Ongoing Results of a Phase 1B/2 Dose-Escalation and Cohort-Expansion Study of the Selective, Noncovalent, Reversible Bruton'S Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Cell Malignancies
Authors: Allan John N. , Patel Krish , Mato Anthony R. , Wierda William G. , Pinilla Ibarz Javier , Choi Michael Y. , O'Brien Susan M. , Sharman Jeff P. , Shadman Mazyar , Gladstone Douglas E , Davids Matthew S. , Pagel John M. , Ward Renee , Acton Gary , Taverna Pietro , Fox Judith A. , Furman Richard R. , Brown Jennifer R. 
Published: November 2019

Background: Vecabrutinib is a selective, reversible, noncovalent BTK inhibitor (BTKi) with potent in vitro inhibitory activity against both wild type and C481S-mutated BTK, the most common mutation detected in patients (pts) with CLL relapsing on treatment with covalent BTKi (cBTKi).
Methods: This is an open-label, modified 3+3 dose-escalation, cohort expansion phase 1b/2 trial to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and antitumor activity of oral vecabrutinib in adult pts with relapsed/refractory advanced B-cell malignancies who must have received ≥2 prior regimens and progressed on therapy with a cBTKi where available as an approved indication. Prespecified dose levels are 25 to 500 mg PO BID. Patients continue to receive vecabrutinib until time of progression or intolerable toxicity. The safety period for DLT assessment is Cycle 1 (4 weeks). Activity is monitored throughout study treatment and for survival. Molecular profiles, PK, and PD are also evaluated.
Results: To date, 27 pts (chronic lymphocytic leukemia [CLL], n=21; mantle cell lymphoma [MCL], n=2; Waldenström's macroglobulinemia [WM], n=3; marginal zone lymphoma (MZL), n=1) have been treated (Cohort 1, 25 mg BID, n=3; Cohort 2, 50 mg BID, n=10; Cohort 3, 100 mg BID n=7, Cohort 4, 200 mg BID n=4, Cohort 5, 300 mg BID n=3): median age 66 yrs (range: 47-77), 96% ECOG PS 0-1, 73% male, median prior regimens 4 (range: 2-9) all including a cBTKi (23 pts ibrutinib, 4 pts acalabrutinib). At screening, 76% (19/25) had mutated or deleted TP53, 48% (12/25) had BTK C481 mutations and 20% (5/25) had phospholipase C gamma 2 (PLCg2) mutations. BTK C481 mutation was found in 11 CLL pts (C481S n= 8 variant allelic frequency [VAF] 7-93%, C481R n=2, [VAF 49%, 77%], C481P n=1 [VAF 28%]) and in one pt with WM (C481S [VAF 8%]). One CLL pt had both BTK C481S (VAF 20%) and T474I (gatekeeper residue, VAF 32%) mutation. Five pts (3 CLL, 1 WM and 1 MZL) had PLCg2 mutations; only one of the CLL pts had an activating PLCg2 mutation (S707F; VAF 8%). Overall, NGS on a panel of 128 genes known to be recurrently mutated in lymphoid malignancies detected a median of 5 mutations/pt; the most common mutated genes were SF3B1 (24%), NOTCH1 and ATM (20% each). Safety: the MTD has not been reached through Cohort 4. Adverse Events (AEs) are available for 24 pts; the most common all-grade AEs were anemia (37.5%), headache, neutropenia and night sweats (each 25%). Drug-related Grade 3 AEs occurred in 3 pts, all from Cohort 2: increased ALT, neutropenia and worsening anemia (all in 1 pt), and leukocytosis (2 pts). Cohort 2 was expanded per protocol due to a DLT (insufficient doses received due to Grade 3 drug-related ALT increase). There were no drug-related serious AEs. Stable disease (investigator assessed) was seen in 4 pts with CLL, 3 of whom had BTK C481S mutation (Cohort 1, n=1, Cohort 2, n=2, Cohort 3, n=1); these pts remained on treatment 72->196 days. One CLL BTK C481S pt remains on treatment and in Cycle 7 was dose-escalated from 100 to 200 mg BID; two CLL pts with BTK C481S (50 mg, 100 mg BID) showed improvement in B-symptoms and decreased tumor burden (-47%, -16% SPD change). Two pts with CLL (200 mg BID) are in Cycle 3, one with BTK C481S, T474I and one with PLCG2 S707F; 3 pts (300 mg BID; 2 CLL, 1 MZL) are currently in Cycle 1. Cycle 1 Day 8 vecabrutinib median steady-state Cmin values increased with dose: 75 ng/mL (Cohort 1, n=3), 451 ng/mL (Cohort 2, n=10), 873 ng/ml (Cohort 3, n=4) and 1124 ng/ml (Cohort 4, n=4) indicating that doses of ≥200 mg BID should result in consistent and high levels of BTK inhibition (Neuman ASH 2017). PD assessments (BTK phosphorylation; changes in chemokines) confirmed on-target inhibition of BTK. Of 20 pts evaluated, 12 had interpretable pBTK data with decreases seen as early as 1 hour post-first dose (avg 81%; range 37-100%) and sustained inhibition at end of Cycle 1 (avg 80%; range 48-100%). Most pts who completed cycle 1 had a decrease in at least 2 of 3 cytokines (CCL2, CCL3, CCL4).
Conclusions: To date, vecabrutinib safety profile in 25-200 mg BID cohorts was acceptable with evidence of clinical activity. Dose levels are under investigation that may result in greater clinical activity in pts whose disease remains adequately sensitive to BTK inhibition. Evaluation of the 300 mg BID cohort is ongoing and updated trial results will be presented.

Disclosures
Allan: Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Sunesis: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Wierda:Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding. Pinilla Ibarz:Bayer: Speakers Bureau; Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. O'Brien:Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Acerta: Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Eisai: Consultancy. Sharman:AstraZeneca: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Shadman:Mustang Bio: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Celgene: Research Funding; ADC Therapeutics: Consultancy; Acerta Pharma: Research Funding; Astra Zeneca: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Sound Biologics: Consultancy; TG Therapeutic: Research Funding; BeiGene: Research Funding; Sunesis: Research Funding; Atara Biotherapeutics: Consultancy. Davids:AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ward:Sunesis Pharmaceuticals: Consultancy. Acton:Sunesis Pharmaceuticals: Consultancy. Taverna:Sunesis Pharmaceuticals: Employment. Fox:Sunesis Pharmaceuticals: Employment. Furman:Acerta Pharma: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Oncotracker: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Verastem: Consultancy. Brown:Juno/Celgene: Consultancy; Gilead: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy.