ITK is expressed in T cells and NK cells and is involved in multiple signaling pathways including T cell receptor activation, differentiation of naïve helper T cells and FAS mediated activation-induced cell death. Selective knock-out or inhibition of ITK results in Th1 skewing and enhancement of T effector memory cell function. We have synthesized soquelitinib, a selective inhibitor of ITK, and evaluated its therapeutic potential in relapsed (R/R) T cell lymphomas (TCL) where tonic T cell receptor signaling and/or dysregulated growth exists. Soquelitinib was first evaluated in a dose escalation trial in patients (pts) with R/R TCL with daily oral doses ranging from 100mg bid to 600mg bid. No dose limiting toxicities were reported. Objective responses and full ITK occupancy were observed at doses of ≥200mg bid. In an expansion cohort, twenty-three evaluable pts (≤3 prior therapies) with R/R TCL including PTCL-NOS, AITL, ALCL, NKTCL, CTCL were enrolled at the 200mg bid dose. Nine objective responses (3 PRs and 6 CRs) were observed. The median DOR was 17.2 months. The median PFS was 6.2 months, with 18-month PFS rate of 30%. Paired tumor biopsies demonstrated increase in TEMRA+ cells (T effector memory RA positive) with enhanced expression of granzyme and perforins suggesting the induction of a host anti-tumor response. The most common (>1pts) Grade 3/4 AEs were: anemia, pyrexia, neutropenia, and pruritus. Soquelitinib appears to induce anti-tumor responses by novel mechanisms related to modulation of T cell function. A randomized Phase 3 trial in R/R PTCL is underway.
