Ibrutinib in Association with R-DHAP/Ox for Patients with Relapsed/Refractory B-Cell Lymphoma: Preliminary Results of the Biblos Phase Ib Lysa Study

Background: Ibrutinib is a first-in-class selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK) approved for the treatment of patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) and R/R chronic lymphocytic leukemia. In heavily pretreated MCL, in monotherapy, an ORR of 68% was observed in a phase II study (Wang, 2013). Toxicity is mainly hematological and gastrointestinal. Safety profiles for combination of ibrutinib with R-CHOP or R-benda are acceptable and these combinations are under evaluation in phase III randomized studies (Younes, 2014; Maddocks 2015). We present here preliminary data of a phase Ib study evaluating the safety and tolerability of ibrutinib in association with R-DHAP or R-DHAOx for patients with B-cell lymphoma after first or second treatment failure who are candidates for autologous stem cell transplantation (ASCT).

Patients & methods: Eligible patients were planned to receive 3 cycles, given every 21 days, of rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1 to 4, cytarabine 2 g/m² bid on day 2 and cisplatin 100 mg/m² on day 1 (R-DHAP) or oxaliplatin 130 mg/m² on day 1 (R-DHAOx) in association with escalating doses of ibrutinib. The starting dose (dose level 1, DL1) was 420 mg/day on days 1 to 21. The dose-variation scheme followed a traditional "3+3" design (DL-1: 280 mg/day on days 1 to 21; DL2: 560 mg/day on days 1 to 21). Dose-limiting toxicities (DLT) were considered during the first cycle. DLT were defined as: non-hematological toxicity grade (Gr) 3-4 excluding alopecia, diarrhea and/or nausea/vomiting and/or fatigue/asthenia for less than 7 days; any Gr ≥ 2 hemorrhagic events; any Gr≥ 1 intracranial hemorrhage and any Gr≥ 4 hematological toxicity lasting more than 7 days.

Results: Between May 2014 and July 2015, 25 patients have been treated (R-DHAP: 13, 1 non evaluable for DLT; R-DHAOx: 12). In the DL1 cohort (420 mg/day), DLTs assessed as related to ibrutinib were observed in 3/6 patients receiving R-DHAOx (Gr3 cutaneous eruption, Gr3 febrile neutropenia and prostatic infection, Gr4 thrombocytopenia) and in 3/6 patients receiving R-DHAP (Gr4 cutaneous eruption, Gr4 thrombocytopenia and Gr4 sepsis). According to protocol, ibrutinib dose was decreased to 280 mg/day. Thirteen patients were treated at DL-1 with 1 patient experiencing DLT in each cohort (1/6 evaluable patients in R-DHAP group: Gr4 thrombocytopenia and Gr4 gastric hemorrhage, Gr3 atrial fibrillation; 1/6 patient in R-DHAOx group: Gr3 epigastric pain). Six (50%) patients treated with ibrutinib at the dose of 420 mg and 10 (77%) of those treated at the dose of 280 mg received more than 80% of the planned dose before ASCT. All 25patients experienced one or more adverse events (AE). Diarrhea occurred in 8% of patients. All 25 patients presented Gr3-4 hematological adverse events (neutropenia: 17 patients, including 7 with febrile neutropenia; thrombocytopenia: 25). Three patients presented serious hemorrhagic events. Four patients developed cutaneous eruptions (all of them received prophylactic sulfamethoxazole-trimethoprim). There was 1 death attributable to cardiac toxicity (assessed as unrelated to ibrutinib). Nine patients discontinued ibrutinib (7 due to toxicities, including DLTs, and 2 due to patient's decision). Response to treatment (Cheson 2007 criteria) is currently evaluable in 16 patients (64%). Fourteen responded to the treatment: 8 CR (50%) and 6 PR (37%). Stem cells were harvested in 16 patients and all of them underwent ASCT (CD34+ cells > 3.0x10⁶/kg in 94% of the collected patients after one sole apheresis).

Conclusion: Our preliminary result show thatthe DHAP/Ox plus ibrutinib (administered continuously from D1-21) regimen led to several dose-limiting toxicities. Because the dose of 280 mg might be insufficient to improve the quality of response, the protocol was amended in October 2015 in order to change the schedule of Ibrutinib. A new escalation phase using ibrutinib only from day 5 to day 18 is currently ongoing. Pharmacokinetics analyses are also performed.