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

Abstract

serves on speakers bureaus for Gilead Sciences and Teva; S.S.M. was an employee of Gilead Sciences and is an equity holder of Gilead Sciences and Five Prime Therapeutics; P.B. is an employee of and has stock holdings in Gilead Sciences, holds a leadership role on the board of directors for Tioma Therapeutics, consults for Dicerna Pharmaceuticals, and has intellectual property interests with Sanofi and AVEO Pharmaceuticals; P.C.Y., R.H., X.H., and J.J. are employees and stockholders of Gilead Sciences; C.D.F. declares no competing financial interests. Z.Z. was an employee of Gilead Sciences.

Effects of novel Btk and Syk inhibitors on platelet functions alone and in combination in vitro and in vivo

“…* P < .05, ** P < .01, *** P < .001 according to two-way ANOVA test for surface coverage. 11.8% or 13.3% of the cases with either rare cases of bleeding 22,24 or no bleeding event. 21 However, a long-term follow-up of a cohort of 28 CLL patients treated with tirabrutinib reported low-grade bleeding events including bruising (35.7%), hematoma (25%), and petechiae (21.4%) and one case of grade 3 bleeding event that occurred in a patient not receiving anticoagulation therapy.…”

“…Btk inhibitor tirabrutinib and the Syk inhibitor entospletinib was first tested on collagen-induced platelet aggregation in PRP from healthy volunteers. Compared with ibrutinib, 16,17 tirabrutinib had a modest effect as only concentrations above 2 µmol/L (maximal clinically relevant blood concentration is 1.5 µmol/L for 160 mg/d 21,24 ) significantly affected maximal platelet aggregation induced by collagen 3.3 µg/mL. However, from 0.5 µmol/L, tirabrutinib induced a significant delay in the aggregation response as shown by the decrease in the area under the aggregation curve and the profile of the aggregation trace ( Figure 1A).…”

“…Low-grade bleeding events (35.7% of patients had bruising and 25% hematoma) were also observed in patients receiving tirabrutinib. 20,24 Moreover, several Syk inhibitors are currently assessed in clinical trials. 25 Entospletinib (GS-9973), a second-generation Syk inhibitor, acting as an adenosine triphosphate competitive inhibitor, has shown relative efficacy and safety in relapsed or refractory CLL or mantle cell lymphoma patients.…”

In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

“…Indinavir (Rank 91, BE=-8.5, B00224) is an antiretroviral drug for the treatment of HIV infection [104][105][106] . Idelalisib (Rank 97, BE=-8.4, B09054) is indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL), and has been of interest for renal cell cancer [107][108][109][110] . Trametinib (Rank 108, BE=-8.4, B08911) is indicated for the treatment of unresectable or metastatic melanoma [107] , advanced rectal [111] , breast [112] , biliary [113] , colorectal, non-small cell lung, and pancreatic cancer [114] .…”

<p>Lights and Shade of Next-Generation Pi3k Inhibitors in Chronic Lymphocytic Leukemia</p>

“…66 These adverse events were more common in young and treatment-naive patients, likely with a better T-cell function. Although prophylaxis, careful monitoring and prompt steroid treatment can prevent severe events, disappointing trials showed that toxicities were more common and severe in combination regimens 67 and in treatment-naive patients 68 precluding further studies.…”