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|Ref Type||Journal Article|
|Authors||Barr PM, Saylors GB, Spurgeon SE, Cheson BD, Greenwald DR, O'Brien SM, Liem AK, Mclntyre RE, Joshi A, Abella-Dominicis E, Hawkins MJ, Reddy A, Di Paolo J, Lee H, He J, Hu J, Dreiling LK, Friedberg JW|
|Title||Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.|
|Date||2016 May 19|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||non-Hodgkin lymphoma||not applicable||Entospletinib + Idelalisib||Phase II||Actionable||In a Phase II trial, Zydelig (idelalisib) and Entospletinib combination treatment resulted in objective response in 36% of patients with non-Hodgkin lymphoma, but was terminated due to severe treatment-emergent pneumonitis (PMID: 26968534).||26968534|
|Unknown unknown||chronic lymphocytic leukemia||not applicable||Entospletinib + Idelalisib||Phase II||Actionable||In a Phase II trial, Zydelig (idelalisib) and Entospletinib combination treatment resulted in objective response in 60% of patients with chronic lymphocytic leukemia, but was terminated due to severe treatment-emergent pneumonitis (PMID: 26968534).||26968534|