A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies

Purpose: MAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single- agent MAK683 in advanced malignancies. Methods: MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles. Safety assessments included the nature of dose-limiting toxicities (DLTs) and the incidence and severity of adverse events (AEs) and serious AEs. The PK profile of MAK683 was assessed in sequential blood samples of cycles 1-6, and pharmacodynamic profiles were measured by H3K27me3 changes from baseline. Results: Overall, 139 patients (clear cell carcinoma of the ovary [CCCO], 9 [6.5%]; castration-resistant prostate cancer [CRPC], 22 [15.8 %]; diffuse large B-cell lymphoma [DLBCL], 31 [22.3%]; epithelioid sarcoma [ES], 17 [12.2 %]; gastric cancer [GC], 37 [26.6 %]; nasopharyngeal carcinoma [NPC], 17 [12.2 %]; SWI/SNF-mutated sarcoma, 6 [4.3 %]) received MAK683. Median duration of exposure was 57 days (range: 4-1006). Fifteen patients experienced 22 DLTs including thrombocytopenia (4.9 %) and febrile neutropenia (3.3 %). MAK683- related AEs were reported in 98 patients (70.5 %); 43 patients had grade 3/4 drug-related AEs, including neu- tropenia, thrombocytopenia, and anemia. MAK683 was quickly absorbed, with peak plasma concentrations ranging from 0.975 to 4.08 h. Median progression-free survival was 1.9 months (90 % confidence interval [CI]: 1.8-2.3), and overall response rate was 5.8 % (90% CI: 2.52-11.03 %). Clinical activity was observed in patients with advanced DLBCL and ES. Conclusion: Overall, MAK683 treatment was well tolerated, and clinical activity was observed in patients with advanced DLBCL and ES. Clinical Trial Information: NCT02900651.