Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-cell Lymphoma
Mené sur 105 patients atteints d’un lymphome à cellules B, cet essai de phase I évalue la dose maximale tolérée et l’efficacité, du point de vue du taux de réponse, d’un composé appelé TAK-659, un inhibiteur de SYK/FLT3
Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, maximum tolerated dose (MTD)/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Experimental Design: Patients received continuous, once-daily oral TAK-659 60-120 mg in 28-day cycles until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in 5 disease cohorts at the MTD. Results: Overall, 105 patients were enrolled (dose escalation, n=36 [solid tumors n=19, lymphoma n=17]; expansion, n=69). The MTD was 100 mg once-daily. TAK-659 absorption was fast (Tmax ~2 hours) with a long terminal half-life (~37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% (23% intent-to-treat [ITT]). Responses were seen in both de-novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.