A Phase I/II, First in Human Trial of the Bruton's Tyrosine Kinase Inhibitor M7583 in Patients with B-Cell Malignancies
Authors: Jurczak Wojciech , Rule Simon , Townsend William , Tucker David , Sarholz Barbara , Scheele Jürgen , Gribben John G. , Zinzani Pier Luigi 
Published: October 2019

Abstract
Background: Bruton's tyrosine kinase (BTK) has a key role in B-cell receptor mediated pathways that are implicated in the pathogenesis of several B-cell malignancies. Inhibition of BTK has been shown to block several B-cell functions, including proliferation, antigen presentation, antibody production and cell migration. Small molecule BTK-inhibitors (BTKi) have been approved for the treatment of several B-cell malignancies, including resistant/refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia (WM). M7583 is a potent and highly selective BTKi, which is currently being investigated in a two-part, phase I/II trial (NCT02825836) in patients with refractory/resistant B cell malignancies.
Methods: In the dose-escalation part of the study (Part 1), patients with refractory/resistant B cell malignancies received once-daily (QD) M7583 in 28-day cycles in ascending dose cohorts following an adaptive Bayesian design; the starting dose was 80 mg for 3 days followed by 160 mg (80/160 mg QD). The dose-expansion part of the study (Part 2) will investigate M7583 in patients with diffuse large B cell lymphoma (DLBCL; activated B-cell subtype) or MCL who have failed 1-3 lines of previous therapy. Here, we present safety and tumor response outcomes as assessed by the investigators according to Cheson/CLL/Owen criteria for patients in Part 1.
Results: In total, 25 patients were screened for inclusion in Part 1, as of 20th May 2018 18 had received treatment with M7583 in 5 dose cohorts (80/160 mg, n=3; 300 mg QD, n=3; 600 mg QD, n=5; 300 mg BID, n=3; 900 mg QD, n=4). Treatment is ongoing in 11 patients. Patients were mostly male (72%, n=13), aged 43-80 years (median 63 years) and had a diagnosis of MCL (n=8), WM (n=4), DLBCL (n=3), marginal zone lymphoma (n=2), or small lymphocytic lymphoma (n=1). Treatment-emergent adverse events (TEAEs) occurred in 89% (n=16/18) of patients; the most common TEAE was diarrhea (n=6/18; 33%). No dose-limiting toxicities were reported. Grade ≥3 TEAEs occurred in 10 patients (56%), events in 3 (17%) were considered related to treatment. Six patients (33%) had serious TEAEs and 2 patients (11%) had treatment-related serious TEAEs. The maximum tolerated dose was not reached. Patients received M7583 for up to 20 months (median 7.9 [range 0.5-20] months). Preliminary study data show the objective response rate was 50% (9 of 18 subjects). Disease control was observed in 14 of 18 subjects (disease control rate 78%): 2 subjects had a complete response (CR), 7 subjects had a partial response (PR), 1 subjects had a minor response (MR) and 4 subjects had stable disease (SD). Responses were observed across all doses: 80/160 mg QD, 1 PR, 2 SD; 300 mg QD, 2 PR, 1 MR; 600 mg QD, 1 CR, 2 PR; 300 mg BID, 2 PR, 1 SD; 900 mg QD, 1 CR, 1 SD. Both the 300 mg BID and 900 mg QD doses met the criteria for the optimal biological dose, therefore, these doses represent potential recommended phase 2 doses in support of further development.
Conclusions: Clinical benefit was observed with M7583 across the doses investigated and was well tolerated in patients with refractory/resistant B cell malignancies. These outcomes indicate a favorable benefit:risk profile for M7583.

Disclosures
Jurczak: TG therapeutics: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Acerta: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency: Consultancy; Servier: Consultancy, Honoraria, Research Funding. Rule:Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees. Townsend:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Sarholz:Merck KGaA: Employment. Scheele:Merck KGaA: Employment. Gribben:TG Therapeutics: Honoraria; Wellcome Trust: Research Funding; Medical Research Council: Research Funding; Roche: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria; Cancer Research UK: Research Funding; Unum: Equity Ownership; Kite: Honoraria; NIH: Research Funding; Pharmacyclics: Honoraria. Zinzani:MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.