Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.

Autor:	Haverkos B; Division of Hematology, University of Colorado, Denver, CO., Alpdogan O; Division of Hematologic Malignancies and Hematopoetic Stem Cell Transplantation, Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA., Baiocchi R; The Ohio State University James Comprehensive Cancer Center, Columbus, OH., Brammer JE; The Ohio State University James Comprehensive Cancer Center, Columbus, OH., Feldman TA; John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ., Capra M; Centro Integrado de Hematologia e Oncologia - Hospital Mãe de Deus, Porto Alegre, Brazil., Brem EA; Division of Hematology/Oncology, Deptartment of Medicine, University of California, Irvine, Orange, CA., Nair S; Mid Florida Hematology and Oncology Center, Orange City, FL., Scheinberg P; Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil., Pereira J; Division of Hematology, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Shune L; University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS., Joffe E; Memorial Sloan Kettering Cancer Center, New York, NY., Young P; Ronald Reagan UCLA Medical Center, Los Angeles, CA., Spruill S; Applied Statistics and Consulting, Spruce Pine, NC., Katkov A; Viracta Therapeutics, Inc, Cardiff, CA., McRae R; Viracta Therapeutics, Inc, Cardiff, CA., Royston I; Viracta Therapeutics, Inc, Cardiff, CA., Faller DV; Viracta Therapeutics, Inc, Cardiff, CA., Rojkjaer L; Viracta Therapeutics, Inc, Cardiff, CA., Porcu P; Division of Hematologic Malignancies and Hematopoetic Stem Cell Transplantation, Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2023 Oct 24; Vol. 7 (20), pp. 6339-6350.
DOI:	10.1182/bloodadvances.2023010330
Abstrakt:	Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706. (© 2023 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)
Databáze:	MEDLINE
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