A K Gopal1, M A Fanale2, C H Moskowitz3, A R Shustov1, S Mitra4, W Ye4, A Younes3, A J Moskowitz3. 1. Division of Medical Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle. 2. Division of Cancer Medicine, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston. 3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York. 4. Clinical research, Gilead Sciences Inc., Foster City, USA.
Abstract
BACKGROUND: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study. PATIENTS AND METHODS: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression. RESULTS: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia). CONCLUSIONS: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01393106.
BACKGROUND: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study. PATIENTS AND METHODS: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression. RESULTS: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia). CONCLUSIONS: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01393106.
Authors: Sarah A Meadows; Francisco Vega; Adam Kashishian; Dave Johnson; Volker Diehl; Langdon L Miller; Anas Younes; Brian J Lannutti Journal: Blood Date: 2011-12-30 Impact factor: 22.113
Authors: Xuguang Tai; François Van Laethem; Leonid Pobezinsky; Terry Guinter; Susan O Sharrow; Anthony Adams; Larry Granger; Michael Kruhlak; Tullia Lindsten; Craig B Thompson; Lionel Feigenbaum; Alfred Singer Journal: Blood Date: 2012-03-07 Impact factor: 22.113
Authors: Giorgio Raimondi; William J Shufesky; Daisuke Tokita; Adrian E Morelli; Angus W Thomson Journal: J Immunol Date: 2006-03-01 Impact factor: 5.422
Authors: Ajay K Gopal; Brad S Kahl; Sven de Vos; Nina D Wagner-Johnston; Stephen J Schuster; Wojciech J Jurczak; Ian W Flinn; Christopher R Flowers; Peter Martin; Andreas Viardot; Kristie A Blum; Andre H Goy; Andrew J Davies; Pier Luigi Zinzani; Martin Dreyling; Dave Johnson; Langdon L Miller; Leanne Holes; Daniel Li; Roger D Dansey; Wayne R Godfrey; Gilles A Salles Journal: N Engl J Med Date: 2014-01-22 Impact factor: 91.245
Authors: Maika Onishi; Solomon A Graf; Leona Holmberg; Sanaz Behnia; Andrei R Shustov; Karen Schiavo; Mary Philip; Edward N Libby; Ryan D Cassaday; John M Pagel; Jennifer E Roden; David G Maloney; Damian J Green; Brian G Till; Oliver W Press; Stephen D Smith; Ajay K Gopal Journal: Hematol Oncol Date: 2014-09-18 Impact factor: 5.271
Authors: Bruce D Cheson; Beate Pfistner; Malik E Juweid; Randy D Gascoyne; Lena Specht; Sandra J Horning; Bertrand Coiffier; Richard I Fisher; Anton Hagenbeek; Emanuele Zucca; Steven T Rosen; Sigrid Stroobants; T Andrew Lister; Richard T Hoppe; Martin Dreyling; Kensei Tobinai; Julie M Vose; Joseph M Connors; Massimo Federico; Volker Diehl Journal: J Clin Oncol Date: 2007-01-22 Impact factor: 44.544
Authors: Taemin Oh; Michael E Ivan; Matthew Z Sun; Michael Safaee; Shayan Fakurnejad; Aaron J Clark; Eli T Sayegh; Orin Bloch; Andrew T Parsa Journal: Immunotherapy Date: 2014 Impact factor: 4.196
Authors: Stephen M Ansell; Alexander M Lesokhin; Ivan Borrello; Ahmad Halwani; Emma C Scott; Martin Gutierrez; Stephen J Schuster; Michael M Millenson; Deepika Cattry; Gordon J Freeman; Scott J Rodig; Bjoern Chapuy; Azra H Ligon; Lili Zhu; Joseph F Grosso; Su Young Kim; John M Timmerman; Margaret A Shipp; Philippe Armand Journal: N Engl J Med Date: 2014-12-06 Impact factor: 91.245
Authors: Daniel T Patton; Oliver A Garden; Wayne P Pearce; Louise E Clough; Clare R Monk; Eva Leung; Wendy C Rowan; Sara Sancho; Lucy S K Walker; Bart Vanhaesebroeck; Klaus Okkenhaug Journal: J Immunol Date: 2006-11-15 Impact factor: 5.422
Authors: Alex Reza Gholiha; Peter Hollander; Ingrid Glimelius; Gustaf Hedstrom; Daniel Molin; Henrik Hjalgrim; Karin E Smedby; Jamileh Hashemi; Rose-Marie Amini; Gunilla Enblad Journal: Blood Adv Date: 2021-03-23
Authors: Tycel J Phillips; Andres Forero-Torres; Taimur Sher; Catherine S Diefenbach; Patrick Johnston; Moshe Talpaz; Jennifer Pulini; Li Zhou; Peggy Scherle; Xuejun Chen; Paul M Barr Journal: Blood Date: 2018-04-25 Impact factor: 22.113