SAKK 36/13-IBRUTINIB AND BORTEZOMIB FOLLOWED BY IBRUTINIB MAINTENANCE IN PATIENTS WITH RELAPSED AND REFRACTORY MANTLE CELL LYMPHOMA: PHASE I REPORT OF A PHASE I/II TRIAL

Introduction: Mantle-cell lymphoma (MCL) remains incurable with frequent relapses, limited treatment options and progressively shorter disease-free survival with every relapse. The Bruton's tyrosine kinase inhibitor ibrutinib (IBRU) and the proteasome inhibitor bortezomib (BOR) have both single agent activity and regulatory approval in MCL. IBRU and BOR both result in a downregulation of NF-κB activity via different molecular targets. IBRU resistance involves mutations in genes of the NF-κB pathway. The combination of both drugs provides synergistic cytotoxicity in BOR-sensitive and refractory MCL in vitro. Methods: We included patients (pts.) with confirmed MCL, refractory or relapsed after ≤2 lines of a non-BOR-containing chemotherapy (incl. high-dose chemotherapy), and excluded pts. with prior BOR/IBRU therapy, with CNS disease, in need of anticoagulation (warfarin, vitamin K antagonists), and with active Hepatitis B, C or HIV infection. Pts. received 6 21-days cycles of IBRU + BOR, followed by IBRU maintenance until disease progression or unacceptable toxicity. To establish the recommended phase II dose, a 3 + 3 dose escalation design was used. BOR was given s.c. at the labelled dose (1.3 mg/m2, days 1, 4, 8, 11 q3w), and IBRU continuously at 420 mg/day (level 1), and 560 mg/day (level 2). Dose-limiting toxicities (DLTs) were assessed in cycle 1 and were defined as study drug-related adverse events (AE, CTCAE, v4.0) including ≥7 missed days of IBRU, ≥2 missed doses of BOR, delay of >2 weeks of cycle 2, hematological DLTs (ANC < 0.5 for ≥7 consecutive days, febrile neutropenia, and G4 thrombocytopenia), and non-hematological DLTs ≥ G3. The antitumor activity of the combination was a secondary objective. Results: No patient experienced a DLT during the first cycle, the minimum of 9 pts. was needed. The most frequent AEs of the combination treatment included thrombocytopenia (8 pts), peripheral polyneuropathy (PNP) and fatigue (6 pts. each), anemia and diarrhea (5 pts. each). The majority of the AEs were G1 & 2. Six pts. experienced G3 AEs with thrombocytopenia (3 pts.), PNP, lung infections, lymphocyte count decreased (2 pts.), and one pt had a G4 thrombocytopenia. Although considered G1, an unexpected AE in 5 pts. was an injection site reaction. In a protocol amendment, 8 mg dexamethasone will now be allowed as co-medication prior to injecting BOR. At data cut-off (January 31, 2017), 2 pts. had stopped therapy because of progressive disease (one at end of cycle 3, one during maintenance). 3 pts. are in follow-up incl. 1 pt who went on to successful stem-cell transplantation. Conclusions: IBRU with twice-weekly BOR at 1.3 mg/m2 s.c. can safely be administered. We define IBRU 560 mg/day as the recommended phase II dose for the combination with standard dose BOR. The safety and clinical efficacy of dose is currently being tested in the ongoing phase II part of this trial. (ClinicalTrials.gov Identifier: NCT02356458). Keywords: bortezomib; ibrutinib; mantle cell lymphoma (MCL)