Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Poster I
Hematology Disease Topics & Pathways:
Diseases, Hodgkin Lymphoma, Therapies, Combinations, Non-Hodgkin Lymphoma, DLBCL, B-Cell Lymphoma, Biological Processes, T-Cell Lymphoma, epigenetics, Lymphoid Malignancies
METHODS: Pts with biopsy-proven EBV+ lymphomas (by EBER-ISH; any positive tumor cell) that had failed ≥1 prior systemic therapy and lacked treatment options by investigator’s judgment were eligible for enrollment. Phase 1b used a 3x3 design to determine the RP2D of Nstat + VGCV. Phase 2 pts received the RP2D (Nstat 20 mg days (d) 1-4/7 + VGCV 900 mg orally daily in 28 d cycles) until PD or withdrawal. Primary endpoints were safety/RP2D selection (phase 1b) and ORR (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response (TTR), progression free survival (PFS) and overall survival (OS). Response assessments began after Cycle 2 using Lugano 2014 response criteria.
RESULTS: As of 5 July 2020, 43 pts have enrolled (phase 1b: 25; phase 2: 18). Lymphoma subtypes were diffuse large B cell (DLBCL) (6), extranodal NK/T-cell (ENKTL) (6), peripheral T cell, NOS (PTCL-NOS) (3), angioimmunoblastic (AITL) (4), cutaneous T cell (CTCL) (1), Hodgkin (HL) (8), other B cell (2), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (13), including post-transplant lymphoproliferative disorder (PTLD) (4), HIV-associated (5), and other [4: systemic lupus erythematosus (SLE) (2), common variable immunodeficiency/primary immunodeficiency (2)]. Pts had a median of 2 prior therapies (range 1-11); 77% with ≥2 prior therapies, 86% were refractory to their most recent previous therapy and 77% had exhausted standard therapies in the judgment of the investigator. EBER positivity ranged from <1 to 80% in 18 pre-study tumor biopsies with central lab review. Most treatment-related AEs (TRAEs) were mild or moderate, most commonly thrombocytopenia (33%), nausea (29%), neutropenia (26%) and fatigue (24%). At the RP2D, 23 pts were evaluable for safety. The most frequent G3/4 TRAEs (in ≥5% of pts) were neutropenia (14%), anemia (9%), and nausea (9%). For all evaluable pts (n=34), the ORR was 44% (15/34), with 8 (24%) complete responses (CR). The median TTR was 53 d (range 44-161 d). Responses for the 10 evaluable T/NK-NHL pts (ORR/CR 80%/40%) are shown in Table 1 [ENKTL (n=5; 1 CR 3 PR); T cell (n=5; 3 CR 1 PR)]. Two pts (ENKTL and PTCL-NOS) in PR/CR respectively were withdrawn for autologous stem cell transplantation (ASCT). For DLBCL (n=6), ORR/CR was 66%/33% (both CRs were in pts refractory to first-line R-CHOP). For IA-LPD (predominantly B-cell), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). The median DoR for all responders is 10.6 months, with a median follow-up from response of 5.0 m (range 0.4-22.9 m).
CONCLUSIONS: Co-administration of oral Nstat with VGCV has a favorable safety profile, may be suitable for combination with additional agents, and shows promising efficacy in pts with a variety of R/R, heavily pre-treated EBV+ lymphomas, the majority of whom were lacking therapeutic options. Preliminary data suggests that this regimen is highly active in EBV+ T/NK-NHL pts who are refractory to standard therapies, including ASCT (Table 1), and promising in EBV+ DLBCL. Thus far, no apparent correlation was noted between degree of EBER positivity in pre-study tumor biopsies and ORR.
Disclosures: Porcu: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy; Miragen: Research Funding; Kura Oncology: Research Funding; Kiowa Kirin: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Daiichi: Consultancy, Honoraria; Cell Medica: Research Funding; Celgene: Research Funding. Haverkos: Viracta THerapeutics: Consultancy. Alpdogan: Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Baiocchi: viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. Brammer: Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Feldman: AstraZeneca: Consultancy; Janssen: Speakers Bureau; Portola: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Brem: KITE: Consultancy; TG Therapeutics: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Pharmacyclics: Speakers Bureau. Scheinberg: Novartis Brasil S.A.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment.
OffLabel Disclosure: Nanatinostat(VRx-3996) is a Class I-selective oral HDAC inhibitor active against HDAC1-3 that induces the expression of EBV protein kinases which activate the anti-viral nucleoside analogue VGCV via mono-phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), causing apoptosis.
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