title: Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.
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.
authors.affiliation: James P. Wilmot Cancer Center Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Paul M
authors.identifier: 0000-0002-9733-401X
authors.initials: PM
authors.lastname: Barr
authors.affiliation: Charleston Hematology/Oncology Associates, Charleston, SC;
authors.forename: Gene B
authors.initials: GB
authors.lastname: Saylors
authors.affiliation: Oregon Health & Science University, Portland, OR;
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Spurgeon
authors.affiliation: Georgetown University Medical Center, Washington, DC;
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cheson
authors.affiliation: Cancer Center of Santa Barbara, Santa Barbara, CA;
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Greenwald
authors.affiliation: University of California, Irvine, Irvine, CA;
authors.forename: Susan M
authors.initials: SM
authors.lastname: O'Brien
authors.affiliation: Pacific Shores Medical Group, Long Beach, CA;
authors.forename: Andre K D
authors.initials: AK
authors.lastname: Liem
authors.affiliation: Ventura Oncology, Ventura, CA; and.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Mclntyre
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Abella-Dominicis
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hawkins
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Anita
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Julie
authors.initials: J
authors.lastname: Di Paolo
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Hank
authors.initials: H
authors.lastname: Lee
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Joyce
authors.initials: J
authors.lastname: He
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Gilead Sciences Inc., Foster City, CA.
authors.forename: Lyndah K
authors.initials: LK
authors.lastname: Dreiling
authors.affiliation: James P. Wilmot Cancer Center Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000378:metabolism; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011014:Pneumonia / Q000139:chemically induced*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects*; D052999:Quinazolinones / Q000008:administration & dosage / Q000009:adverse effects*; D016879:Salvage Therapy; D000072377:Syk Kinase / Q000037:antagonists & inhibitors; D009025:Morpholines
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D007191:Indazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D011719:Pyrazines; D052999:Quinazolinones; D000072377:Syk Kinase; C000589391:6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; D009025:Morpholines; C486018:PIK3CD protein, human; C000606896:SYK protein, human; C552946:idelalisib