Abstract: NFAT transcription factors are highly phosphorylated proteins residing in the cytoplasm of resting cells. Upon dephosphorylation by the phosphatase calcineurin, NFAT translocates to the nucleus, where it orchestrates developmental and activation programs in diverse cell types. NFAT is rephosphorylated and inactivated through the concerted action of at least three different kinases: CK1, GSK-3 and DYRK. NFAT signalling is further implicated in lymphocyte homeostasis and its deregulation has been suggested to be involved in the pathogenesis of different malignancies. Previous studies have primarily concentrated on NFAT2, which was found to be overexpressed and constitutively activated in a majority of biopsies from Diffuse Large B-Cell lymphomas and Burkitt’s lymphomas, presumably reflecting activation of the Ca/NFAT signalling pathway as part of their pathogenesis. Other recent studies have demonstrated that NFAT2 activation can lead to increased expression of different cell survival factors (CD154, BLyS) in several NHL subtypes. Here, we analyzed the role of NFAT1 in malignant transformation and in the pathogenesis of T-ALL using a transgenic mouse model for the disease. We show that sustained activity of NFAT1 and NFAT2 induces opposite phenotypes in NIH 3T3 cells. While NIH 3T3 cells infected with empty retrovirus showed normal viability and stopped growing upon reaching confluence, cells infected with a constitutively active version of NFAT2 overgrew the monolayer and continued to proliferate beyond confluence. NIH 3T3 cells expressing a constitutively active form of NFAT1 on the contrary exhibited a remarkable reduction in cell proliferation and never reached confluence, suggesting opposite roles for NFAT1 and NFAT2 in the control of cell growth and proliferation. To directly test whether NFAT1 has the capability to suppress tumor growth and to subvert a transformed cell type, we generated NIH 3T3 cell clones harboring the oncogene H-rasV12, which showed a typical transformed phenotype. Expression of constitutively active NFAT1 in the transformed NIH 3T3-HrasV12 cells leads to a significant reduction in cell proliferation which was accomanied by a large decrease in DNA replication and an accumulation in the G1 phase of the cell cycle. To test if NFAT1 has tumor suppressor characteristics in vivo, we generated transgenic mice conditionally expressing a hyperactivable form of NFAT1 from the ROSA26 locus. These mice were subsequently bred to Tel-Jak2 transgenic mice, which develop T-ALL at 8–20 wks of age. Mice that expressed hyperactivable NFAT1 in their T cells in addition to the disease inducing Tel-Jak2 transgene exhibited a significantly attenuated phenotype of the disease. Infiltration of vital organs such as lung, liver and bone marrow was significantly delayed and overall survival was almost twice as long in the animals that expressed hyperactivable NFAT1 in their T cell compartment (88 days vs. 159 days). To summarize, our data identify NFAT1 as a novel tumor suppressor gene in T-ALL and emphasize the importance of the Ca/NFAT signalling pathway in the pathogenesis of hematologic malignancies.

Abstract: Background: Anti-PD1 antibodies have the potential to increase rituximab-mediated effector mechanisms, to target the microenvironment and PD-1 in aggressive Non-Hodgkin Lymphoma (NHL). Addition of Nivolumab (Nivo) might increase efficacy of chemotherapy. The NIVEAU trial is an ongoing international, multicenter, randomized, open label, phase 3 study testing Nivo in combination with Rituximab, Gemcitabine, Oxaliplatin ((R-)GemOx) (NCT03366272). We performed a pre-planned safety analysis comparing the experimental arm (including safety run-in phase) and standard arm. Methods: Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell and peripheral T-cell lymphoma (PTCL)), ineligibility for HDT (defined as & gt;65 years of age or older than 18 years if HCT-CI score & gt;2), only 1 prior chemotherapy including an anthracycline and R in case of B-NHL. Patients (Pts) were planned to receive 8 bi-weekly cycles of GemOx (Gem 1000 mg/m2, Ox 100 mg/m2) and R 375 mg/m2 for B-NHL at d1 of each cycle. Pts randomized into the experimental arm additionally received Nivo 3 mg/kg every two weeks for a total of 26 applications or until progression. Safety analysis was performed after 30 pts had been included into the experimental arm. Results: The analysis (data cut-off 29-August-2019) included 59 pts (44 with B-NHL, 15 with PTCL). 22 pts with B-NHL were randomized in the standard arm, 22 in the experimental arm. 7 pts with PTCL were randomized in the standard arm, 8 in the experimental arm. Median age was 78 years (range: 59; 87) for B-NHL and 70 years (range: 53; 80) for PTCL. 18 (41%) pts with B-NHL and 7 (47%) with PTCL were male. Twenty-five (57%) pts with B-NHL and 11 (73%) with PTCL had duration of first response ≤ 12 months. Due to the non-randomized safety run-in phase where all pts were treated in the experimental arm, the cumulative observation time of the experimental arm was longer. The most common adverse events (AE) (≥5%) during (immuno-)chemotherapy for pts treated with (R-)GemOx (grade ≥3) per documented cycles were thrombocytopenia 9/64 (14%), infection 7/64 (11%), leukocytopenia 5/64 (8%), peripheral sensory neuropathy 4/64 (6%) and anemia 4/63 (6%). Other frequent AEs gr. 3 (n & gt;1) and/or life-threatening AEs (grade ≥4) were 2 gastrointestinal hemorrhages (1x gr. 4, 1x gr. 3), 1 gastric perforation gr. 4 and 2 tumor lysis syndromes gr. 3. In pts treated with (R-)GemOx 1 therapy-related death occurred after 2 cycles of (immuno-)chemotherapy. One pt with gastric involvement of lymphoma terminated treatment early due to sepsis after surgical intervention after gastrointestinal bleeding. The most common AEs (≥5%) during immunochemotherapy for pts treated with (R-)GemOx+Nivo (grade ≥3) per documented cycles were thrombocytopenia 37/140 (26%), anemia 22/140 (16%), increased lipase 13/129 (10%), leukocytopenia 11/140 (8%) and infection 7/141 (5%). Other frequent AEs gr. 3 (n & gt;1) and/or life-threatening AEs (grade ≥4) were 2 gastrointestinal hemorrhages (1x gr. 5, 1x gr. 3), 1 renal failure gr. 5, 1 CNS vasculitis (gr. 4), 9 neutropenia (1x gr. 4, 8x gr. 3), 5 lymphopenias (2x gr. 4, 3x gr. 3), 19 increased yGT (each gr. 3), 2 hypertension (2x gr. 3), 2 syncopes (2x gr. 3) and 2 infusion related reactions (2x gr. 3). During consolidation with Nivo until 100 days after end of therapy most common AEs (≥5%, grade ≥3) were: lymphopenia 15/114 (13%), neutropenia 9/114 (8%) and leukocytopenia 8/114 (7%). Other frequent AEs gr. 3 (n & gt;1) and/or life-threatening AEs (grade ≥4) were 6x increased yGT (each gr. 3) and 3 back pains (gr. 3). In pts treated with (R-)GemOx+Nivo 2 pts terminated treatment early, 1 due to elevated liver enzymes and 1 due to CNS vasculitis. Conclusion: So far, a moderately higher toxicity of the experimental arm, the combination of (R)-GemOx with Nivo, was observed. However, this does not influence the overall risk profile of the trial. No increased rate of progressions in pts with PTCL treated with Nivo was observed. The randomized phase 3 study continues as planned with continuous evaluation of toxicity. Supported by BMS Disclosures Thurner: EUSA-Pharm: Other: travel grants; Takeda: Consultancy; Astra-Zeneca: Consultancy; Merck: Consultancy; Janssen: Other: travel grants. Poeschel:Amgen: Other: travel grants; Abbvie: Other: travel grants; Roche: Other: travel grants. Tilly:BMS: Honoraria. Andre:Takeda: Consultancy; BMS: Consultancy, Other: travel grants; Karyopharm: Consultancy; Gilead: Consultancy, Other: travel grants; Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Roche: Other: travel grants; Amgen: Other: travel grants; Johnson & Johnson: Research Funding; Celgene: Other, Research Funding. Dreyling:Roche: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Bayer: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy. Kerkhoff:BMS: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Stilgenbauer:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Haioun:Novartis: Honoraria; Takeda: Honoraria; Gilead: Honoraria; Roche: Honoraria; Servier: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Miltenyi: Honoraria. Held:BMS: Consultancy, Other: Travel Grants, Research Funding; Roche: Consultancy, Other: travel grants, Research Funding; MSD: Consultancy; Acrotech, Spectrum: Research Funding; Amgen: Research Funding. OffLabel Disclosure: The IMP is Nivolumab. The Trial is for patients with Aggressive Non-Hodgkin Lymphoma (B -and T- cell lymphoma) in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx) Plus Rituximab (R) in Case of B-Cell Lymphoma

Abstract: Introduction Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphomas, which usually carry a poor prognosis. Malignant T-cells may overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal on normal T-cells further suppressing antitumor immunity. They can also express PD1 which may act as a tumor suppressor on malignant T-cells (Wartewig et al, Nature 2017). Thus, blocking the PD1/PDL1 synapse in PTCL may lead to tumor regression or progression. The NIVEAU trial is an ongoing international, multicenter, randomized, open label, phase 3 study testing Nivolumab (Nivo) in combination with (Rituximab), Gemcitabine, Oxaliplatin ((R-)GemOx) for patients with aggressive (B and T-cell) Non-Hodgkin Lymphoma in first relapse or progression not eligible for High-Dose Chemotherapy (NCT03366272). Here, we performed a preliminary analysis of the experimental arm (Nivo-GemOx) of the PTCL cohort to assess the safety and efficacy of this regimen in this population. Methods Key eligibility criteria include: first relapse or progression of peripheral T-cell lymphoma (PTCL), ineligibility for high dose therapy (defined as & gt;65 years of age or older than 18 years if HCT-CI score & gt; 2), only one prior chemotherapy regimen including an anthracycline. Pts were planned to receive 8 cycles Nivolumab (3mg/kg) plus Gemcitabine and Oxaliplatin in 2-wk intervals followed by additional 18 Nivolumab (3mg/kg) biweekly as consolidation or until progression. Response was evaluated after 4 and 8 cycles of GemOx. Each progression/relapse of PTCL had to be reported as a SAE. Results The analysis (data cut-off 13-July-2020) included 12 PTCL pts enrolled in the experimental arm (Table 1): 4 (33%) PTCL NOS, 3 (25%) AITL, 1 (8%) PTCL TFH-type, 2 (17%) ALCL ALK-, 1 (8%) EATL, and 1 (8%) MEITL. Median age was 69.5 years (range, 53-80), 7 (58%) patients were male, 2 (17%) had received a prior autologous stem cell transplantation, and 5 (42%) were refractory to first line therapy. At enrollment, performance status was 0-1 in 9 (75%) pts and 2 in 3 (25%) pts, 11 (92%) had Ann Arbor stage III-IV, 2 (17%) had B-symptoms, 7 (58%) had more than one extra-nodal site and 4 (33%) had elevated LDH. PD1 and PD-L1 were expressed by the tumor cells in 6/10 (60%) and 2/11 (18%) patients, respectively (Table 1). Pts have received a median of 6 (1-8) cycles of GemOx and 7 (1-26) infusions of nivolumab. Treatment was prematurely discontinued in 9 pts (7 during induction and 2 during consolidation), due to lymphoma progression (n=6), toxicity (n=2) and an intercurrent disease (n=1). There were 26 SAE in 10 patients, including 8 progressive diseases. Nine (75%) patients achieved an objective response (4 CR and 5 PR). Two patients (pt 9: MEITL PD1-negative; and pt 12: PTCL-NOS strongly PD1-positive) experienced primary progression upon Nivo-GemOx (Table 1). Median PFS2 (time from randomisation to 2nd rel/prog/death) was 6.9 months (95% CI: 1.9-11.9) vs 7.7 months (95% CI: 7.2-8.2) for PFS1 (time from diagnosis to 1st rel/prog). PFS2 was superior to PFS1 in 2 out of 8 patients (25%), and not informative in 4 pts: 3 who are still on therapy (ongoing PFS) and 1 who died prematurely due to infection (pt 8) (Figure 1). Median OS was 24.8 months (95% CI: 0-49.8). After a median follow-up of 22.8 months, 7 patients have died (5 from lymphoma and 2 from infection (1 COVID-19 infection and 1 yeast septicemia)), and 5 remain alive. Conclusions Nivolumab in combination with GemOx was well tolerated in PTCL. The response rate and PFS2 (compared to PFS1) are encouraging. Marked differences in PFS2 might reflect heterogeneity of biology and susceptibility to PD-1 blockade in combination with GemOx chemotherapy. Furthermore, the translational research program of the study might help to identify markers which are predictive for efficacy of PD-1 blockade in PTCL. This phase 3 trial is actively enrolling patients and an update of these results will be presented at the meeting. Disclosure: ISR financially supported by Bristol Myers Squibb. Disclosures Houot: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Bristol-Myers Squibb: Honoraria. Poeschel:Roche: Other: Travel, Accommodations, Expenses; Amgen: Other: Travel, Accommodations, Expenses; Abbvie: Other: Travel, Accommodations, Expenses. André:Abbvie: Consultancy; Celgene: Other, Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Seattle Genetics: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Johnson & Johnson: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Dreyling:Beigene: Consultancy; Bayer: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Tilly:BMS: Honoraria. Casasnovas:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Kerkhoff:BMS: Honoraria. De Leval:Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Lunaphore Technologies SA: Consultancy, Honoraria; Abbvie: Honoraria; Roche Diagnostics: Honoraria. Gaulard:takeda: Honoraria, Research Funding; innate pharma: Research Funding. Held:Roche: Consultancy, Other: travel grants, Research Funding; MSD: Consultancy; Acrotech, Spectrum: Research Funding; Amgen: Research Funding; BMS: Consultancy, Other: Travel Grants, Research Funding. OffLabel Disclosure: Nivolumab in peripheral T-cell lymphoma

Abstract: Background: Nivolumab, a human anti-PD1 antibody has the potential to increase rituximab-mediated effector mechanism, to target the microenviroment and PD-1 in aggressive Non-Hodgkin lymphoma. Addition of nivolumab might increase efficacy conventional chemotherapy, which is always combined with rituximab in case of B-cell lymphoma. Therefore, a safety run-in was conducted to determine the tolerability of the combination prior to proceeding with a larger randomized phase 3 study aimed to compare of (R)-GemOx vs. Nivolumab plus (R)-GemOx. Methods: This is an ongoing international, multicenter, randomized, open label study. Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell as well as peripheral T-cell lymphoma (PTCL)), ineligibility for HDT (defined as 〉 65 years of age or older than 18 years if HCT-CI score 〉 2), only one prior chemotherapy regimen including an anthracycline and rituximab (R) in case of B-cell lymphoma. A non-randomized safety run-in phase was performed in 16 pts to assess potential toxicities of Nivolumab in combination with (R)-GemOx. Pts were planned to receive 8 bi-weekly cycles of Gemcitabine 1000 mg/m2, Oxaliplatin 100 mg/m2, R 375 mg/m2 all given on day 1. Nivolumab 3 mg/kg was given every two weeks for a total of 26 applications or until progression. Importantly, first application of Nivolumab was prior to first application of R. Response was evaluated after 4 and 8 cycles of (R)-Gemox. Safety analysis was performed after the last patient had gone through interim restaging after 4 cycles of (R)-GemOx. Progression/relapse of PTCL was scored as severe adverse event (SAE). Results: Sixteen pts were enrolled in the safety run-in, 10 pts with B cell lymphoma, all DLBCLs and 6 with PTCL. Recruitment was from 12-Jan-2018 until 17-May-2018, snapshot of database on 09-Aug-2018. Median age was 76 years, 9 (56%) pts were male, 8 (50%) had time-to-treatment failure 〈 = 12 months; 14 (88%) had Ann Arbor stage ≥III disease; 10 (63%) had an elevated lactate dehydrogenase level, and 10 (63%) had an International Prognostic Index of 3 to 5. Pts received a median of 6 (1-8) cycles of (R)-GemOx and 7 (1-10) applications of nivolumab. The most common treatment-emergent adverse events (grade ≥3) per documented cycles were thrombocytopenia 24/90 (27%), anemia 11/90 (12%), infection 8/92 (9%), leukocytopenia/neutropenia 6/90 (7%), elevated lipase 3/84 (4%), hyperglycemia 2/79 (3%), pruritus 2/90 (2%), rash 2/90 (2%). Fourteen serious adverse events related to nivolumab occurred in 9 (56%) patients (4 infections, 3 thrombocytopenia, 1 vertigo, 1 hyperkalemia, 1 renal failure, 1 rash, 1 diarrhoea, 1 pyrexia, 1 leptomeningeal vasculitis). Four immune-related AEs occurred (2 grade 3-4 rash, 1 grade 2 pneumonitis, 1 grade 4 leptomeningeal vasculitis leading to treatment discontinuation). Treatment was discontinued due to lymphoma progression in 3 pts with DLBCL and 1 pt with PTCL. One patient with PTCL discontinued treatment due to an immune-related AE (leptomeningeal vasculitis after the 1st cycle). Because inhibition of PD-1 might conversely induce progression of PTCL, efficacy is part of the safety analysis. So far 3/6 PTCL pts are in ongoing CR for 17, 16 and 14 months, respectively (an update will be presented at the meeting). Conclusion: The overall safety profile of nivolumab in combination with (R)-GemOx was consistent with those previously reported for (R)-GemOx and nivolumab. The combination does not to result in an increased frequency of immune-related AEs. However, the occurrence of very rare events needs assessment of longer follow-up and recruitment of more pts. Duration of response in PTCL is promising, without evidence for hyperprogression. The trial proceeded to the randomized phase 3 study and is actively recruiting. An additional safety analysis will be performed after 30 pts have been randomized to the experimental arm. Disclosures Held: Acrotech: Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Molina:merck: Consultancy; novartis: Consultancy; celgene: Consultancy. Rosenwald:MorphoSys: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Dreyling:Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Poeschel:Astra Zeneca: Other: Travel support; Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support. OffLabel Disclosure: nivolumab, aggressive Non-Hodgkin Lymphoma

Abstract: Background: Relapse of aggressive B-cell as well as peripheral T-cell lymphoma (PTLC) has a very poor prognosis, especially in pts ineligible for high-dose chemotherapy. Nivolumab, a human anti-PD1 antibody has the potential to increase rituximab-mediated effector mechanisms and to target the microenvironment in Non-Hodgkin lymphoma. Addition of nivolumab might also increase the efficacy of conventional chemotherapy. Therefore, the NIVEAU trial is testing a common conventional chemotherapy regimen (R)-GemOx vs. Nivolumab plus (R)-GemOx (ClinicalTrials.gov Identifier:NCT03366272). Design and study population: This is an ongoing joint international, multicenter, randomized, open label study proceeded by a safety run-in phase conducted by several European cooperative study groups (LYSA, HOVON, PLRG, KLS, AGMT, GLA). Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell as well as PTCL), ineligibility for HDT (defined as 〉 65 years of age or older than 18 years if HCT-CI score 〉 2 or pts who underwent prior autologous stem cell transplantation and are not eligible for allogeneic stem cell transplantation), only one prior chemotherapy regimen including an anthracycline and rituximab (R) in case of B-cell lymphoma. Statistical methods: The primary endpoint is 1-year PFS rate. We aim to demonstrate an improvement from 27% to 42% (i.e. a hazard ratio of 0.66), importantly in B-cell lymphoma only. The two-sided question will be answered with an error probability of alpha= 5% (two sided) and a power of 80%. Therefore, it will be necessary to analyze 292 pts. A drop-out rate of 5% of pts results in a sample size of 310 pts with B-cell lymphoma to be randomized. In parallel a maximum of 78 pts with PTCL will be included and randomized without statistical assumption. Based on the results and possible further increasing scientific knowledge an estimation will be done whether an improvement of prognosis of PTCL can be expected. Potentially an adapted statistical hypothesis will be defined and the trial amended to recruit the appropriate sample size of PTCL. Analysis: A non-randomized safety run-in phase with 16 pts (10 DLBCL/6 PTCL) was performed in 2018. A 2nd safety analysis will be done after randomization of 30 pts to the experimental arm to allow for comparative description of toxicities between the arms. An interim analysis of efficacy will be performed including the first 180 patients from the B-cell cohort. The final analysis of the primary and secondary endpoint will be performed two years after recruitment of the last pt with B-cell lymphoma. A comprehensive translational research program will be performed on paired samples of primary diagnosis and relapse (NGS targeted resequencing, gene expression profiling, comparative genomic hybridization), PBMC (flow cytometry), serum, plasma and cell-free DNA. Study treatment: (R)-GemOx is Gemcitabine 1000 mg/m2, d1, Oxaliplatin 100 mg/m2, d1, Rituximab 375 mg/m2 in case of B-cell lymphoma disease, repeated every 2 wks. Standard arm: eight cycles of (R)-GemOx. Experimental arm: eight cycles of nivolumab (3 mg/kg) plus (R)-GemOx in 2-wk intervals followed by additional 18 infusions of Nivolumab (3 mg/kg) in 2-wk intervals as consolidation or up to progression or unacceptable toxicity. Endpoints: The primary endpoint is 1-year PFS. Secondary endpoints represent efficacy (response rates, duration of response, progression rate, relapse rate, EFS, OS), toxicity (AEs, SAEs, treatment related deaths, secondary malignancies, long-term sequelae), protocol adherence (number of chemotherapy cycles, duration of chemotherapy cycles, cumulative dose and relative dose of gemcitabine, oxaliplatin, rituximab, nivolumab), quality of life (assessed by 5Q-5D-5L) and outcome according to biology. Conclusion: The NIVEAU-study represents a trial with a clear phase 3 design aiming to improve outcome in pts. with relapsed aggressive B-cell lymphoma ineligible for HDT. Additive recruitment and randomization of PTCL allows to adapt and define a precise statistical assumption in future, depending on interim-results, upcoming knowledge and recruitment. The approach allows to provide phase 3 evidence also in very rare disease entities. Disclosures Held: Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Trneny:Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. Rosenwald:MorphoSys: Consultancy. Rymkiewicz:Roche: Other: Travel support. Tarte:Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Poeschel:Abbvie: Other: Travel support; Amgen: Other: Travel support; Roche: Other: Travel support; Hexal: Speakers Bureau. Haioun:Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria. OffLabel Disclosure: nivolumab, aggressive Non-Hodgkin Lymphoma