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Phase Ib Study of Tirabrutinib in Combination with Idelalisib Or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia a C Alexey V

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Phase Ib Study of Tirabrutinib in Combination with Idelalisib Or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia a C Alexey V Published OnlineFirst March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia A C Alexey V. Danilov1,2, Charles Herbaux3, Harriet S. Walter4, Peter Hillmen5, Simon A. Rule6, Ebenezer A. Kio7, Lionel Karlin8, Martin J.S. Dyer4, Siddhartha S. Mitra9, Ping Cheng Yi9, Rita Humeniuk9, Xi Huang9, Ziqian Zhou9, Pankaj Bhargava9, Juliane M. Jurgensmeier€ 9, and Christopher D. Fegan10 ABSTRACT ◥ Purpose: Bruton tyrosine kinase (BTK) inhibition alone leads to bination therapy. No MTD was identified. Across all treatment incomplete responses in chronic lymphocytic leukemia (CLL). groups, the most common adverse event was diarrhea (43%, Combination therapy may reduce activation of escape pathways 1patientgrade≥3); discontinuation due to adverse events was and deepen responses. This open-label, phase Ib, sequential dose- uncommon (13%). Objective response rates were 83%, 93%, and escalation and dose-expansion study evaluated the safety, tolerabil- 100%, and complete responses were 7%, 7%, and 10% in patients ity, pharmacokinetics, and preliminary efficacy of the selective BTK receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/ inhibitor tirabrutinib alone, in combination with the PI3K delta entospletinib, respectively. As of February 21, 2019, 46 of 53 (PI3Kd) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) patients continue to receive treatment on study. inhibitor entospletinib in patients with relapsed/refractory CLL. Conclusions: Tirabrutinib in combination with idelalisib or Patients and Methods: Patients received either tirabrutinib entospletinib was well tolerated in patients with CLL, establish- monotherapy (80 mg every day) or tirabrutinib 20–150 mg every ing an acceptable safety profile for concurrent selective inhibi- day in combination with either idelalisib (50 mg twice a day or tion of BTK with either PI3Kd or SYK. This small study did not 100 mg every day) or entospletinib (200 mg or 400 mg every day). establish a superior efficacy of the combinations over tirabru- Results: Fifty-three patients were included. Systemic tirabru- tinib alone. This trial is registered at www.clinicaltrials.gov tinib exposure was comparable between monotherapy and com- (NCT02457598). Introduction lack the active site cysteine residue, in some cases with comparable affinity as binding to BTK (3–5). Binding of ibrutinib to these In the past two decades, signaling through the B-cell receptor (BCR) additional kinases may potentially be responsible for side effects such has been a major focus of pharmacologic research. Several BCR- as rash, diarrhea, bleeding, and atrial fibrillation (6–9). targeted agents are now approved for patients with chronic lympho- Selective BTK inhibitors have been developed to minimize these off- cytic leukemia (CLL), including the Bruton tyrosine kinase (BTK) target effects. Tirabrutinib (formerly ONO/GS-4059) is a selective, inhibitors ibrutinib and acalabrutinib (1, 2), idelalisib and duvelisib irreversible, second-generation, small-molecule BTK inhibitor (5, 10). (PI3K inhibitors), and venetoclax (a BCL2 inhibitor). Tirabrutinib irreversibly binds to C481 of BTK with greater target Ibrutinib, a first-generation BTK inhibitor, irreversibly inhibits at selectivity. In a recent study, the IC values for inhibition of kinases by least 11 other kinases with an IC of approximately 11 nmol/L or less: 50 50 tirabrutinib were: BTK, 6.8 nmol/L; BMX, 6 nmol/L; BLK, 300 nmol/L; BTK, BLK, BMX, CSK, FGR, BRK, HCK, EGFR, YES, ErbB2, and TEC, 48 nmol/L; EGFR, 3020 nmol/L; ErbB2, 7313 nmol/L; and ITK, ITK (3, 4). In addition, ibrutinib reversibly binds to other kinases that >20,000 nmol/L. Tirabrutinib showed a 440-fold and >2,940-fold selectivity for BTK over EGFR and ITK, respectively (11). In a phase I dose-escalation trial, tirabrutinib demonstrated an overall 1Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. 2City of Hope National Medical Center, Duarte, California. 3Service des response rate (ORR) of 96% in 28 patients with relapsed/refractory Maladies du Sang, CHU Lille, Lille, France. 4Ernest and Helen Scott Haemato- (R/R) CLL, with no MTD identified up to 600 mg every day (5). Long- logical Research Institute, University of Leicester, Leicester, United Kingdom. term follow-up of that study (for a median of 32.5 months) demon- 5Experimental Haematology, University of Leeds, Leeds, United Kingdom. strated an estimated median progression-free survival (PFS) of 6 Department of Haematology, Plymouth University Medical School, Plymouth, 38.5 months and median overall survival of 44.9 months (12). Despite 7 United Kingdom. Goshen Hospital Center for Cancer Care, Goshen, Indiana. the high ORR achieved with BTK inhibitors, most patients with CLL 8Department of Hematology, Lyon University Hospital, Pierre-Benite, France. 9Gilead Sciences, Inc., Foster City, California. 10University Hospital of Wales, will progress while on therapy. Thus, new therapeutic strategies are Cardiff, United Kingdom. needed to achieve an increased depth of response to improve remission duration and reduce the emergence of resistant subclones, without Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). additional toxicities. The BCR signaling cascade consists of divergent signaling pathways. Corresponding Author: Alexey V. Danilov, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010. Phone: 626-218-3279; Fax: 626-218-5446; BCR cross-linking leads to activation of proximal tyrosine kinases, E-mail: [email protected] including BTK, PI3K, and spleen tyrosine kinase (SYK). The signal is further transmitted through multiple downstream mediators, leading Clin Cancer Res 2020;XX:XX–XX to upregulation of antiapoptotic proteins such as MCL1 and doi: 10.1158/1078-0432.CCR-19-3504 BCL2 (13, 14). The potential benefit of combining agents targeting Ó2020 American Association for Cancer Research. BTK, PI3K, and SYK has been well documented in CLL and non- AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-3504 Danilov et al. CLL treatment regimen, and no prior exposure to AKT, BTK, PI3K, Translational Relevance JAK, mTOR, or SYK inhibitors (see Supplementary Table S1 for more Pharmacologic targeting of the B-cell receptor (BCR) signaling details). Institutional review boards at each of the study sites approved pathway is an active area of drug development in chronic lym- the protocols. All patients provided written informed consent. This phocytic leukemia (CLL) and non-Hodgkin lymphoma. However, study was conducted in accordance with the Declaration of Helsinki. few clinical trials have evaluated concurrent inhibition of multiple A standard 3þ3 dose-escalation schema was followed (Supplemen- targets in this pathway and none have employed second-generation tary Table S2). Patients receiving the tirabrutinib/idelalisib combina- selective Bruton tyrosine kinase (BTK) inhibitors in combination tion were treated on 28-day cycles with either idelalisib 50 mg twice a with alternative BCR-associated kinases. This is the first study to day or 100 mg every day and tirabrutinib ranging from 20 to 160 mg evaluate tirabrutinib, a second-generation BTK inhibitor, com- every day. Patients receiving the tirabrutinib/entospletinib combina- bined with either the first-in-class PI3K delta inhibitor idelalisib or tion were treated with either entospletinib 200 mg or 400 mg every day the first-in-class spleen tyrosine kinase inhibitor entospletinib in and tirabrutinib ranging from 40 to 150 mg every day. Tirabrutinib patients with relapsed/refractory CLL. The trial demonstrated the monotherapy was given at 80 mg every day. Patients received a single safety of the regimen, a low treatment discontinuation rate, and dose of tirabrutinib on cycle 1, day 1, before initiating idelalisib or high efficacy. This study paves the way for further investigations of entospletinib in combination with tirabrutinib on cycle 1, day 2 (or concurrent targeting of multiple kinases within the BCR signaling continuation with tirabrutinib monotherapy). After completion of pathway as part of multiagent therapeutic regimens poised to study treatment, patients attended a 30-day safety follow-up visit. prolong and deepen responses and prevent emergence of resistance Determination of CLL response and progression was based on the in CLL. 2008 standardized International Workshop on CLL (iwCLL) Criteria, which were current at the time the study protocol was finalized (21). Patients with CLL had CT or MRI scans performed at baseline, at 24 weeks, and at the time of progression. Bone marrow aspirates were Hodgkin lymphoma (NHL) preclinical models. Concurrent targeting collected at the time of suspected complete response (CR) for minimal of BTK and PI3K in a murine CLL model led to improved survival and residual disease (MRD) testing using the CLL ERIC MRD flow reduction in tumor burden compared with either agent alone (15). cytometry panel at Covance/Labcorp, Indianapolis, IN, based on Additive or synergistic effects of the combination of ibrutinib and Rawstrom and colleagues, 2007, and Rawstrom and colleagues, idelalisib have been reported
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