Phase 2 study of idelalisib and entospletinib

Pneumonitis limits combination therapy in relapsed refractory CLL and NHL

Paul M. Barr, Gene B. Saylors, Stephen 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

Research output: Contribution to journalArticle

71 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2411-2415
Number of pages5
JournalBlood
Volume127
Issue number20
DOIs
StatePublished - May 19 2016

Fingerprint

Biomarkers
B-Cell Chronic Lymphocytic Leukemia
Refractory materials
Non-Hodgkin's Lymphoma
Pneumonia
Pharmacodynamics
Phosphatidylinositol 3-Kinase
Chemokines
Protein-Tyrosine Kinases
Interferons
Toxicity
Interleukin-6
Steroids
Cells
Cytokines
Plasmas
Monitoring
Therapeutics
Interleukin-7
Follicular Lymphoma

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Barr, P. M., Saylors, G. B., Spurgeon, S., Cheson, B. D., Greenwald, D. R., O'Brien, S. M., ... Friedberg, J. W. (2016). Phase 2 study of idelalisib and entospletinib: Pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood, 127(20), 2411-2415. https://doi.org/10.1182/blood-2015-12-683516

Phase 2 study of idelalisib and entospletinib : Pneumonitis limits combination therapy in relapsed refractory CLL and NHL. / Barr, Paul M.; Saylors, Gene B.; Spurgeon, Stephen; Cheson, Bruce D.; Greenwald, Daniel R.; O'Brien, Susan M.; Liem, Andre K D; Mclntyre, Rosemary E.; Joshi, Adarsh; Abella-Dominicis, Esteban; Hawkins, Michael J.; Reddy, Anita; Paolo, Julie Di; Lee, Hank; He, Joyce; Hu, Jing; Dreiling, Lyndah K.; Friedberg, Jonathan W.

In: Blood, Vol. 127, No. 20, 19.05.2016, p. 2411-2415.

Research output: Contribution to journalArticle

Barr, PM, Saylors, GB, Spurgeon, S, Cheson, BD, Greenwald, DR, O'Brien, SM, Liem, AKD, Mclntyre, RE, Joshi, A, Abella-Dominicis, E, Hawkins, MJ, Reddy, A, Paolo, JD, Lee, H, He, J, Hu, J, Dreiling, LK & Friedberg, JW 2016, 'Phase 2 study of idelalisib and entospletinib: Pneumonitis limits combination therapy in relapsed refractory CLL and NHL', Blood, vol. 127, no. 20, pp. 2411-2415. https://doi.org/10.1182/blood-2015-12-683516
Barr, Paul M. ; Saylors, Gene B. ; Spurgeon, Stephen ; Cheson, Bruce D. ; Greenwald, Daniel R. ; O'Brien, Susan M. ; Liem, Andre K D ; Mclntyre, Rosemary E. ; Joshi, Adarsh ; Abella-Dominicis, Esteban ; Hawkins, Michael J. ; Reddy, Anita ; Paolo, Julie Di ; Lee, Hank ; He, Joyce ; Hu, Jing ; Dreiling, Lyndah K. ; Friedberg, Jonathan W. / Phase 2 study of idelalisib and entospletinib : Pneumonitis limits combination therapy in relapsed refractory CLL and NHL. In: Blood. 2016 ; Vol. 127, No. 20. pp. 2411-2415.
@article{953ec3ba8978401287816e543c063c37,
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.",
author = "Barr, {Paul M.} and Saylors, {Gene B.} and Stephen Spurgeon and Cheson, {Bruce D.} and Greenwald, {Daniel R.} and O'Brien, {Susan M.} and Liem, {Andre K D} and Mclntyre, {Rosemary E.} and Adarsh Joshi and Esteban Abella-Dominicis and Hawkins, {Michael J.} and Anita Reddy and Paolo, {Julie Di} and Hank Lee and Joyce He and Jing Hu and Dreiling, {Lyndah K.} and Friedberg, {Jonathan W.}",
year = "2016",
month = "5",
day = "19",
doi = "10.1182/blood-2015-12-683516",
language = "English (US)",
volume = "127",
pages = "2411--2415",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "20",

}

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

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84974604103&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84974604103&partnerID=8YFLogxK

U2 - 10.1182/blood-2015-12-683516

DO - 10.1182/blood-2015-12-683516

M3 - Article

VL - 127

SP - 2411

EP - 2415

JO - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -