PS1148 PRELIMINARY RESULTS OF A PHASE 1B/2 DOSE‐ESCALATION AND COHORT‐EXPANSION STUDY OF THE NONCOVALENT, REVERSIBLE BRUTON'S TYROSINE KINASE INHIBITOR (BTKI), VECABRUTINIB, IN B‐CELL MALIGNANCIES

Abstract

Background:Vecabrutinib is a selective, reversible, noncovalent BTKi that has shown potent inhibitory activity in vitro against both wild type and C481S‐mutated BTK, the most common mutation associated with resistance to ibrutinib.Aims:To evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and antitumor activity of vecabrutinib in adult patients (pts) with relapsed/refractory (R/R) advanced B‐cell malignancies who must have received ≥2 prior regimens and progressed during therapy with a covalent BTKi (cBTKi) for an approved indication.Methods:This is an open‐label, modified 3+3 dose‐escalation, cohort expansion phase 1b/2 trial in pts with advanced B‐cell malignancies. Dose levels specified are 25 to 500 mg BID PO. The safety period for DLT assessment is Cycle 1 (4 weeks). Activity is monitored throughout study treatment and in follow‐up. Molecular profiles, PK, and PD are evaluated.Results:To date, 16 pts (chronic lymphocytic leukemia [CLL], n = 12; mantle cell lymphoma [MCL], n = 2; Waldenström's macroglobulinemia [WM], n = 2) have been treated (Cohort 1, 25 mg BID, n = 3; Cohort 2, 50 mg BID, n = 10. Cohort 3, 100 mg BID n = 3): median age 66 yrs (range: 47–75), all ECOG PS 0–1, 75% male, and median prior regimens 4.5 (range: 2–7) and all included a cBTKi (14 pts ibrutinib, 2 pts acalabrutinib). At screening, 75% (12/16) pts had TP53 mutations or deletions, 44% (7/16) BTK C481 mutations and 19% (3/16) phospholipase C gamma 2 (PLCg2) mutations. BTK C481 mutations were found only in CLL pts (C481S n = 5 variant allelic frequency [VAF] 7–93%, C481R n = 2, [VAF 49%, 77%]. PLCg2 mutations of uncertain clinical significance were found in 2 CLL pts (E877D; VAF 48% and D993 V; VAF 35%) and 1 WM pt (E877D; VAF 20%). Safety: Thus far, the MTD has not been reached. Adverse Events (AEs) are available for 13 pts; the most common AEs were anemia (54%), neutropenia and night sweats (each 46%), AST increased and thrombocytopenia (each 31%). Grade 3 drug‐related AEs were ALT increased, neutropenia and worsening anemia (all in 1 pt), and leukocytosis (2 pts). In cohort 2, 1 pt had a DLT of receiving fewer than the prespecified number of doses due to a Grade 3 related AE (ALT increased) and the cohort was expanded: 7 evaluable, 3 non‐evaluable due to progressive disease in Cycle 1. There were no drug‐related serious AEs. Stable disease was seen in 3 CLL pts, 2 of whom had BTK C481S mutations (Cohort 1, n = 1, Cohort 2, n = 2); these pts remained on treatment 72–120 days. Improvement in clinical symptoms was noted in 2 pts in cohort 2 (1 CLL with BTK C481S,1 WM). Vecabrutinib was absorbed rapidly (median Tmax 1 hr). Exposure was generally dose proportional, with median steady‐state Day 8 trough values of 264 ng/mL (Cohort 1, n = 3) and 513 ng/mL (Cohort 2, n = 10). PD activity was observed in pts with and without pBTK C481 mutations. Among the 8 pts with evaluable data, pBTK decrease was seen as early as 1 hour post‐first dose (avg 81%; range 37–100%) and was sustained at end of Cycle 1 (avg 79%; range 70–99%). All pts who completed cycle 1 had a decrease in at least 2 of 3 cytokines (CCL2, CCL3, CCL4).Summary/Conclusion:Vecabrutinib safety profile at 25 and 50 mg BID dose levels was acceptable. Dose escalation continues; evaluation of the 100 mg BID dose level is ongoing and data from this cohort will be presented. Exposure was sustained during the dosing interval and inhibition of B‐cell receptor signalling pathway activation was observed in pts with advanced B‐cell malignancies with and without BTK C481 mutations.