TAK‐659, AN INVESTIGATIONAL REVERSIBLE DUAL SYK/FLT‐3 INHIBITOR, IN PATIENTS WITH LYMPHOMA: UPDATED RESULTS FROM DOSE‐ESCALATION AND EXPANSION COHORTS OF a PHASE 1 STUDY

Abstract

Introduction: Spleen tyrosine kinase (SYK) is a nonreceptor kinase with a key role in B-cell receptor signaling-driven tumourigenesis and is a key regulator of FMS-like tyrosine kinase 3 (FLT-3). SYK is also involved in CD38 signaling in chronic lymphocytic leukemia (CLL) (Benkisser-Petersen et al. PLoS One 2016;e0169159). TAK-659 selectively inhibits SYK/FLT-3 activity, resulting in inhibition of cell proliferation in vitro and dose-dependent tumor growth inhibition in lymphoma xenograft models. The dose-escalation phase of this study determined 100 mg (daily dose, QD) as the MTD/RP2D of TAK-659 in patients (pts) with advanced solid tumors/lymphoma (Petrich et al. Blood 2015;1262693). Here we report updated data for the lymphoma population from the dose-escalation and expansion cohorts. Method(s): Adult pts with relapsed and/or refractory lymphoma received oral TAK-659 60-120 mg (escalation) or 100 mg (expansion; including CLL, DLBCL, iNHL, MCL and PTLD) QD in 28-d cycles. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Plasma and urine PK assessments occurred during C1 in dose escalation. Response was assessed using IWG modified criteria (lymphoma) or IWCLL criteria (CLL) between d22 and d29 (predose) of C2 (both phases), then during C4, C6 and every 3 cycles (escalation), or every even numbered cycle until C12, then every 4 cycles (expansion). Result(s): At data cut-off (12 Jan 2017), 77 pts with lymphoma (DLBCL 57; iNHL 11; CLL 5; MCL 3; PTLD 1) received TAK-659 60-120 mg QD (69 pts at 100 mg). Median age was 65 yrs (range 23-84), 52 pts (68%) were male. Pts received a median of 2 (range, 1-31) treatment cycles. Response and outcomes among 57 response-evaluable pts are shown in Table 1 and Figure 1. of 52 (68%) pts with >=1 drug-related Gr >=3 AE, the most common AEs were elevated amylase (25%), hypophosphatemia (18%), neutropenia (16%), elevated blood creatine phosphokinase and elevated lipase (both 12%); enzyme elevations were generally asymptomatic. of 23 lymphoma pts who died on study, 3 were considered drug-related (respiratory failure, multiorgan failure, and disseminated varicella). TAK-659 was absorbed quickly (median Tmax; 2 h), with moderate variability (50% CV) in dose-normalized (Table Presented) AUCss, mean peak/trough ratio of 4.2, and mean accumulation of 2.1-fold. Renal clearance accounted for 34% of apparent oral clearance. Conclusion(s): Our data suggest TAK-659 is generally well-tolerated in lymphoma pts, with evidence of single-agent activity across various lymphoma subtypes. TAK-659 PK profile supports QD dosing. Enrolment of pts with DLBCL, iNHL, CLL, MCL, and PTLD is ongoing, with planned accrual of ~152 pts in the expansion phase.