Abstract: Chronic lymphocytic leukemia (CLL) cells can secrete immunoglobulin M. However, it is not clear whether secretory IgM (sIgM) plays a role in disease progression. We crossed the Eμ-TCL1 mouse model of CLL, in which the expression of human TCL1 oncogene was driven by the V(H) promoter-Ig(H)-Eμ enhancer, with MD4 mice whose B cells produced B-cell receptor (membrane-bound IgM) and sIgM with specificity for hen egg lysozyme (HEL). CLL cells that developed in these MD4/Eμ-TCL1 mice reactivated a parental Ig gene allele and secreted IgM, and did not recognize HEL. The MD4/Eμ-TCL1 mice had reduced survival, increased myeloid-derived suppressor cells (MDSC), and decreased numbers of T cells. We tested whether sIgM could contribute to the accumulation of MDSCs by crossing μS–/– mice, which could not produce sIgM, with Eμ-TCL1 mice. The μS–/–/Eμ-TCL1 mice survived longer than Eμ-TCL1 mice and developed decreased numbers of MDSCs which were less able to suppress proliferation of T cells. We targeted the synthesis of sIgM by deleting the function of XBP-1s and showed that targeting XBP-1s genetically or pharmacologically could lead to decreased sIgM, accompanied by decreased numbers and reduced functions of MDSCs in MD4/Eμ-TCL1 mice. Additionally, MDSCs from μS–/– mice grafted with Lewis lung carcinoma were inefficient suppressors of T cells, resulting in slower tumor growth. These results demonstrate that sIgM produced by B cells can upregulate the functions of MDSCs in tumor-bearing mice to aggravate cancer progression. In a mouse model of CLL, production of secretory IgM led to more MDSCs, fewer T cells, and shorter survival times for the mice. Thus, secretory IgM may aggravate the progression of this cancer. Cancer Immunol Res; 6(6); 696–710. ©2018 AACR.

Abstract: Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive (“watch and wait”), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi’s; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi’s at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi’s in COVID-19 are needed to provide definitive evidence of benefit.

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.

Abstract: Manufacturing CART19 by transfecting autologous T cells with messenger RNA is feasible. Targeting CD19+ B cells in cHL using nonviral RNA CART19 was well tolerated and resulted in transient responses in a pilot study.

Abstract: Background: Covalent BTK inhibitors (BTKi) have transformed the management of CLL/SLL. Despite the marked efficacy of covalent BTKi, treatment failure can occur through the development of resistance and discontinuation for adverse events. The activity of covalent BTK inhibitors is markedly reduced or absent in the presence of BTK cysteine binding site (C481) mutations. Moreover, these agents share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, ultimately manifesting as acquired resistance in some patients (pts). To address these limitations, LOXO-305, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. The aim of the BRUIN trial was to define the safety and early efficacy of LOXO-305 in pts with B-cell malignancies. Here we report these data in pts with previously treated CLL/SLL. Methods: BRUIN is a multicenter phase 1/2 trial (NCT 03740529) enrolling pts with advanced B-cell malignancies who have received & gt;2 prior therapies. Dose was escalated according to a standard 3+3 design with LOXO-305 dosed orally in 28-day cycles. The primary endpoint was MTD/RP2D identification. Intra-patient dose-escalation to previously cleared dose levels was permitted. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L). Safety was assessed in all pts (CLL/SLL and NHL, n=186). Results: As of 30 April 2020, 186 pts with B-cell malignancies (94 CLL/SLL, 38 MCL, 19 DLBCL, 17 WM, 6 FL, 5 MZL, and 7 Other [B-PLL and Richter's transformation]) were treated on 7 dose levels (25mg to 300mg QD). Among the 94 pts with CLL/SLL, the median age was 69 (range 36-84) years and median number of prior therapies was 4 (range 1-10). 84% of CLL/SLL pts had received a prior BTKi, and 69% had received an anti-CD20 antibody, chemotherapy, and BTKi. In addition, 21% had received a PI3K inhibitor and 31% venetoclax. At enrollment, central molecular characterization for high-risk features in available samples revealed 17p deletion in 21% (13/63), TP53 mutation in 30% (27/91), and unmutated IGHV in 84% (51/61). LOXO-305 demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. There were no DLTs or dose reductions. Consistent with LOXO-305's selectivity, the only treatment-emergent adverse events regardless of attribution or grade seen in & gt;10% of pts (n=186) were fatigue (n=29, 16%) and diarrhea (n=28, 15%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 88 CLL/SLL pts (94%) remained on therapy and 65 CLL/SLL pts were efficacy-evaluable (58 BTKi-treated, 7 BTKi-naïve). Median follow up time was 3 months (range 0.1-13) for all pts and 6.7 months for responders. The ORR was 57%, with 23 PRs, 14 PR-Ls, 26 SDs, 1 PD, and 1 NE (Figure). An additional 29 pts were ongoing and awaiting initial radiologic assessment. As has been observed with covalent BTK inhibitors, responses deepened over time; among pts with at least 6 months of follow-up (n=26), the ORR was 77%. Response rate was not influenced by the presence or absence of a pretreatment BTK C481 mutation, the reason for prior BTKi discontinuation (i.e. progression vs intolerance), or other classes of prior therapy received (including a covalent BTK and BCL2 inhibitor). Of the 37 responding pts, all except 2 remain on therapy (1 progressed and 1 achieved a PR and electively discontinued treatment to undergo an allogeneic stem cell transplant). The longest-followed responding patient has been on treatment for 13.5 months and is ongoing. Responding pts with BTK C481 mutations demonstrated corresponding decreases in mutant disease burden by ddPCR. Conclusion: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis CLL/SLL pts following multiple prior lines of therapy including covalent BTKi and a BCL2 inhibitor. Importantly, the activity of LOXO-305 was not restricted to pts with BTK C481 mutations. LOXO-305 was well tolerated and exhibited a wide therapeutic index. Figure Disclosures Mato: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Shah:TG Therapeutics: Consultancy; Celgene: Consultancy, Honoraria; Incyte: Consultancy; Cell Vault: Research Funding; Kite Pharma: Consultancy, Honoraria; Miltenyi Biotec: Honoraria, Research Funding; Verastim: Consultancy; Lily: Consultancy, Honoraria. Lamanna:Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; MingSight: Other: Institutional research grants, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Columbia University Medical Center: Current Employment; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: 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, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Loxo: Research Funding; Octapharma: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lech-Marańda:Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy; Roche, Amgen, Gilead: Speakers Bureau. Eyre:Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support. Woyach:Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. Roeker:AbbVie: Other: spouse with minority ownership interest ; Abbott Laboratories: Other: spouse with minority ownership interest ; American Society of Hematology: Research Funding. Fakhri:University of California San Francisco: Current Employment. Tam:Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Gerson:Genentech: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Loxo: Research Funding. Alencar:Genentech, Celgene, KITE, Loxo Oncology at Lilly: Consultancy. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Ghia:MEI: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Celgene/Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Adaptive, Dynamo: Consultancy, Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Chen:Loxo Oncology at Lilly: Current Employment. Nair:Loxo Oncology at Lilly: Current Employment. Tsai:Loxo Oncology at Lilly: Current Employment. Ku:Loxo Oncology at Lilly: Current Employment. Brown:Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding. Jurczak:Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months.

Abstract: 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.

Abstract: Ibrutinib provided effective salvage therapy in CLL relapse post–alloHCT, resulting in sustained MRD negativity without GVHD development. Ibrutinib selectively depleted pre–germinal B cells and Th2 helper cells and may enhance donor Th1 T-cell–mediated GVL effects.