TY - JOUR
T1 - A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
AU - Ribrag, Vincent
AU - Lee, Seung Tae
AU - Rizzieri, David
AU - Dyer, Martin J.S.
AU - Fayad, Luis
AU - Kurzrock, Razelle
AU - Andritsos, Leslie
AU - Bouabdallah, Reda
AU - Hayat, Amjad
AU - Bacon, Larry
AU - Jiang, Yu
AU - Miah, Kowser
AU - Delafont, Bruno
AU - Hamid, Oday
AU - Anyanwu, Stephanie
AU - Martinez, Pablo
AU - Hess, Brian
N1 - Funding Information:
V.R. reports: consultant, speaker, and/or advisory board fees from Gilead, Infinity, Merck Sharp & Dohme, Bristol Myers Squibb, Epizyme, Nanostring, Incyte, Servier, Roche, and AstraZeneca; and research funding from Argenx. D.R. reports: consultant, speaker, and/or advisory board fees from AbbVie, Agios, AROG, Bayer, Celgene, Celltrion, Gilead, Jazz, Mustang, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva, Kite, Incyte, Amgen, Acro Biotech, UCART, and Chimerix Inc; research funding from Stemline; other in data safety and monitoring from UCART and Chimerix Inc. R.K. reports: research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, AstraZeneca, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant; consultant, speaker, and/or advisory board fees from Xbiotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, and Bicara Therapeutics Inc; equity interest in IDbyDNA and CureMatch Inc; and board membership for CureMatch and CureMetrix, and cofounder of CureMatch. L.A., Y.J., K.M., B.D., O.H., S.A., and P.M. report: employee of and stockholder in AstraZeneca. B.H. reports: consultancy and advisory committee membership for ADC Therapeutics; and speakers bureau for Bristol Myers Squibb and AstraZeneca. The other authors have stated that they have no conflict of interest.This study was funded by AstraZeneca. Medical writing support was provided by James Holland, PhD, of Cirrus Communications, an Ashfield company, and was funded by AstraZeneca.
Funding Information:
This study was funded by AstraZeneca . Medical writing support was provided by James Holland, PhD, of Cirrus Communications, an Ashfield company , and was funded by AstraZeneca .
Publisher Copyright:
© 2020 The Authors
PY - 2021/5
Y1 - 2021/5
N2 - Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti–programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti–cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity. Patients and Methods: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. Results: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks). Conclusion: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
AB - Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti–programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti–cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity. Patients and Methods: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. Results: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks). Conclusion: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
KW - DLBCL
KW - Danvatirsen
KW - Durvalumab
KW - Phase 1
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85101261976&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101261976&partnerID=8YFLogxK
U2 - 10.1016/j.clml.2020.12.012
DO - 10.1016/j.clml.2020.12.012
M3 - Article
C2 - 33632668
AN - SCOPUS:85101261976
SN - 2152-2650
VL - 21
SP - 309-317.e3
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 5
ER -