A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib for MYC-Aberrant Lymphoid Malignancies: The DACIPHOR Regimen.

MYC-aberrant non-Hodgkin lymphoma (NHL) is associated with poor outcomes with conventional chemotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that targets drivers of MYC expression and has demonstrated preclinical activity in aggressive MYC-aberrant NHL. We conducted a phase I/II study evaluating the safety and efficacy of induction DA-EPOCH-R and ixazomib followed by ixazomib maintenance in aggressive MYC-aberrant NHL. For induction, patients received 6 cycles of DA-EPOCH-R with ixazomib administered twice per 21-day cycle; ixazomib maintenance was administered weekly in responders for up to 1 year. Primary objectives were to determine the maximum tolerated dose (MTD) in phase I and efficacy of DA-EPOCH-R with ixazomib as measured by 12-month PFS rate in phase II. Thirty-six patients were evaluable for response. Median age was 63 years (range 31-77) and 44% had double/triple hit lymphoma. In phase I, 3mg of ixazomib was established as RP2D. Twenty-nine (76.3%) patients completed 6 cycles of DA-EPOCH-R and 25 (65.8%) underwent dose escalations. The ORR after induction was 97% (95% CI, 81% to 100%) with a CR rate of 69%. At median follow-up of 18.8 months, the 12-month PFS and OS rates were 78% and 86%, respectively. For DHL/THL vs DEL, 12-month PFS rates were 53% vs 95% and 12-month OS rates were 65% vs 100%, respectively. During induction and maintenance, grade ≥3 toxicities were predominantly hematologic. Twenty-seven (75%) of patients experienced neuropathy, all low-grade except one. In aggressive MYC-aberrant NHL, DA-EPOCH-R induction with ixazomib followed by maintenance ixazomib is feasible and appears effective in DEL patients. (NCT02481310, ClinicalTrials.gov).