First in Human, Phase I/II Trial of the Bruton's Tyrosine Kinase Inhibitor (BTKi) M7583 in Patients with B Cell Malignancies: Study Design and Initial Outcomes

Background: Signaling through the B-cell receptor controls normal cellular B cell functions, but its aberrant function is implicated in oncogenesis in B-cell malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBLC). BTK is a key protein involved in transmitting signal from the B-cell receptor. Inhibition of BTK blocks various B-cell functions. The small molecule BTK inhibitor (BTKi) ibrutinib is approved for the treatment of resistant/refractory CLL, MCL, marginal zone lymphoma and Waldenström's macroglobulinemia (WM). M7583 is a potent, highly selective BTKi that is being investigated in an ongoing first-in-human trial to determine its safety and preliminary antitumor activity in patients (pts) with refractory/resistant B-cell malignancies.

Methods: This phase I/II trial (NCT02825836) has two parts: dose escalation followed by dose expansion. The starting dose and dose escalation levels were determined based on the percent (%) of BTK bound by M7583 at steady state, which was predicted using a PK-PD model for an irreversible enzyme inhibitor with enzyme turnover incorporated. Population pharmacokinetic (PK) analysis, using the inter-subject variability of a related compound, was utilized to predict the BTK occupancy expected in a population (n=1,000) after administration of each proposed dose level. Pts with refractory/resistant B-cell malignancies who have failed 1-3 prior lines of therapy are being enrolled into the dose-escalation phase of the phase I/II and are receiving once-daily (QD) M7583, starting at 80 mg (3 initial days)/160 mg (full 28-day cycle) and increasing in predefined dose levels according to an adaptive Bayesian design. Dose-limiting toxicities (DLTs) will be assessed and the maximum tolerated dose (MTD) or the safe optimal biological dose (OBD) determined (OBD based on safety, tolerability, PK, and BTK occupancy of peripheral blood mononuclear cells); preliminary efficacy will also be assessed. For the dose expansion part, pts with DLBCL (ABC subtype) who have failed 1-3 prior lines of therapy will receive the OBD of daily oral M7583; best overall response will be evaluated.

Results: Clinically observed BTK occupancy levels were consistent with the PK-PD model predictions: the average BTK occupancy predicted was 80% and 90% at the 80 mg and 160 mg M7583 QD doses, respectively, compared to clinically observed peak BTK occupancies of 85% (n=3) and 99% (n=3), respectively. These data confirm the PK/PD predictions and, therefore, the continuation of the planned dosing strategy in the dose escalation phase of this study. The doses selected to achieve desired BTK occupancy were also acceptable based on traditional toxicology data. Nine pts have been enrolled at the first three dose levels (DL), 80/160, 300, and 600 mg M7583 (as of 07/13/17) (6 men and 3 women, median age 63 years, range 49 - 80 years; WM n=4, MCL n=3, marginal zone lymphoma n=2). Pts had received a median of 2 cycles (range, 1 - 4) of prior chemotherapy before entering the study. Patients have received 7, 4-6, and 1 cycle of M7583 at 160, 300, and 600 mg, respectively, with no DLTs reported. Treatment emergent adverse events (TEAEs) observed have been mainly grade 1 or 2, with 3 grade 3 TEAEs in different patients: increased lipase (n=1, 160 mg), decreased lymphocyte count (n=1, 160 mg) and chest pain (n=1, 600 mg). Other TEAEs (n=1 for each) were lower respiratory infection, upper abdominal pain, fever and bilateral conjunctivitis (all grade 2), and dysuria, abdominal distension, arthralgia, arthropathy, eczema, reflux, viral infection dry skin, bruising, anemia, and fatigue (all grade 1). Grade 3 chest pain and grade 2 fever were also considered serious adverse events (reported in one pt receiving 600 mg; unrelated to treatment). Clinical benefit has been observed in 5 of 6 pts treated with M7583 160 or 300 mg; one pt with MCL treated with M7583 600 mg died due to extensive progressive disease during the first cycle of M7583. The study is ongoing; updated safety and efficacy results will be presented.

Conclusions: M7583 has been well tolerated at all three doses used to date with some evidence of clinical benefit/objective response at a dose of 160 mg and 300 mg. M7583 appears to have a favorable benefit:risk profile.