Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL
Paul M Barr, Gene B Saylors, Stephen E Spurgeon, Bruce D Cheson, Daniel R Greenwald, Susan M O'Brien, Andre K D Liem, Rosemary E Mclntyre, Adarsh Joshi, Esteban Abella-Dominicis, Michael J Hawkins, Anita Reddy, Julie Di Paolo, Hank Lee, Joyce He, Jing Hu, Lyndah K Dreiling, Jonathan W Friedberg, Paul M Barr, Gene B Saylors, Stephen E Spurgeon, Bruce D Cheson, Daniel R Greenwald, Susan M O'Brien, Andre K D Liem, Rosemary E Mclntyre, Adarsh Joshi, Esteban Abella-Dominicis, Michael J Hawkins, Anita Reddy, Julie Di Paolo, Hank Lee, Joyce He, Jing Hu, Lyndah K Dreiling, Jonathan W Friedberg
Abstract
Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.
© 2016 by The American Society of Hematology.
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Source: PubMed