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Phase 1b Study of Tirabrutinib in Combination With Idelalisib or 1
Entospletinib in Previously Treated Chronic Lymphocytic Leukemia 2
3
Running title: Phase 1b Study of Tirabrutinib Combinations in CLL 4
Alexey V. Danilov,*1,2 Charles Herbaux,3 Harriet S. Walter,4 Peter Hillmen,5 Simon A. Rule,6 5
Ebenezer A. Kio,7 Lionel Karlin,8 Martin J.S. Dyer,4 Siddhartha S. Mitra,9 Ping C. Yi,9 Rita 6
Humeniuk,9 Xi Huang,9 Ziqian Zhou,9 Pankaj Bhargava,9 Juliane M. Jürgensmeier,9 Christopher 7
D. Fegan10 8
1Knight Cancer Institute, Oregon Health and Science University, Portland, OR, US 9 2City of Hope National Medical Center, Duarte, CA, US 10 3Service des Maladies du Sang, CHU Lille, Lille, France 11 4Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, 12 UK 13 5Experimental Haematology, University of Leeds, Leeds, UK 14 6Department of Haematology, Plymouth University Medical School, Plymouth, UK 15 7Goshen Hospital Center for Cancer Care, Goshen, IN, US 16 8Hematology Department, Lyon University Hospital, Pierre-Benite, France 17 9Gilead Sciences, Inc., Foster City, CA, US 18 10University Hospital of Wales, Cardiff, UK 19 20
Alexey V. Danilov, MD, PhD 24 City of Hope National Medical Center 25 1500 E Duarte Rd 26 Duarte, CA 91010 27 [email protected] 28 Phone 626-218-3279 29 30
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Contribution: A.V.D., C.H., S.S.M., S.A.R., R.H., P.C.Y., J.M.J., and X.H. designed and 461
performed research; S.S.M., R.H., J.M.J., X.H., Z.Z., P.B., and P.C.Y. analyzed data; all authors 462
participated in drafting, revising, and approving the final manuscript. 463
464
References 465
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Best overall response, n (%) Complete response Partial response Partial response with lymphocytosis Stable disease Progressive disease Nonevaluable Discontinued study‡
2 (7)
19 (66) 3 (10) 2 (7)
0 0
3 (10)
1 (7)
11 (79) 1 (7) 1 (7)
0 0 0
1 (10) 9 (90)
0 0 0 0 0
High cytogenetic risk,† N Overall response rate,* n (%)
6 5 (83)
5 4 (80)
1 1 (100)
Best overall response Complete response Partial response Partial response with lymphocytosis Stable disease Progressive disease Nonevaluable Discontinued study‡
1 (17) 4 (67)
0 1 (17)
0 0 0
0
4 (80) 0
1 (20) 0 0 0
0
1 (100) 0 0 0 0 0
Standard cytogenetic risk,† N Overall response rate,* n (%)
21 18 (86)
9 9 (100)
7 7 (100)
Best overall response, n (%) Complete response Partial response Partial response with lymphocytosis Stable disease Progressive disease Nonevaluable Discontinued study‡
1 (5)
15 (71) 2 (10)
0 0 0
3 (14)
1 (11) 7 (78) 1 (11)
0 0 0 0
1 (14) 6 (86)
0 0 0 0 0
*Overall response rate = complete response + partial response + partial response with lymphocytosis. 648 †Cytogenetic risk was categorized as high for patients with TP53 aberrations (deletions and/or mutations in the TP53 gene 649
determined by NGS or FISH panels), and standard risk for those with no detectable TP53 aberrations. 650 ‡Discontinued study or started new anticancer therapy before first assessment.651
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504
Published OnlineFirst March 10, 2020.Clin Cancer Res Alexey V. Danilov, Charles HERBAUX, Harriet S Walter, et al. LeukemiaEntospletinib in Previously Treated Chronic Lymphocytic Phase 1b Study of Tirabrutinib in Combination With Idelalisib or
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504