ONO‐4059 (GS‐4059), A NEXT GENERATION BTK INHIBITOR, MONOTHERAPY IN PATIENTS WITH B‐CELL MALIGNANCIES IN THE JAPANESE PHASE 1, DOSE‐ESCALATION STUDY

Abstract

Introduction: Bruton's tyrosine kinase (BTK) plays an important role in B‐cell signaling, cell proliferation and survival. The highly selective BTK inhibitor, ONO‐4059 (GS‐4059) showed manageable safety and tolerability as a single agent in B‐cell non‐Hodgkin lymphoma (B‐NHL) and chronic lymphocytic leukemia (CLL) in an European phase 1 study (Walter et al. Blood 2016). This phase 1 study was designed to evaluate the maximum tolerated dose, safety, efficacy and pharmacokinetics (PK) of ONO‐4059 as monotherapy in Japanese patients (pts) with relapsed or refractory B‐NHL and CLL. This was a company sponsored trial (Ono Pharmaceutical Co., Ltd.). Methods: Pts with previously treated B‐NHL/CLL were eligible. Four dose cohorts consisted of 160 mg QD, 320 mg QD, 480 mg QD and 300 mg BID were defined as cohort 1 to 4, respectively. Pts were enrolled using a 3 + 3 dose escalation design, and were observed for a 28‐day period to identify dose‐limiting toxicity (DLT). All pts provided written informed consent. Results: Seventeen pts were enrolled (n = 3, 3, 4, and 7 in cohort 1‐4, respectively) and 9 pts remained on study as of March 7, 2016. The disease subtypes enrolled were FL n = 5, MCL n = 4, non‐GCB DLBCL n = 4, DLBCL n = 1, WMn = 2, and CLL n = 1. Median age was 70 yrs [range, 37‐80], and median number of prior therapy was 3 [range 1‐11]. Maximum tolerated dose (MTD) was not reached though one DLT of grade 3 pneumonitis was observed in cohort 4. The most common AEs were rash (35%) and vomiting (29%), but no grade ≥ 3 was reported. The most common grade ≥ 3 AEs were neutropenia (18%) and anemia (12%). The overall response rate (ORR) was 71% (12/17 pts) and median progression‐free survival (PFS) was not estimable across all cohorts; ORR in each subtype was 80% (4/5 pts) in DLBCL with 1 CR, 20% (1/5) in FL, and 100% in MCL with 2 CR, WM, and CLL. Interestingly, 4 pts with DLBCL who achieved objective responses had no CD79A/B, MYD88 and CARD11 mutations. of note, CARD11 mutation was identified in one DLBCL pt who had disease progression. Furthermore, one CLL pt who had TP53 mutation, del 13q, and del 17p achieved PR and remained on therapy. The tendency of CXCL‐10 increase was observed in pts who achieved objective responses.Increases in Cmax and AUC were approximately dose‐proportional from 160 to 480 mg QD. The mean half‐life (t1/2) of ONO‐4059 was comparable across dose levels. Conclusions: MTD was not reached, and the safety profiles in Japanese pts with B‐NHL/CLL were similar to previous findings in the European Phase 1 study. ORR was observed in 71% of pts including 4 DLBCL with no mutations of CD79A/B, MYD88 and 1 CLL with TP53 mutation, del 13q and del 17p, that is promising data for future development. ONO‐4059 exhibited approximately dose‐proportional exposure, and there was little accumulation of exposure following multiple doses. Further investigation is warranted.