TY - JOUR
T1 - Phase 2 study of idelalisib and entospletinib
T2 - Pneumonitis limits combination therapy in relapsed refractory CLL and NHL
AU - Barr, Paul M.
AU - Saylors, Gene B.
AU - Spurgeon, Stephen E.
AU - Cheson, Bruce D.
AU - Greenwald, Daniel R.
AU - O'Brien, Susan M.
AU - Liem, Andre K.D.
AU - Mclntyre, Rosemary E.
AU - Joshi, Adarsh
AU - Abella-Dominicis, Esteban
AU - Hawkins, Michael J.
AU - Reddy, Anita
AU - Paolo, Julie Di
AU - Lee, Hank
AU - He, Joyce
AU - Hu, Jing
AU - Dreiling, Lyndah K.
AU - Friedberg, Jonathan W.
N1 - Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/5/19
Y1 - 2016/5/19
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2015-12-683516
DO - 10.1182/blood-2015-12-683516
M3 - Article
C2 - 26968534
AN - SCOPUS:84974604103
SN - 0006-4971
VL - 127
SP - 2411
EP - 2415
JO - Blood
JF - Blood
IS - 20
ER -