Safety and Efficacy of a DNA Oligonucleotide Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Abstract 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 2, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory diffuse large B-cell lymphoma (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 overall response rate (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. Micro Abstract: PNT2258 was an experimental, first-in-class agent designed to target the regulatory region upstream of the BCL2 gene. Results from a small Phase 2 study suggested PNT2258 had clinically significant, durable responses and an acceptable safety profile in subjects with relapsed/refractory B-cell malignancies. This Phase 2 study investigated antitumor activity in patients with relapsed/refractory diffuse large B-cell lymphoma. PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. However, despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development.