ALBERT

Description: Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control. Patients and Methods:Of 336 eligible and evaluable HIV-negative patients enrolled in S0816, 49 had an end-of-treatment PET (termed "PET3," to be done 6-8 weeks after completion of chemotherapy) that was positive (i.e. Deauville 4-5) upon central review. We simulated the progression free survival (PFS) if XRT had been delivered per HD15 criteria (PET positive disease and ≥2.5 cm), evaluating by assumptions of 50, 80 and 90% control of the disease within the XRT fields. Receiver operating characteristics (ROC) analyses were performed with additional size cut-off points of 2.0 and 1.5 cm. Results:The median follow-up for the 49 PET3 positive patients was 71 months (range 9.7-92.6). For these 49 patients, the observed landmark PFS at 2 years after the date of PET3 was 30.6%. Twenty-four (49%), 33(67%), and 40 (82%) of the 49 patients had at least one site of disease that met the HD15 criteria for XRT with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm size cut-offs respectively. Sixteen, 19, and 25 patients had disease progression respectively from each group at median of 1.4-1.5 months. Twelve, 12, and 15 patients had relapses limited to the sites that would have been radiated following HD15 criteria with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm respectively. Estimated landmark PFS at 2 years for the 49 PET3 positive patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are summarized in columns A, B, and C of the table respectively. For the entire group of 336 patients, the observed PFS at 2 years was 79%. Estimated 2-year PFS for the entire group of 336 patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are in columns D, E, and F of the table respectively. Conclusion: Among the PET3 positive patients, consolidation XRT per HD15 criteria with cut-off points of 2.5, 2.0, and 1.5 cm could have raised the 2-year PFS by 12-28 % assuming 50-90% local control within radiated sites. However, the improvement in PFS is more moderate at 1.6-3.9 % if we consider the entire cohort of 336 patients. Although there may be some gain in PFS as the cut-off point is lowered by our ROC analysis, one needs to consider the trade-off against potentially increasing normal tissue toxicity as more sites are irradiated. Table. Table. Disclosures Brem: Pharamcyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Bartlett:Merck & Co: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Millennium: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Janssen: Consultancy; Tesaro: Research Funding; Bayer: Consultancy; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy; Juno: Consultancy; Celgene: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Description: Molecular profiling and real-time detection of therapy-resistant lymphoma cells have the potential to improve clinical outcomes by identifying biomarkers capable of predicting treatment efficacy, providing insight into key regulatory signaling pathways suitable for therapeutic targeting, and tailoring treatment selection. Czuczman et al developed and characterized several cell-line models to study the mechanisms involved in the acquirement of rituximab-resistance in B-cell lymphoma. Rituximab-resistant cell lines (RRCLs) were found to be also resistant to multiple chemotherapy agents when compared to rituximab-sensitive cell lines (RSCL). RRCLs have decreased expression of Bax and Bak, key pro-apoptotic members of the Bcl-2 family of proteins. Expression of Bcl-2 family members favoring cell survival has been seen in other lymphoma cell lines that are known to be chemotherapy resistant. It is important to validate the role of Bax/Bak expression in rituximab/chemotherapy resistance in a more clinically relevant setting and to develop assays that detect rituximab/chemotherapy resistant cells in real-time, ideally before therapy is started in a given patient. To this end, we studied 1) correlations in clinical outcomes in lymphoma patients based on pre-treatment Bax/Bak levels an 2) differences in BH3 profiling, a technique that allows for functional assessment of how “primed” cells are (that is, how capable they are of undergoing apoptosis) between RSCL and RRCL. To study the pattern of expression of Bax/Bak in lymphoma and its clinical significance, we retrospectively evaluated differences in the expression these pro-apoptotic proteins in patients evaluated at the Dana-Farber/Brigham and Women’s Cancer Center using a tissue micro-array (TMA) containing samples from 180 patients with different subtypes of B-cell lymphoma. Demographic, clinical and pharmacological characteristics were obtained for each patient. Bax/Bak staining was reported as negative, weak, moderate, or intense. In addition, RSCL and RRCL underwent BH3 priming studies. Briefly, RSCL or RRCL were exposed to a panel of BH3 only, pro-apoptotic proteins, and the amount of mitochondrial outer membrane permeabilization (MOMP) was measured over time as previously described. In highly primed cells, MOMP occurs quickly after addition of BH3 peptides, indicating that balance of pro- and anti-apoptotic members of the Bcl-2 family is in favor of apoptosis. This technique permits the assessment of the apoptotic potential in real-time. Generally, there were high levels of Bax and Bak expression amongst the lymphoma specimens represented on the TMA. Of those that could be analyzed, 90% of samples stained moderately or intensely for Bax, and 70% stained moderately or intensely for Bak. Those specimens with decreased expression did not reliably correspond with a more refractory clinical course based on the data available. Ten (10) of the patients included in the TMA had been previously treated with rituximab. Of these patients, 90% stained moderately or intensely for Bax. Nine (9) of these patient samples could be stained for Bak, and 88.9% of them stained moderately or intensely. Significant differences were observed in the BH3 profiling of RSCL and RRCL. Raji 2R and Raji4RH (RRCLs) were less primed than Raji cells (RSCL), suggesting a decrease in the mitochondrial potential. In summary, while Bcl-2 family members play an important role in the development, maintenance, and progression of B-cell lymphoma, the level expression of each individual Bcl-2 family member (i.e. Bax or Bak) appears to have less of an effect on clinical outcome that the overall balance between pro- and anti-apoptotic members. This underscores the need to develop and validate a real-time assay to define the apoptotic threshold of a cancer cell. BH3 priming further demonstrated that RRCL have impaired MOMP. Potentially, this could be adapted for the clinical setting to identify patients most likely to require alternative therapeutic strategies. 1Czuczman MS et al. Clin Cancer Res. 2008;14:1561-70. 2Olejniczak S. et al. Clin Cancer Res. 2008;14:1550-60. 3Deng J et al. Cancer Cell. 2007;12:171-185 4 Ryan J, et al. PNAS. 2010; 107(29):12895-12900. Disclosures: No relevant conflicts of interest to declare.

Description: There is a pressing need for more effective therapies to treat patients with T-cell lymphomas (TCLs), including first-line approaches that increase the response rate to cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) chemotherapy. We characterized the mitochondrial apoptosis pathway in cell lines and patient-derived xenograft (PDX) models of TCL and assessed the in vitro efficacy of BH3 mimetics, including the BCL2 inhibitor venetoclax, the BCL2/BCL-xL inhibitor navitoclax, and the novel MCL1 inhibitor AZD5991. The abundance of antiapoptotic BCL2 family members based on immunoblotting or RNA transcript levels correlated poorly with the activity of BH3 mimetics. In contrast, the functional approach BH3 profiling reliably predicted sensitivity to BH3 mimetics in vitro and in vivo. We used BH3 profiling to select TCL PDX that were dependent on MCL1. Mice xenografted with these PDX and treated with AZD5991 had markedly improved survival. The combination of AZD5991 and CHOP achieved synergy based on survival improvement beyond a mathematical “sum of benefits” model. Thus, MCL1 inhibition is a promising strategy as both a single agent and in combination with chemotherapy for patients with TCL and functional dependence on MCL1.

Description: Multiple Myeloma (MM) is a disease of malignant plasma cells for which if left untreated, patients face a 6 month median survival (Osgood, 1960). New agents and combinations continue to improve MM outcomes, extending the median survival to 5 years; however, patients will ultimately succumb to the disease after exhausting treatment options (Fonseca et al., 2017). A novel class of drugs, BH3 mimetics, specifically inhibit the gatekeepers of apoptosis known as pro-survival BCL2 family members BCL2, MCL1 and BCL-xL (Figure 1A). BCL-2 selective BH3 mimetic, venetoclax (ABT-199), has shown promise in a subset of MM patients; however, combinations are required to improve the depth of response. (Moreau et al., 2017) Our lab is pioneering the novel combination of apoptosis-promoting BH3 mimetics with the cancer-killing effect of statins in blood cancers (Lee et al., 2018). Statins are FDA-approved for their ability to lower cholesterol by blocking the synthesis of a key precursor: mevalonate, a major biosynthetic substrate (Figure 1B). Inhibition of the mevalonate pathway by statins stops the synthesis of intermediates necessary for small GTPase function, providing an attractive avenue for targeting these "undruggable" oncogenes (Berndt, Hamilton, & Sebti, 2011; ten Klooster & Hordijk, 2007). Though this potential has been long recognized, previous work on repurposing statins reported effective concentrations that are well above the plasma levels typically achieved in patients receiving standard doses for hypercholesterolemia (Ahmed, Hayslip, & Leggas, 2013; Björkhem-Bergman, Lindh, & Bergman, 2011; van der Spek et al., 2006). Furthermore, previous studies provided insufficient rationale for mechanism-based combination strategies. We have achieved a breakthrough towards this goal by combining statins with the BCL2-specific BH3 mimetic, venetoclax. Our retrospective analysis of chronic lymphocytic leukemia (CLL) clinical trial data revealed that subjects taking statins at the FDA-approved dose had significantly higher frequency of complete remissions following venetoclax treatment (Lee et al., 2018). Through mechanistic studies we showed that statins increase expression of the pro-apoptotic, BH3-only sensitizer PUMA, thereby synergizing with venetoclax to induce apoptosis in various leukemia and lymphoma cell types. Our current work leverages these findings to treat MM. Retrospective analysis of clinical trials of venetoclax in combination with bortezomib and dexamethasone in the venetoclax-sensitive subset of MM demonstrates a similar trend as in the CLL clinical trials in support of background doses of statins (Roberts et al., 2017). Pre-clinical results of MCL-1 BH3 mimetics in development support their future use in MM (Kotschy et al., 2016). Based on these data, we tested two BH3 mimetics, venetoclax and a pre-clinical MCL-1 inhibitor, S63845. Using a panel of 9 human MM cell lines, the data demonstrate that statins potentiate BH3 mimetic-induced apoptosis as measured by reductions in BH3 mimetic IC50. Sensitivity to the combination was maintained in both MM1R and MM1S, MM lines from the same origin that model glucocorticoid resistance and sensitivity respectively, while venetoclax combination with dexamethasone was lost in MM1R cells (Greenstein et al., 2003; Matulis et al., 2016). Additionally, combination-sensitive cell lines corroborate a p53-independent induction of PUMA expression. These data suggest that BH3 mimetic and statin combination may be useful in the clinical settings of dexamethasone resistance and high risk p53-null (17p deleted) patients. To further guide the appropriate application of BH3 mimetics and statins, we are validating that dynamic BH3 profiling can predict efficacy of statins in combination-sensitive versus non-sensitive MM lines. Moreover, preliminary ex vivo studies on freshly isolated CD138+ MM cells from patient bone-marrow aspirates demonstrate combined killing with BH3 mimetics and statins. Ongoing studies will investigate the dependence on upstream GTPase signaling on survival and PUMA upregulation. Disclosures Brem: Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharamcyclics: Membership on an entity's Board of Directors or advisory committees.

Description: Background: EBV-positive (EBV+) cells are detectable in a variable but significant fraction of lymphomas of all lineages and histologic type by in situ hybridization for EBV-encoded RNA (EBER-ISH). EBV positivity generally confers a worse prognosis in lymphoma but, with the exception of adoptive T-cell therapies, no EBV-targeting mechanism-based anti-lymphoma therapeutics are in development. EBV's DNA genome encodes a viral thymidine kinase (vTK, BXLF1) and a serine/threonine protein kinase (PK, BGLF4), which are expressed only during lytic cycle, and can activate anti-viral nucleoside analogues via mono-phosphorylation, leading to inhibition of EBV DNA synthesis. Nstat is able to induce the expression of PK/BGLF4 and vTK/BXLF1. This effect supports the mechanism-based strategy of leveraging EBV's presence in lymphoma by combining Nstat with VGCV, the oral prodrug for ganciclovir (GCV). EBV's PK phosphorylates GCV, which inhibits both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells (bystander effect). Based on this targeted approach, a phase 1b/2a trial was launched to determine the safety and activity of this combination in R/R EBV+ lymphomas of various lineages and histology. Here we report the phase 1b results. Methods: Eligible patients had biopsy-proven R/R EBV+ lymphoma by EBER-ISH (any positive cell) and had failed ≥1 prior systemic therapy. Phase 1b followed a 3+3 design over 5 dose ranging cohorts. The phase 1b primary objectives were safety/tolerability of Nstat/VGCV and recommended phase 2 dose (RP2D). In cohorts 1-4, variable doses of Nstat and VGCV were administered orally continuously on 28-day cycles. In cohort 5 Nstat was administered for the first 4 days of each week with daily VGCV. Toxicity was assessed by CTCAE 5.0. Efficacy was assessed by local and central radiology every 2 cycles by PET/CT (Lugano 2014 Classification). Correlative studies for phase 1b include PK/PD and other exploratory biomarkers. Results: Phase 1b enrolled 25 patients. The median age was 58 (19-84) with 72% males. Thirteen patients had either EBV+ T/NK-cell lymphoma (N=8; 5 TCL, 3 NKL), or Hodgkin lymphoma (HL) (N=5). Twelve patients had EBV+ B-cell lymphoma (BCL) (Table 1), of which 4 were HIV+ and 3 had a history of PTLD. Median number of prior therapies was 2 (1-9). Two patients with TCL had failed prior HDACi therapy. In cohorts 1-4, the most frequent treatment related hematologic grade 3-4 (G3-4) adverse events (AE) were thrombocytopenia (35%), neutropenia (25%), and lymphopenia (15%), none of which occurred at G3-4 in cohort 5. No non-hematologic G3-G4 AE were observed in 〉10% of patients in any cohort and no patient discontinued therapy due to AE. The RP2D was declared to be Nstat 20 mg days 1-4 each week and VGCV 900 mg daily on a 28-day cycle. At the RP2D there have been no G3-4AE. Seventeen patients are evaluable for response (8 BCL 5 T/NK, 4 HL). ORR was 53% (9/17), with 29% CRR (5/17). The Clinical Benefit Rate (CBR; CR/PR/Stable Disease) was 76% (13/17). Responses were seen across histologic subtypes and in heavily pre-treated patients. Durable responses were observed (one 〉12 months and one 〉10 months). For the 14 evaluable HIV-negative patients (5 BCL, 5 T/NK, 4 HL) ORR, CRR, and CBR were 64%, 36%, and 93%, respectively, with CRs and PRs in all histologic subtypes. The ORR was 3/5 for BCL (2 CR, 1 PR); 5/5 for T/NK (2 CR, 3 PR); and 1/4 in HL (1 CR). One BCL patient with combined variable immunodeficiency (CVID) achieved a CR. Only 1 of 3 BCL patients with a history of PTLD was evaluable and achieved a CR. All three evaluable HIV+ BCL patients progressed. Of 8 patients with detectable baseline plasma EBV DNA, 7 demonstrated a reduction (-17% to -83%). Other biomarker studies are in progress. Conclusion: In this phase 1b study, the combination of oral Nstat and VGCV was well tolerated in patients with EBV+ lymphomas, with no unexpected G3-G4 AE, and showed a very encouraging signal of efficacy, especially in HIV-negative patients, with CRs in BCL, TCL, and HL. The combination of Nstat and VGCV is a compelling targeted oral therapy for R/R EBV+ lymphomas of different lineage and histologic type and should be explored in other EBV+ malignancies. The phase 2a portion of this study is actively recruiting (NCT03397706). Disclosures Porcu: Viracta: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brem:Celgene: Honoraria, Speakers Bureau; BMS/Pfizer: Honoraria; Janssen: Honoraria, Speakers Bureau; Bayer: Honoraria; Genetech: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Barta:Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Trauger:Viracta: Employment. Gutheil:Viracta Therapeutics: Consultancy. Katkov:Viracta: Employment. McRae:Viracta: Employment. Royston:Viracta: Employment.

Description: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphoid malignancies with generally poor outcomes when treated with current regimens. The pro-survival BCL-2 family members BCL-2, BCL-xL, and MCL-1 contribute to tumor maintenance, progression, and chemoresistance across a range of cancers but their contributions in distinct subtypes of PTCL are poorly understood. Immunohistochemical analyses of PTCL specimens have revealed a distinct expression pattern of BCL-2 family members, most notably the high level expression of BCL-2 in up to 50% of certain PTCL entities (Rassidakis et al., J Pathol 2003). In fact, high BCL-2 expression has been associated with unfavorable prognosis (Ling et al., Biomed Environ Sci 2011). We amassed a collection of 21 T-cell lymphoma cell lines (representing Alk+ ALCL, Alk- ALCL, PTCL-NOS, cutaneous T-cell lymphoma (CTCL) and rare subtypes) and 7 patient-derived xenograft (PDX) models of T-cell lymphoma. The latter include models of Alk+ ALCL, Alk- ALCL, ATLL, NK-T cell lymphoma and AITL (available at http://www.PRoXe.org) (Townsend et al. Cancer Cell 2016). To assess the expression level and protein abundance of BCL2 family members, we performed RNA-Seq and immunoblotting. To functionally characterize dependence on BCL-2 family members, we utilized BH3 profiling, a technique that allows for assessment for how "primed" or close to the cell death threshold cells are by evaluating the degree of mitochondrial outer membrane permeabilization (MOMP), induced by a panel of BH3 domain peptides (Ryan and Letai, Cell Death and Differentiation 2013). Binding specificity of BH3 domain peptides allows for determination of which pro-survival Bcl-2 family members cells are dependent on for survival and thus makes it a powerful tool to predict response to BH3 mimetics. Finally, we assessed in vitro the cytotoxicity induced by the BH3 mimetics venetocxlax (ABT-199, a BCL-2 specific agent) and navitoclax (ABT-263, which targets both BCL-2 and BCL-xL) in PTCL cell lines. Gene expression and protein levels of the anti-apoptotic BCL-2 family members showed a distinct pattern in the cell lines that closely recapitulated immunohistochemical analysis of clinical samples (Rassidakis et al., J Pathol 2003). Specifically, both MCL-1 and BCL-xL were ubiquitously expressed, with higher levels of MCL-1 in ALCL cell lines and the PTCL-NOS cell line SMZ-1, while BCL-xL was highly expressed predominately in CTCL cell lines. While cell lines and PDX models from Alk+ ALCL and CTCL universally did not express BCL-2, approximately two-thirds of cell lines and PDX models representing Alk- ALCL, PTCL-NOS, AITL, NK/T-cell lymphoma, ATLL and rare subtypes of T-cell lymphomas did express BCL-2. Despite this expression, only 3 of 8 BCL2-expressing cell lines were sensitive to ABT-199 (IC50

Description: BACKGROUND: EBV-positive (EBV+) lymphomas including Hodgkin, B and T cell lymphomas, are generally associated with poor clinical outcomes, particularly for patients (pts) who have relapsed or are refractory (R/R) to standard therapies. There are currently no approved therapies for EBV+ lymphomas and with the exception of adoptive T-cell therapies, no EBV-targeted anti-lymphoma therapeutics are in development. EBV is detectable in cancer cells by in situ hybridization for EBV-encoded RNAs (EBER-ISH). Nstat (VRx-3996), a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC1-3, 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. This trial is the first to explore the safety and clinical activity of this targeted approach using oral Nstat in combination with oral VGCV in pts with R/R EBV+ lymphomas. Here we present an update of safety and efficacy for all enrolled patients, plus the preliminary safety of the recommended phase 2 doses (RP2D) of Nstat and VGCV (NCT03397706). 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