Safety and Efficacy of a DNA Oligonucleotide Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma |
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| Affiliation: | 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;11. Wayne State University, Lymphoma Research Lab, Detroit, MI;1. Institute for Clinical Research & Health Policy Studies, Tufts Medical Center, Boston, MA;2. Division of Hematology/Oncology, Tufts Medical Center, Boston, MA;3. Department of Medicine and Pediatrics, Tufts University School of Medicine, Boston, MA;1. Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil;2. Laboratorio de Genética Hematológica, Instituto de Medicina Experimental (IMEX-CONICET)/Academia Nacional de Medicina;3. On behalf of the Grupo de Estudio de SMD, Sociedad Argentina de Hematología, Buenos Aires, Argentina;4. Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil;5. Hematology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina;6. Hematology Department, Hospital Italiano de La Plata, Buenos Aires, Argentina;7. Federal University of Ceara, Departament of Internal Medicine, Ceara, Brazil;8. Hematology Department, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil;9. Laboratory of Pathology of the Heart Institute (InCor), Hospital das Clinicas (HC-FMUSP), University of Sao Paulo, Sao Paulo, Brazil;10. The Fleury Group, Sao Paulo/SP, Brazil;11. Department of Imaging, Hematology and Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil;12. Genetics Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil;1. Shanghai Institute of Hematology, National Research Center for Translational Medicine, Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine，Shanghai, China;2. Department of Physiology, Second Military Medical University, Shanghai, 200433, China;3. Department of Hematology, Shanghai Tenth People''s Hospital, Tongji University School of Medicine, Shanghai, 200072, China;4. The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;5. Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China;1. Hematology department, CHRU Nancy, F-54000, Nancy, France;2. Hematology department, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris, Paris, France;3. Unit of Methodology, Data-management, and Statistics (UMDS), University hospital of Nancy, France;4. Centre Hospitalier Lyon Sud, Pavillon Marcel Bérard -Bat 1G, Service Hematologie, Lyon, France;5. Hematology department, Hôpital Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Paris, France;6. Hematology department, Hôpital Claude Huriez, Lille, France;7. Hematology department, Hôpital Saint Eloi, Montpellier, France;8. Hematology department, Hôpital Haut-Levêque, Bordeaux, France;9. Hematology department, Hôpital La Pitié Salpêtrière, Paris, France;10. Hematology department, Institut Paoli Calmette, Marseille, France;11. Hematology department, Hôpital Dupuytren, Limoges, France;12. Service de Thérapie Cellulaire et d''Hématologie Clinique Adulte, Université d''Auvergne, CHU Clermont-Ferrand Hôpital Estaing, Clermont-Ferrand, France;13. Hematology Department, Institut de Cancerologie Strasbourg Europe (ICANS), Strasbourg, France;14. Hematology department, Hôpital Necker, Assistance Publique des Hôpitaux de Paris, Paris, France;15. Hematology department, CHU Besançon, F-25000, Besançon, France;1. Division of Hematology and Oncology, University of California San Diego, La Jolla, CA;2. Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI |
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| Abstract: | BackgroundPNT2258 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.MethodsThis 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.ResultsThe 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%).ConclusionsPNT2258 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. |
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