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

作者：Bradley M. Haverkos, Önder Alpdoğan, Robert A. Baiocchi, Jonathan E. Brammer, Tatyana Feldman, Marcelo Capra, Elizabeth Brém, Santosh Nair, Phillip Scheinberg, Juliana Pereira, Leyla Shune, Erel Joffe, Patricia A. Young, Susan E. Spruill, Afton Katkov, Robert McRae, Ivor Royston, Douglas V. Faller, Lisa Rojkjaer, Pierluigi Porcu · 发表于：Blood Advances · 年份：2023 · DOI：10.1182/bloodadvances.2023010330 · 被引用次数：51 · 研究领域：Viral-associated cancers and disorders、Cytomegalovirus and herpesvirus research、Lymphoma Diagnosis and Treatment

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 ...