Phase I study of novel SYK inhibitor TAK‐659 (mivavotinib) in combination with R‐CHOP for front‐line treatment of high‐risk diffuse large B‐cell lymphoma

Background: TAK‐659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B‐cell lymphoma (DLBCL). We report results of a phase I single‐institution escalation study of front‐line treatment with R‐CHOP and TAK‐659 in treatment‐naïve high‐risk DLBCL. Methods: Patients with high‐risk DLBCL were treated with R‐CHOP for 1 cycle, followed by combined R‐CHOP and TAK‐659 for an additional five cycles, with TAK‐659 dosing escalated from 60 mg, to 80 mg, to 100 mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK‐659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100 mg) was established as the MTD. Dose level 1 (60 mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow‐up of 21 months, 92% of patients achieved complete response (CR). The most common treatment‐emergent adverse events were lymphopenia (100%), infection (50%, n = 3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK‐659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R‐CHOP and TAK‐659 in patients with newly diagnosed high‐risk DLBCL produces promising CR rates.