Evaluating the Efficacy, Safety, and Dose Dependent Activities of Entospletinib in Patients with Chronic Lymphocytic Leukemia
Authors: Sharman Jeffrey P. , Kolibaba Kathryn S. , Azar Jose , Balaraman Rama , Lyons Roger M. , Smith Mitchell R. , Abella-Dominicis Esteban , Ye Wei , Shi Wen , Giever Thomas , Forero-Torres Andres 
Published: April 2021

Abstract
Introduction: Despite recent therapeutic advances for the treatment of chronic lymphocytic leukemia (CLL), a need remains for novel treatment strategies. Entospletinib (ENTO) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B cells. Following our initial report of clinical activity of ENTO in CLL, a new formulation of spray-dried dispersion (SDD) of ENTO was made to optimize pharmacokinetic aspects of the medication such as lesser drug-drug interactions. We present results based on a data cutoff of June 8, 2017.
Methods: Eligible patients with relapsed and refractory (R/R) CLL were randomized at 1:1:1 ratio to 3 treatment groups receiving 100 mg, 200 mg, and 400 mg of the SDD form of ENTO, twice daily (BID) in a phase 2 trial (NCT01799889). Tumor response was assessed based on the modified International Workshop on Chronic Lymphocytic Leukemia criteria, with imaging (CT/MRI) planned at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was progression-free survival (PFS) at week 24. All efficacy data were assessed by an Independent Review Committee.
Results: A cohort of 61 patients with R/R CLL was enrolled, and 60 received ≥1 dose of ENTO (100 mg: n=19; 200 mg: n=22; 400 mg: n=19). Two patients (3.3%, 1 each in the 100 mg and 200 mg groups) discontinued prior to initial tumor assessment. One patient at 400 mg was not included in the response evaluation due to pending scan review. Demographics of the 100 mg, 200 mg, and 400 mg ENTO groups were men (47%, 68%, and 63%, respectively) with median ages of 71, 75, and 65 years, respectively. Most had previously received rituximab (68% to 95% across groups), and median prior therapies were 1-2 (across groups). The median duration of ENTO exposure was highest in the 400 mg group (67 weeks) compared to the 100 mg and 200 mg groups (36 and 28 weeks, respectively). The PFS rates at week 24 were as follows: 100 mg: 66% (95% CI: 36% to 85%); 200 mg: 83% (95% CI: 54% to 94%), and 400 mg: 82% (95%CI: 55% to 94%). The median PFS for each group was: 100 mg: 16.6 mo (95% CI: 5.4 mo, not reached (NR)); 200 mg: 16.8 mo (95% CI: 8.1 mo, NR), and 400 mg: 16.4 mo (95% CI: 5.6 mo, NR). The objective response rate (ORR) was 28% (90% CI: 12% to 50%), 43% (90% CI: 25% to 63%), and 61% (90% CI: 39% to 80%) for 100 mg, 200 mg, and 400 mg groups, respectively. One patient in the 400 mg group achieved a complete response.
Figure 1 shows individual patients' changes in tumor size. Highest lymph node response rate of 67% (90% CI: 45% to 84%) was observed in the 400 mg group compared to 33% (90% CI: 16% to 55%) and 38% (90% CI: 21% to 58%) for the 100 mg and 200 mg groups, respectively. The most common treatment-related adverse events (TEAEs; any grade/≥grade 3, independent of causality) and common lab abnormalities are summarized in Table 1. There were 10 TEAEs in 9 patients that led to study drug discontinuation. Two deaths were reported for the 400 mg group, but neither was related to study drug. Overall safety and efficacy results for the ENTO SDD formulation were comparable with those reported for CLL patients enrolled in the original cohort taking the 800 mg mono-mesylate formulation BID. As of this data cutoff point, 32% (n=6) of the 100 mg ENTO group, 32% (n=7) of the 200 mg ENTO group, and 53% (n=10) of the 400 mg ENTO group were continuing ENTO treatment. Discontinuations were primarily for disease progression (21% to 27%) or AEs (5% to 21%).
Conclusions: ENTO in SDD formulation was well tolerated among the 3 different doses tested. There is no evidence of increased clinically significant toxicity associated with ENTO administered at 400 mg. Moreover, there were increases in ORR, PFS rate at 24 weeks, and median duration of exposure in 400 mg compared to the 200 mg and 100 mg groups. Median PFS was comparable between the 3 different dose groups evaluated. These results support the rationale for 400 mg BID of ENTO SDD to be the starting dose for future phase 2 trials in CLL. Further development of ENTO in CLL will focus on its role in combination therapies.

Disclosures
Sharman: Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kolibaba: Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Janssen: Research Funding; Gilead Sciences, Inc: Consultancy, Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Acerta: Research Funding. Balaraman: Eli Lilly: Honoraria; Abbvie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Smith: Kite Pharma: Research Funding; Gilead: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy. Abella-Dominicis: Gilead Sciences, Inc: Employment. Ye: Gilead Sciences, Inc: Employment, Equity Ownership. Shi: Gilead Sciences, Inc: Employment. Forero-Torres: 47 Pharmaceutical: Research Funding; GSK: Research Funding; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Incyte: Research Funding; Pfizer: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Novartis: Research Funding; Affimed: Research Funding.