A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes.

Abstract

PURPOSE:

Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria.

EXPERIMENTAL DESIGN:

Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.

RESULTS:

The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI.

CONCLUSIONS:

ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study.

• Authors: Guillermo Garcia-Manero, Hanna J Khoury, Elias Jabbour, Jeffrey Lancet, Shannon L Winski, LouAnn Cable, Selena Rush, Lara Maloney, Grant Hogeland, Mieke Ptaszynski, Monica Cabrero Calvo, Zach Bohannan, Alan List, Hagop Kantarjian, Rami Komrokji
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 5 Pg. 985-94 (Mar 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25480830 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Indazoles
• Protein Kinase Inhibitors
• pexmetinib
• Urea
• Receptor, TIE-2
• p38 Mitogen-Activated Protein Kinases

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Bone Marrow (metabolism, pathology)
• Female
• Humans
• Indazoles (administration & dosage, therapeutic use)
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Receptor, TIE-2 (antagonists & inhibitors, metabolism)
• Treatment Outcome
• Urea (administration & dosage, analogs & derivatives, therapeutic use)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)