Preliminary Safety, Pharmacokinetic, and Pharmacodynamic Results from a Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Noncovalent, Reversible Bruton's Tyrosine Kinase Inhibitor (BTKi), Vecabrutinib, in B-Lymphoid Malignancies
Authors: Allan John N. , Wierda William G. , Patel Krish , O'Brien Susan M. , Mato Anthony R , Davids Matthew S , Furman Richard R. , Pagel John M. , Fox Judith A. , Ward Renee , Taverna Pietro , Brown Jennifer R. 
Published: October 2019

Abstract
Background: Vecabrutinib (formerly SNS-062, the succinate salt of vecabrutinib) is a reversible, noncovalent BTKi that has demonstrated in vitro activity in BTK wild-type and C481S mutated cells (Binnerts AACR-NCI-EORTC 2015; Fabian AACR 2017; Libre EHA 2018). Acquired mutations of BTK at C481 (BTK C481), the covalent binding site for ibrutinib, were reported prior to, and at, clinical progression in ibrutinib-treated patients (pts); therefore, vecabrutinib may have therapeutic potential in this setting. A phase 1a study of vecabrutinib in healthy subjects showed favorable safety pharmacokinetic (PK)/pharmacodynamic (PD) profiles, supporting twice-daily (BID) oral dosing (Neuman ASH 2016). Here we report preliminary results of the ongoing phase 1b/2 study of vecabrutinib in adult pts with relapsed/refractory (R/R) advanced B-cell malignancies.
Methods: The phase 1b dose-escalation portion of the study employs a standard 3+3 design in pts with histologically confirmed R/R chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, and follicular lymphoma who have received ≥2 prior lines of systemic therapy, including use of a covalent BTKi where approved for their disease. The objectives of this study are to assess safety, establish the maximum tolerated dose, and identify the recommended phase 2 dose of vecabrutinib. Pts aged ≥18 years with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2 are eligible. Dose-limiting toxicity (DLT) is assessed over an initial 4-week period (1 treatment cycle). Molecular profiles, PK, and PD (inhibition of BTK phosphorylation [pBTK] and cytokine levels) are evaluated throughout Cycle 1. Vecabrutinib succinate dose levels from 25 to 500 mg BID were specified for evaluation. Early safety, PK, and PD data from pts treated to date at dose levels of 25 and 50 mg BID are reported.
Results: Nine pts (CLL, n=6; MCL, n=2; WM, n=1) have been treated in the phase 1b portion of the study (25 mg BID, n=3; 50 mg BID, n=6). Median pt age was 66 years (range: 47-75), all had an ECOG PS of 0 or 1, 78% were male, and median number of prior regimens was 5 (range: 2-7). Prior therapies included ≥1 chemotherapy regimen (n=9), BTKi (ibrutinib, n=8; acalabrutinib, n=1), venetoclax (n=4), and chimeric antigen receptor T-cell therapy (n=2). At baseline, 67% (6/9) of pts had TP53 mutations or deletions. The CLL pts had 83% (5/6) unmutated IGHV, 83% (5/6) deleted or mutated TP53, 50% (3/6) detectable BTK C481 mutations by next-generation sequencing (C481S: n=2, variant allelic frequency [VAF]: 16%, 58%; C481R: n=1, VAF: 77%), and no mutations in PLCg2 were detected. No mutations in BTK 481 or PLCg2 were found in MCL or WM pts.
The most common treatment-emergent adverse events (TEAEs) of any grade were anemia and night sweats (43%, 3/7 each), and leukopenia, neutropenia, thrombocytopenia, abdominal distension, constipation, fatigue, alanine aminotransferase levels (ALT) increased, aspartate aminotransferase levels increased, back pain, and pyrexia (29%, 2/7 each). In the second cohort, 1 pt experienced a DLT of an inadequate number of Cycle 1 doses administered due to a grade 3 ALT elevation. This resulted in expansion of the cohort to 6 pts. Grade ≥3 TEAEs considered related to study drug thus far occurred only in this 1 pt (anemia, neutropenia, and ALT levels increased). Three pts from the 50-mg cohort experienced disease progression prior to the end of Cycle 1 requiring replacement. Pts evaluable for DLT have remained on study up to 5 cycles (range: 1-5), but no responses have been observed to date.
The vecabrutinib PK profile was consistent with the results from the phase 1a study (Figure 1). Vecabrutinib was rapidly absorbed (median time to maximum concentration [Tmax]: 2 hr [range: 1-6]), and exposure increased with dose. Decreased pBTK was observed in 2 CLL pts and 1 MCL pt; no consistent effect on chemokines has yet been observed. BTK C481S VAF appeared stable at end of treatment (EOT) in the two CLL pts with baseline mutations who provided EOT samples.
Conclusions: These data show sustained vecabrutinib exposure throughout the dosing interval, and preliminary evidence of PD activity in pts with R/R B-lymphoid malignancies. The study (NCT03037645) continues enrollment in the dose-escalation phase. Planning is ongoing for subsequent phase 2 expansion cohorts in selected indications.

Disclosures
Allan: Acerta: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Patel:Genentech: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Consultancy; Pharmacyclics/Janssen: Speakers Bureau; Juno Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy. O'Brien:Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding; Alexion: Consultancy; Abbvie: Consultancy; Kite Pharma: Research Funding; Sunesis: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Vaniam Group LLC: Consultancy; Aptose Biosciences Inc.: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Astellas: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Pfizer: Consultancy, Research Funding. Mato:Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy; Acerta: Research Funding; Celgene: Consultancy; Regeneron: Research Funding; TG Therapeutics: Research Funding; Prime Oncology: Speakers Bureau; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding. Davids:Celgene: Consultancy; Surface Oncology: Research Funding; BMS: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; BMS: Research Funding; Roche: Consultancy; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding. Furman:Gilead: Consultancy; Janssen: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; Loxo Oncology: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Acerta: Consultancy, Research Funding; Incyte: Consultancy, Other: DSMB. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Fox:Sunesis Pharmaceuticals: Employment; Amphivena Therapeutics: Employment. Ward:Sunesis Pharmaceuticals: Consultancy. Taverna:Sunesis Pharmaceuticals: Employment. Brown:Boehringer: Consultancy; Sunesis: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Verastem: Consultancy, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Sun Pharmaceutical Industries: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy; Loxo: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Gilead: Consultancy, Research Funding; TG Therapeutics: Consultancy; Janssen: Consultancy.