200 mg BID) in patients who had received at least 1 week of continuous dosing. Plasma concentrations of rebastinib were determined by LC-MS/MS as described in Methods. IC80 values for inhibition of BCR-ABL1 phosphorylation of CRKL in ex vivo assays using whole blood from CML patients with BCR-ABL1 or BCR-ABL1 T315I are indicated. BID: twice daily; Conc: concentration; pCRKL: phosphorylated CT10 Regulator of Kinase-like.

Figure 2.

Pharmacodynamic analyses of pCRKL and pSTAT5 inhibition pre- and post-rebastinib dose. Serial peripheral blood samples were obtained from patients following the first dose of rebastinib (Cycle 1 Day 1) and on Day 8 of continuous twice daily dosing (Cycle 1 Day 8). Mononuclear cells were isolated, lysed, and the indicated proteins and phosphoproteins analyzed by immunoblotting as described in Methods. (A) Patient with relapsed chronic phase CML BCR-ABL1 V299L mutation who demonstrated >75% inhibition of pCRKL 4h following the Day 8 morning dose. (B) Patient with relapsed chronic phase CML and BCR-ABL1 T315I mutation who demonstrated >90% inhibition of pSTAT5 at 1h following the Day 8 morning dose. In this patient, the degree of inhibition of pCRKL was less pronounced (~25%). PK: pharmacokinetics; pCRKL: phosphorylated CT10 regulator of kinase-like; CRKL: CT10 regulator of kinase-like; eIF4E: eukaryotic translation initiation factor 4E; pSTAT5: phosphorylated signal transducer and activator of transcription 5; STAT5: signal transducer and activator of transcription 5.