TY - JOUR
T1 - Safety and Efficacy of a DNA Oligonucleotide Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
AU - Westin, Jason
AU - Maris, Michael B.
AU - Jacobson, Caron A.
AU - Patel, Prapti
AU - Lakhani, Nehal
AU - Harb, Wael
AU - Patel-Donnelly, Dipti
AU - McCaul, Kelly
AU - Escobar, Carolina
AU - Klencke, Barbara
AU - Al-Katib, Ayad M.
N1 - Funding Information:
Jason Westin has received research funding from Novartis, BMS, Kite, Genentech, Astra Zeneca, Morphosys, Curis, Forty Seven, Inc., and Janssen and is an advisory board consultant for Novartis, BMS, Kite, Genentech, Astra Zeneca, Morphosys, Curis, and Janssen. Michael B Maris, Dipti Patel-Donnelly, Kelly McCaul and Prapti Patel and Carolina Escobar have no potential conflict of interest to declare. Caron A Jacobson has consulted for Kite, Novartis, Celgene, BMS, Humanigen, Precision Biosciences, Nkarta and received research funding from Pfizer. Nehal J. Lakhani received research funding for clinical trials from: Sierra Oncology, Inc. (formerly ProNAi Therapeutics, Inc.), ALX Therapeutics, Ascentage, Asana, Beigene, Constellation, Cerulean, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, TaiRx, Apexian, Formation Biologics, Coordination Therapeutics, Symphogen, CytomX, lnhibRx, lncyte, Jounce, Livzon, Research, Northern Biologics and Ikena; and advisory board honoraria from Innovent Biologics. Barbara Klencke has employment with Sierra Oncology, Inc. (formerly ProNAi Therapeutics, Inc.). All authors received funding for this trial from Sierra Oncology, Inc. (formerly ProNAi Therapeutics, Inc.).
Funding Information:
The authors would like to thank the investigators, clinical site personnel, and patients for their contributions to the study. The study was sponsored by Sierra Oncology, Inc. formerly ProNai Therapeutics, Inc. The authors gratefully acknowledge the assistance of Lisa Rimsza from the Mayo Clinic for supporting the laboratory analysis of biomarkers.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2022/1
Y1 - 2022/1
N2 - Background: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene. Methods: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit. Criteria were modified to PS of 0 or 1 and at least 1 to ≤3 prior therapies (identified as the target population) after observing an initially high frequency of rapid disease progression in patients with extensive prior therapies or poor PS. Results: The study was stopped early following an interim analysis, despite surpassing the protocol predetermined futility boundary, because the ORR was below the expectations of response in an evolving DLBCL treatment landscape. The final analysis included all 45 enrolled patients and demonstrated an ORR of 11%. In the response evaluable subset (n = 26), defined as patients in the target population with exposure to ≥8 doses of PNT2258 within the first 35 days and evaluable baseline/post-baseline scans, the ORR was 19%. The most common adverse events were fatigue (44%), nausea (42%), diarrhea (40%), pyrexia (36%), anemia (32%), and vomiting (27%). Conclusions: PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. Despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development.
AB - Background: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene. Methods: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit. Criteria were modified to PS of 0 or 1 and at least 1 to ≤3 prior therapies (identified as the target population) after observing an initially high frequency of rapid disease progression in patients with extensive prior therapies or poor PS. Results: The study was stopped early following an interim analysis, despite surpassing the protocol predetermined futility boundary, because the ORR was below the expectations of response in an evolving DLBCL treatment landscape. The final analysis included all 45 enrolled patients and demonstrated an ORR of 11%. In the response evaluable subset (n = 26), defined as patients in the target population with exposure to ≥8 doses of PNT2258 within the first 35 days and evaluable baseline/post-baseline scans, the ORR was 19%. The most common adverse events were fatigue (44%), nausea (42%), diarrhea (40%), pyrexia (36%), anemia (32%), and vomiting (27%). Conclusions: PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. Despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development.
KW - BCL2
KW - Diffuse large B-cell lymphoma
KW - Lymphoma
KW - Oligonucleotide therapy
UR - http://www.scopus.com/inward/record.url?scp=85113641975&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85113641975&partnerID=8YFLogxK
U2 - 10.1016/j.clml.2021.07.020
DO - 10.1016/j.clml.2021.07.020
M3 - Article
C2 - 34454850
AN - SCOPUS:85113641975
SN - 2152-2650
VL - 22
SP - 52
EP - 59
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 1
ER -