TY - JOUR
T1 - Phase Ib study of tirabrutinib in combination with idelalisib or entospletinib in previously treated chronic lymphocytic leukemia
AU - Danilov, Alexey V.
AU - Herbaux, Charles
AU - Walter, Harriet S.
AU - Hillmen, Peter
AU - Rule, Simon A.
AU - Kio, Ebenezer A.
AU - Karlin, Lionel
AU - Dyer, Martin J.S.
AU - Mitra, Siddhartha S.
AU - Yi, Ping Cheng
AU - Humeniuk, Rita
AU - Huang, Xi
AU - Zhou, Ziqian
AU - Bhargava, Pankaj
AU - Jurgensmeier, Juliane M.
AU - Fegan, Christopher D.
N1 - Funding Information:
A.V. Danilov is an employee/paid consultant for Gilead Sciences, Pharmacyclics, AstraZeneca, Verastem Oncology, Beigene, Bayer Oncology, Genentech, TG Therapeutics, Celgene, Rigel Pharm, and Seattle Genetics, and reports receiving commercial research grants from Gilead Sciences, Aptose Bioscences, AstraZeneca, Takeda Oncology, Verastem Oncology, and Bayer Oncology. H.S. Walter is an employee/paid consultant for and reports receiving speakers bureau honoraria from AbbVie, and reports receiving other commercial research support from Janssen, Gilead Sciences, and AbbVie. P. Hillmen reports receiving commercial research grants from Gilead Sciences, Janssen, AbbVie, Roche, and Pharmacyclics, and speakers bureau honoraria from Janssen and AbbVie. M.J.S. Dyer reports receiving speakers bureau honoraria from Kite/Gilead Sciences. S.S. Mitra, R. Humeniuk, Z. Zhou, and J.M. Ju€rgensmeier are employees/paid consultants for Gilead Sciences. P. Bhargava is an employee/paid consultant for and holds ownership interest (including patents) in Gilead Sciences. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This study was funded by Gilead Sciences, Inc. We extend our thanks to the patients and their families. We would also like to thank Jeff Silverman, Helen Yu, Hoa Truong, Julie Lin, Donovan Verrill, Wanying Li, and Nishan Raj for advice, and for experimental, programming, and statistical contributions to the article. Writing and editorial support was provided by Impact Communication Partners, Inc. A.V. Danilov is a Leukemia & Lymphoma Society Scholar in Clinical Research.
Publisher Copyright:
© 2020 American Association for Cancer Research.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/15
Y1 - 2020/6/15
N2 - 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 (PI3Kd) 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 PI3Kd 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).
AB - 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 (PI3Kd) 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 PI3Kd 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).
UR - http://www.scopus.com/inward/record.url?scp=85085117441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085117441&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-3504
DO - 10.1158/1078-0432.CCR-19-3504
M3 - Article
C2 - 32156743
AN - SCOPUS:85085117441
VL - 26
SP - 2810
EP - 2818
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 12
ER -