Selinexor combined with ibrutinib demonstrates tolerability and safety in advanced B-cell malignancies: A phase I study
Mené sur 16 patients atteints d'une leucémie lymphoïde chronique et sur 18 patients atteints d'un lymphome non hodgkinien, cet essai de phase I évalue la dose maximale tolérée du sélinexor en combinaison avec l'ibrutinib, après l'échec de plusieurs lignes thérapeutiques (nombre médian de thérapies antérieures : 4)
Purpose: Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Experimental Design: In this phase I study (clinicaltrials.gov:NCT02303392), adult patients with CLL/NHL, relapsed/refractory to {greater than or equal to}1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine maximum tolerated dose (MTD). Results: Included patients had CLL (n=16) or NHL (n=18; 9 Richter's transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies was 4 (range=1-14) and 59% previously received ibrutinib. The established MTD was 40mg of selinexor (Days 1, 8, 15) and 420mg daily ibrutinib. Common non-hematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [(95%CI:3.9-16.1] and 2.7 (95%CI:0.7-5.4) months, respectively. For CLL patients who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95%CI:44.1-89.2%) and 27.8% (95%CI:10.1-48.9%) for CLL and NHL patients, respectively. Conclusion: The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in CLL patients with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.