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Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.

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journal contribution
posted on 05.06.2020, 10:27 by Alexey V Danilov, Charles Herbaux, Harriet S Walter, Peter Hillmen, Simon A Rule, Ebenezer A Kio, Lionel Karlin, Martin JS Dyer, Siddhartha S Mitra, Ping Cheng Yi, Rita Humeniuk, Xi Huang, Ziqian Zhou, Pankaj Bhargava, Juliane M Jürgensmeier, Christopher D Fegan
PURPOSE:Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL. PATIENTS AND METHODS:Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day). RESULTS:Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study. CONCLUSIONS:Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).

Funding

This study was funded by Gilead Sciences, Inc.

History

Citation

Clinical cancer research (2020)

Version

AM (Accepted Manuscript)

Published in

Clinical cancer research : an official journal of the American Association for Cancer Research

Publisher

American Association for Cancer Research (AACR)

issn

1078-0432

eissn

1557-3265

Acceptance date

06/03/2020

Copyright date

2020

Language

eng

Publisher version

https://clincancerres.aacrjournals.org/content/early/2020/04/21/1078-0432.CCR-19-3504.abstract