Abstract: PF281

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background

TAK-659 is an investigational, reversible, potent dual inhibitor of SYK and FLT‑3. In preclinical studies using diffuse large B-cell lymphoma (DLBCL) models, TAK-659 in combination with bendamustine (BEND) or lenalidomide (LEN) demonstrated synergistic antitumor activity, and TAK-659 with gemcitabine (GEM) or ibrutinib (IBRU) demonstrated additive antitumor activity.

Aims

The primary objective of this phase 1b study (NCT02954406) was to determine the maximum tolerated dose (MTD) of TAK-659 when combined with BEND (+/-rituximab [RITU]), GEM, LEN, or IBRU. Secondary objectives included pharmacokinetics (PK) of TAK-659 and preliminary efficacy.

Methods

This multicenter open-label, dose escalation (3+3) study enrolled adults with NHL who were refractory or relapsed after ≥1 prior line of therapy and for whom no effective standard therapy was available. Informed consent was received. For all treatment groups, pts received oral TAK-659 QD at a starting dose of 60 mg plus one of the following: intravenous (IV) BEND 90 mg/m² days 1 and 2 +/- IV RITU 375 mg/m² day 1 of a 21-day cycle; IV GEM 1000 mg/m² days 1 and 8 of a 21-day cycle; oral LEN 25 mg QD days 1–21 of a 28-day cycle; or oral IBRU 560 mg QD of a 28-day cycle. Treatment was given until progressive disease (PD) or unacceptable toxicity. PK samples were collected pre- and post-dose on days 1, 8 and 15 of cycle 1. Response was by investigator assessment per the International Working Group revised criteria for malignant lymphoma.

Results
As of 17-Nov-2017, 19 pts with advanced NHL (DLBCL n=14; mantle cell lymphoma [MCL] n=2; composite lymphoma [CL] n=2; and follicular lymphoma [FL] n=1) were enrolled to receive TAK‑659+BEND (+/-RITU [n=6 each]), TAK-659+GEM (n=3), TAK-659+LEN (n=3), or TAK‑659+IBRU (n=1). Median age was 64 years (range 44–92), 13 pts (68%) were male, 8 pts (42%) had ≥4 prior therapies, and 13 pts (68%) had an ECOG PS of 1. Across all cohorts, pts received a median of 2 treatment cycles (range 1–4); 17 pts discontinued (13 due to PD). Two pts who received TAK-659 60 mg+LEN had DLTs: one pt with grade 3 skin rash and one pt with grade 4 neutropenia for >7 days. The TAK-659 dose was escalated from 60 mg to 80 mg in three pts for each dose of the TAK-659+BEND and TAK-659+BEND+RITU treatment groups; dose escalation for the remaining cohorts is ongoing. Overall, 18 pts (95%) experienced any-grade adverse events (AEs), 8 pts (42%) had AEs related to TAK-659 and 6 pts (32%) had AEs related to the combination drug(s). Thirteen pts (68%) reported grade ≥3 AEs, 8 pts (42%) and 6 pts (32%) had AEs related to TAK-659 and combinations drug(s), respectively. Serious AEs were reported in 10 pts (53%). The most frequent any-grade and grade ≥3 AEs overall and by treatment groups are shown in the table. There was one on-study death due to a cardiac event (TAK-659+IBRU) that was considered  unrelated to treatment by the investigator. Of the 17 response-evaluable pts, 3 pts (18%) had complete remissions (CRs) (TAK-659 60 mg+BEND in DLBCL, TAK-659 60 mg+BEND+RITU in FL, TAK-659 60 mg+IBRU in MCL) and 2 pts had partial remissions (PRs) (TAK-659 80 mg+BEND in FL and TAK-659 80 mg+BEND+RITU in CL), giving an overall response rate (CR+PR) of 29%. Following co-administration of TAK-659 60 mg+BEND (+/-RITU), preliminary TAK-659 PK profiles were generally comparable with those from single-agent TAK‑659 in lymphoma or solid tumor pts.

Conclusion

The MTDs were not reached and dose escalation is ongoing for each treatment group. Updated safety and efficacy data will be presented.

Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical

Keyword(s): Non-Hodgkin's lymphoma, Pharmacokinetic, Phase I, Safety