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

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

  • Clin Lymphoma Myeloma Leuk. 2022 Jan;22(1):52-59. doi: 10.1016/j.clml.2021.07.020.
Jason Westin 1,  Michael B Maris 2,  Caron A Jacobson 3,  Prapti Patel 4,  Nehal Lakhani 5,  Wael Harb 6,  Dipti Patel-Donnelly 7,  Kelly McCaul 8,  Carolina Escobar 9,  Barbara Klencke 10,  Ayad M Al-Katib 11
Affiliations

Affiliations

  • 1 University of Texas M.D. Anderson Cancer Center, Department of Lymphoma & Myeloma, Houston, TX.
  • 2 Colorado Blood Cancer Institute, Denver, CO.
  • 3 Dana Farber Cancer Institute, Department of Medicine, Boston, MA.
  • 4 University of Texas Southwestern Medical Center, Department of Hematology/Oncology Dallas, TX.
  • 5 Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI.
  • 6 Horizon Oncology Research, Inc., Lafayette, IN.
  • 7 Virginia Cancer Specialists, Fairfax, VA.
  • 8 Avera Cancer Institute, Hematology and Bone Marrow Transplant, Sioux Falls, SD.
  • 9 Baylor Research Institute, Dallas, TX.
  • 10 Sierra Oncology, Inc. (formerly ProNAi Therapeutics, Inc.), San Mateo, CA. Electronic address: [email protected].
  • 11 Wayne State University, Lymphoma Research Lab, Detroit, MI.
PMID: 34454850 DOI: 10.1016/j.clml.2021.07.020
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 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.

Keywords

BCL2; Diffuse large B-cell lymphoma; Lymphoma; Oligonucleotide therapy.

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