Ibrutinib In Association With R-Dhap/Ox For Patients With Relapsed/Refractory B-Cell Lymphoma: Results Of The Escalating Phase Of The Biblos Phase Ib Lysa Study.

e19550 Background: Ibrutinib (Ibru) has shown therapeutic activity in patients (pts) with various B-cells malignancies, making it an appropriate drug to combine with R-DHAP/Ox chemotherapy in pts with R/R B-cell non-Hodgkin lymphoma (NHL). In a 1rst escalating phase (EP) (NCT02055924), combining Ibru given from day (d) 1 to 21, we failed to reach a maximal tolerated dose (MTD) able to safely improve R-DHAP/Ox activity. After amendment, the Ibru administration was restricted from d5 to d18. Methods: Pts with R/R B-cells NHL, candidates for autologous transplantation (ASCT), received 3 cycles of R-DHAOx (IC) (oxaliplatin 130 mg/m² on d1) or R-DHAP in association with escalating doses of Ibru at a starting dose (DL1) of 420 mg/d from d5 to d18 with a “3+3” dose escalation design (DL2: 560 mg/d). Dose-limiting toxicities (DLT) evaluated during the 1rst cycle were defined as: grade (Gr) 3-4 non-hematological toxicity; any Gr≥ 2 hemorrhagic events; any Gr≥ 1 intracranial hemorrhage and any Gr≥ 4 hematological toxicity lasting more than 7 d. Results: 12 NHL pts (DLBCL n = 8; FL n = 3; MZL n = 1) have received R-DHAOx associated with Ibru (d5-d18). 1/6 pts treated at DL1 experienced 1 DLT (Gr3 hepatitis). No DLT was recorded for the 6 pts treated at DL2. 11 pts (92%) presented ≥ 1 adverse event, assessed ad serious in 6 pts: Gr≥ 2 thrombocytopenia (2 pts), Gr≥ 2 infection (2 pts), symptomatic atrial fibrillation (1 pt), various Gr≥2 GI and metabolic toxicities (1 pt). Neither severe hemorrhagic event nor rash was observed. 1 pt discontinued Ibru after cycle 1 (hepatitis as a DLT) and 11 pts completed the 3 cycles of IC. All pts received ≥ 80% of the planned dose of Ibru & ≥ 90% of the IC. Pharmacokinetics analysis didn’t show any interaction between IC and Ibru. All pts received GCSF injections, 3 (25%) red cells & 9 (75%) platelets transfusions. Treatment response (Cheson 2007) evaluated in 11 pts (92%) was: CR 42% and PR 25%; stem cells were successfully harvested in 10 pts and 7 underwent ASCT. In contrast, Ibru+R-DHAP cohort was interrupted due to DLTs encountered at DL1. Conclusions: Ibru 560 mg/d given from d5-d18 in association with R-DHAOx is safe & actually used in the expansion phase. Clinical trial information: NCT02055924.