Background Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of several inflammatory responses, by recruiting and activating neutrophils and monocytes in the lungs. Methods We provide a longitudinal analysis of immune responses, including immune cell phenotyping and assessments of the soluble factors present in the blood and broncho-alveolar lavage fluid (BALF) of patients at various stages of COVID-19 severity: paucisymptomatic, pneumonia and acute respiratory distress syndrome (ARDS) Results We report an increase in soluble C5a levels proportional to COVID-19 severity and high levels of C5aR1 expression in blood and pulmonary myeloid cells, supporting a role for the C5a-C5aR1 axis in the pathophysiology of ARDS. Avdoralimab, an anti-C5aR1 therapeutic monoclonal antibodies (mAbs) prevented C5a-mediated human myeloid cell recruitment and activation, and inhibited acute lung injury (ALI) in human C5aR1 knockin mice. Conclusions These results support the evaluation of avdoralimab to block C5a-C5aR1 axis as a mean of limiting myeloid cell infiltration in damaged organs and preventing the excessive lung inflammation and endothelialitis associated with ARDS in COVID-19 patients Acknowledgements The Explore COVID-19 IPH group, the Explore COVID-19 Marseille Immunopole group. Ethics Approval Human study protocol was approved by the Committee for the Protection of Persons Ile-de-France III – France (#2020-A00757-32). Animal experiments were approved by the ministere de l'enseignement superieur, de la recherche et de l'innovation – France (APAFIS#25418-2020051512242806 v2).

6516 Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8+T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .

The implementation of immune checkpoint inhibitors to the oncology clinic signified a new era in cancer treatment. After the first indication of melanoma, an increasing list of additional cancer types are now treated with immune system targeting antibodies to PD-1, PD-L1 and CTLA-4, alleviating inhibition signals on T cells. Recently, we published proof-of-concept results on a novel checkpoint inhibitor, NKG2A. This receptor is expressed on cytotoxic lymphocytes, including NK cells and subsets of activated CD8+ T cells. Blocking antibodies to NKG2A unleashed the reactivity of these effector cells resulting in tumor control in multiple mouse models and an early clinical trial. Monalizumab is inhibiting this checkpoint in human beings and future clinical trials will have to reveal its potency in combination with other cancer treatment options.

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8(+) T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8(+) T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.

PURPOSE:Anti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers.EXPERIMENTAL DESIGN:Thirty-seven patients with hematological malignancies (n = 22) or solid tumors (n = 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment. In a second (extension) phase 17 patients were treated at 0.015 (n = 9) or 3 mg/kg (n = 8).RESULTS:No dose-limiting toxicity was recorded. The most frequent lirilumab-related adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate. Pharmacokinetics was dose-dependent and linear, with minimal accumulation resulting from the 4-weekly repeated administrations. Full KIR occupancy (>95%) was achieved with all dosages, and the duration of occupancy was dose-related. No significant changes were observed in the number or distribution of lymphocyte subpopulations, nor was any reduction in the distribution of KIR2D-positive NK cells.CONCLUSIONS:This phase 1 trial demonstrated the satisfactory safety profile of lirilumab up to doses that enable full and sustained blockade of KIR.

Abstract Background Inhibitory Killer Immunoglobulin-like Receptors (KIR) negatively regulate Natural Killer (NK) cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions has been associated with antitumor efficacy and increased survival in patients (pts) with AML in CR after haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). IPH2101, a fully human mAb designed to enhance antitumor effects of NK cells by blocking the major inhibitory HLA-C-specific KIR can be safely administered in elderly pts with AML (Vey, Blood 2012). Lirilumab is a 2nd generation anti-KIR mAb currently evaluated in multiple indications and combinations with encouraging preliminary results in combination with nivolumab in pts with squamous cell carcinoma of the head and neck (Leidner, SITC 2016). Here we report the results of a phase 2 trial with lirilumab as single agent in the maintenance therapy of elderly pts with AML in first CR. The objectives of this randomized phase 2 study were to determine if lirilumab could improve leukemia free survival (LFS) and to assess two dose schedules predicted from the phase 1 dose-escalation trial (Vey, ASCO 2015) to be associated with either continuous (CONT) or intermittent (INT) full KIR occupancy. Methods EFFIKIR was a randomized double-blind 3-arm placebo controlled trial (NCT01687387). Eligible pts were: aged 60 to 80 yrs, diagnosed with non-APL AML, in CR1 following standard induction (1 to 2 cycles) and consolidation (1 to 2 cycles) and had: ECOG performance status of 0-1, adequate hematologic, liver and renal function. Pts were randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks (INT) or 1mg/kg q 4 weeks (CONT) according to a minimization algorithm adjusting for center, primary vs. secondary AML, number of consolidation cycles (1 vs. 2) and cytogenetics. Pts were to receive up to 2 yrs of therapy. The primary endpoint was LFS by independent central review. Results Between November 2012 and July 2014, 153 pts were randomized and 152 pts were treated; Pts characteristics are depicted in Table 1. All had received 7+3 induction therapy. Most pts (81%) received 2 cycles of consolidation prior to inclusion. Consolidation chemotherapy consisted of intermediate-dose single agent cytarabine (IDAC) in 53%, and 5+1 in 47% of the pts, according to the recommendations of the ALFA and FILO cooperative groups, respectively. Median time since diagnosis was 4.9 months (mo) [2.8-15.5]. Median time between CR or the last consolidation and randomization were 3.3 [1.1-5.9] and 1.5 mo [0.3-3.5], respectively. The 3 arms were well balanced apart from a slight trend in favor of the placebo arm for lower age, better ECOG, and use of IDAC as consolidation. In March 2015, based upon DSMB recommendation, treatment of pts in CONT was discontinued in light of an excess of early relapses. Mean number of treatment cycles administered was 14.7, 8.8 and 13.8 in the INT, CONT and placebo arms respectively and only 6 pts had one cycle postponed in the lirilumab arms. Major reasons for study discontinuation were relapse (63%) and adverse events (AE) (10%). AE rate was analyzed by taking into account the exposure across pts in each arm. Slightly more AE rate of G1-G2 asthenia, diarrhea and pruritus was observed in CONT arm. Occurrence of hematological disorders did not differ between the 3 arms. 17 pts (11%) experienced second primary malignancies across the 3 arms. PK/PD results were in line with the model predictions: transient full KIR occupancy lasting 7-28 days for the majority of the INT arm pts and permanent full occupancy in the CONT arm. Lirilumab is not significantly immunogenic and does not induce major modifications in peripheral blood NK and T cell subsets. With a median follow-up of 36.6 mo [33.4; 38.2], 108 pts experienced relapses and 2 pts died before relapse. LFS results are presented in Table 2. Conclusions Single agent lirilumab administered for up to 24 cycles was well tolerated. Lirilumab did not result in a statistically significant improvement of LFS in the challenging setting of maintenance in AML in elderly pts. Immune-pharmacological studies will be presented. Potential hypotheses relevant for AML and lirilumab monotherapy (e.g. dosage/schedule optimization, partial desensitization by continuous KIR blockade leading to an impaired immunosurveillance by NK cells) for the non-significant trends will be discussed. Disclosures Recher: Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Pautas: Pfizer: Honoraria. Rousselot: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Research Funding. Castaigne: Pfizer: Honoraria, Research Funding. Jourdan: NOVARTIS: Consultancy, Honoraria. Gardin: Sunesis: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Delannoy: Innate Pharma: Honoraria. Beautier: Innate Pharma: Employment, Equity Ownership. Paturel: Innate Pharma: Employment, Equity Ownership. Andre: Innate Pharma: Employment, Equity Ownership. Zerbib: Innate Pharma: Employment, Equity Ownership. Dulphy: Celgene: Research Funding; Innate Pharma: Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Olive: Imcheck Therapeutics: Other: Cofunder; GSK: Research Funding; Innate Pharma: Research Funding. Pigneux: Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogaran: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dombret: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai/Roche: Consultancy.

Abstract Background Monalizumab is an immune checkpoint inhibitor targeting NKG2A receptors expressed on subsets of tumor-infiltrating cytotoxic CD8 T cells and Natural Killer (NK) cells. NKG2A ligand is HLA-E, a non-classical HLA class I molecule often upregulated in cancer. Preclinical experiments have shown that blocking NKG2A binding to HLA-E may promote NK and T cell anti-tumor responses. NK cell stimulation with a checkpoint inhibitor might also enhance antibody dependent cellular cytotoxicity (ADCC) induced by cetuximab. Although approved in SCCHN after platinum-based therapy, cetuximab has limited activity in that setting (12% response rate). Methods This is a multicenter non-randomized study (NCT02643550). After previous exploration of 5 dose levels of monalizumab (0.4, 1, 2, 4 or 10 mg/kg every 2 weeks) in combination with fixed doses of cetuximab (400 mg/m² load then 250 weekly) using a 3+3 design, the cohort expansion used monalizumab at the highest dose tested (10 mg/kg) and included a futility analysis after the first 11 patients (pts). The trial was open to pts ≥ 18 years old with SCCHN progressing after platinum-based therapy with no more than 2 previous lines, regardless of HLA-E or human papilloma virus status. The primary endpoint for anti-tumor activity was overall response rate per RECIST, assessed every 8 weeks. Pts were treated until disease progression or unacceptable toxicity. Results As of 12/19/2017, 26 pts were enrolled in the expansion part, and 16 pts had a minimum of 16 weeks of follow-up to be evaluable for efficacy. The safety profile was as expected, similar to the single agent experience with either agent. The majority of adverse events (AE) were of Grade 1-2 severity, rapidly reversible and easily manageable, with 3 treatment-related grade 3-4 AE and 1 pt stopped monalizumab due to safety. Median age was 62 years (range: 34-77); 56 % were male; PS was 0 or 1; 4 were HPV+. All 16 pts had received prior platinum-based therapy, 8 prior immune therapy, 2 prior cetuximab with radiation. There were 6 pts with partial responses (PR) (4 confirmed; 2 not yet confirmed) of whom 2 were previously treated with immune therapy and 1 had disease deemed resistant to cetuximab. Median treatment duration for confirmed PR is 25+ weeks (16, 23+, 28+, 35+), 9 pts had stable disease (SD). The study was not stopped for futility and is planned to enroll up to 40 pts. Further follow-up is needed to evaluate duration of response, progression-free and overall survival. Conclusion Preliminary data suggest promising antitumor activity of the combination of monalizumab and cetuximab compared to historical data with single agent cetuximab, with acceptable safety. These encouraging results will need to be confirmed on larger sample size with longer follow up. Citation Format: Roger Cohen, Jérôme Fayette, Marshall Posner, Gautier Lefebvre, Jessica Bauman, Sébastien Salas, Caroline Even, Tanguy Seiwert, Dimitrios Colevas, Antonio Jimeno, Esma Saada, Barbara Burtness, Pascale André, Carine Paturel, Cécile Bonnafous, Anne-Marie Soulié, Anne Tirouvanziam-Martin, Robert Zerbib, Agnès Boyer-Chammard. Phase II study of monalizumab, a first-in-class NKG2A monoclonal antibody, in combination with cetuximab in previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Preliminary assessment of safety and efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT158.

TPS2591 Background: KIR3DL2 is consistently expressed in all subtypes of Cutaneous T-cell Lymphomas (CTCL), irrespectively of disease clinical stage, with the greatest expression in Sézary Syndrome (SS) and transformed Mycosis Fungoides (MF), two subsets with high unmet need. KIR3DL2 belongs to the killer immunoglobulin (Ig)-like receptor (KIRs) family expressed on minor populations of NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It depletes selectively KIR3DL2-expressing cells. Its modes of action include Antibody-Dependent Cell-Cytoxicity (ADCC) and –Phagocytosis (ADCP). IPH4102 has potent efficacy in non-clinical models, in particular ex vivo autologous assays using primary CTCL cells. Methods: IPH4102-101 (NCT02593045) is a first-in-Human Phase I study of single-agent IPH4102 in relapsed/refractory CTCL. The study has two sequential parts, a dose-escalation followed by cohort expansion. The primary objective is to assess the safety and tolerability of increasing doses by characterizing dose-limiting toxicity (DLT) and adverse events. A 3+3 design with accelerated titration is employed. IPH4102 first Human dose and subsequent dose-levels were selected based on a MABEL strategy and PK/PD modeling. The dose-escalation portion aims to determine the maximal tolerated dose (MTD) or recommended Phase 2 dose (RP2D). Secondary objectives include PK, immunogenicity and signals of anti-neoplastic clinical activity. Exploratory objectives include identification of biomarkers of IPH4102 activity in skin lesions and on malignant blood cells when present. Eligible CTCL patients must have received at least 2 lines of systemic therapy. Centrally assessed KIR3DL2 expression in at least one involved organ is also required. In the expansion portion, two CTCL subtype-specific cohorts will include 20 additional patients to further explore the MTD or RP2D. CTCL subtypes will be selected according to dose-escalation findings. Enrollment into study IPH4102-101 started in November 2015. Cohorts 1-3 have been completed without DLT. Enrolment to cohort 4 started in January 2016. Clinical trial information: NCT02593045.

Purpose: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma; however, multiple myeloma cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against multiple myeloma; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class antiinhibitory KIR antibody, has acceptable safety and tolerability in multiple myeloma as a single agent. The present work sought to characterize lenalidomide and IPH2101 as a novel, steroid-sparing, dual immune therapy for multiple myeloma. Experimental Design: A phase I trial enrolled 15 patients in three cohorts. Lenalidomide was administered per os at 10 mg on cohort 1 and 25 mg on cohorts 2 and 3 days 1 to 21 on a 28-day cycle with IPH2101 given intravenously on day 1 of each cycle at 0.2 mg/kg in cohort 1, 1 mg/kg in cohort 2, and 2 mg/kg in cohort 3. No corticosteroids were utilized. The primary endpoint was safety, and secondary endpoints included clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD). Results: The biologic endpoint of full KIR occupancy was achieved across the IPH2101 dosing interval. PD and PK of IPH2101 with lenalidomide were similar to data from a prior single-agent IPH2101 trial. Five serious adverse events (SAE) were reported. Five objective responses occurred. No autoimmunity was seen. Conclusions: These findings suggest that lenalidomide in combination with antiinhibitory KIR therapy warrants further investigation in multiple myeloma as a steroid-sparing, dual immune therapy. This trial was registered at www.clinicaltrials.gov (reference: NCT01217203). Clin Cancer Res; 21(18); 4055–61. ©2015 AACR.

3065 Background: Inhibitory Killer Immunoglobulin-like receptors (KIRs) negatively regulate the killing, by NK cells, of tumors expressing their HLA class I ligands. We showed safety of 1st generation mAb targeting the major inhibitory KIRs (Vey et al Blood 2012).LIRI is a 2nd generation anti KIR mAb. The objectives of this study were to evaluate the safety and PK/PD of LIRI in pretreated pts with HEM or SOL with no or slowly progressive disease. Methods: In the dose escalation 3+3 phase 1 part, six dose levels of LIRI were evaluated: 0.015, 0.3, 1, 3, 6, and 10 mg/kg administered q4w x 4; the time between the first 2 infusions was adjusted to KIR desaturation (KIR occupancy < 30%). In a cohort expansion, pts were treated at 0.015 and 3 mg/kg q4w x 4 Results: Twenty and 17 patients were treated in the dose escalation and cohort expansion parts, respectively Overall median age was 62 years (33-73); 22 had HEM (5 AML, 6 CLL and 11 NHL) and 15, SOL (7 ovarian [OC], 6 breast [BC], and 2 others cancers). LIRI was generally well tolerated with no DLT in the dose-escalation; MTD was not reached. Related AEs observed in > 10% of the pts included fatigue/asthenia (30% of pts), pruritus (20%), infusion related reaction (14%), headache (11%). Only one SAE (G3 urticaria, at 0.015 mg/kg) was reported as treatment-related. Release of cytokines in serum was rare and mild to moderate. Eighteen patients (49%) discontinued the study prematurely including 13 because of disease progression, 3 for AE's and 2 for other reasons. Full KIR occupancy ( > 95%) was sustained during > 4 weeks for dose-levels ≥ 0.3 mg/kg. Conclusions: LIRI was generally well tolerated up to the highest tested dose of 10 mg/kg which was associated with prolonged KIR occupancy. Based on these results, LIRI is currently investigated in a randomized phase 2 trial as maintenance therapy for elderly pts with AML in CR1 and in several phase 1 studies in combination with other immune checkpoints inhibitors or a cytotoxic mAb.

Background Inhibitory killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I-expressing tumors. Anti-KIR treatment resulted in long-term survival in SCID mice inoculated with autologous AML cells (Romagne et al. Blood 114: 2667, 2009). Lack of KIR-HLA class I interactions has been associated with a markedly reduced relapse risk and increased survival in patients with acute myeloid leukemia (AML) upon stem cell transplantation from KIR-mismatched haploidentical donors (Ruggeri et al. Blood 2007). IPH2101 is a fully human monoclonal, hybridoma manufactured antibody (mAb) targeting the KIR2D receptors on NK cells. Results of a dose escalation phase 1 trial conducted in elderly patients with AML in complete remission (CR) indicated a satisfactory safety profile. The maximal tolerated dose was not reached at 3mg/kg. There was a clear correlation between drug exposure and KIR occupancy. Survival was consistent with a dose-related anti-leukemia effect (Vey et al. Blood 120: 4317, 2012. An extension of this phase 1 study was conducted in order to further assess the safety and efficacy of repeated monthly cycles of IPH2101 given at doses producing continuous KIR occupancy. The results of this extension are reported here. Methods This was an open-label, multicenter extension trial to the phase 1 dose-escalation study, conducted in 12 patients ≥ 60 years with an AML in CR. They were to receive up to 6 monthly cycles of IPH2101 at doses of 1 or 2 mg/kg administered as an IV infusion over one hour. Age £ 80, ineligibility for allogeneic cell transplantation, recovery from toxicities of prior chemotherapies and a time lapse ≤ 60 days since the last consolidation cycle were required. Results Twelve patients were enrolled (median age 71 years; range: 64-75). All were in CR after a median of 3 consolidation cycles (range: 1-6). Seven patients received 6 cycles of IPH2101 and the others between 1 and 3 cycles. Premature discontinuation was due to relapse of AML in four patients and to an unrelated adverse event in one patient (worsening of heart failure). Thirty one related adverse events (AEs) occurred in 83% of the patients. No grade 4 related AEs was reported. Four patients had transient grade 3 related AEs: lymphopenia (4) and amylase/lipase increased (1). Related AEs that were observed in more than one patient included lymphopenia (4), pruritus (3) and erythema/ rash (3). There was no suggestion of a dose effect for safety. The first 6 patients received a dose of 1 mg/kg. At this dose level, full KIR2D occupancy (>95%) was not sustained during monthly cycles in 3/6 patients. Six additional patients received 2 mg/kg with continuous full KIR2D occupancy in all patients. After treatment discontinuation, full occupancy persisted for a median of 1 month (range: 1-3). Median follow-up is 62 weeks at the time of this analysis , 5/12 patients were still alive including 1 in continuous CR All deaths were secondary to AML relapse. Analyses are ongoing to document the impact of IPH2101 treatment on various hematological and immunological parameters in serum (cytokine levels) and in peripheral blood (minimal residual disease), distribution of lymphocytes subsets, as well as phenotypic and functional analysis of NK cells. Conclusion The safety of IPH2101 was confirmed in this extension cohort assessing repeated monthly cycles leading to full and sustained KIR occupancy for more than 6 months. Disclosures: Vey: Innate Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Andre: Innate-Pharma: Employment, Equity Ownership. Calmels: Innate-Pharma: Employment, Equity Ownership. Zerbib: Innate Pharma: Employment. Buffet: Innate-Pharma: Employment.

TPS3117^ Background: Inhibitory killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I–expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK cell-mediated antitumor efficacy and increased survival in patients with acute myeloid leukemia (AML) upon haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). Anti-KIR antibody treatment resulted in long-term survival in SCID mice inoculated with lethal autologous AML cells (Romagne, Blood 2009). Lirilumab is a second generation fully human monoclonal antibody targeting the major inhibitory KIR on NK cells. The objectives of this study are to determine if maintenance therapy with lirilumab can improve leukemia-free survival (LFS) of elderly patients in first complete remission (CR1) of AML and to assess two dose schedules leading to either intermittent or continuous KIR occupancy. Methods: EFFIKIR is a randomized double-blind 3-arm placebo controlled trial of lirilumab in elderly patients in CR1 of AML. Patients aged 60 to 80 in CR1 of AML following standard induction and consolidation programs are randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks or 1 mg/kg q 4 weeks according to a minimization algorithm adjusting for center, primary vs. secondary AML, no. of consolidation cycles (1 vs. 2) and cytogenetics (intermediate vs. high risk). Patients are to receive up to 2 yrs of therapy. ECOG performance status of 0-1, adequate hematologic, liver and renal function, and recovery from toxicities of prior chemotherapies are required. Patients are excluded if they are eligible for bone marrow transplantation and if the time interval since last consolidation exceeds 3 mos. The primary endpoint is LFS based on independent central review. The trial will accrue 50 patients in each arm and is powered (80%) to detect an improvement in LFS with a hazard ratio of 0.60 and a one-sided alpha of 0.05. Each dose schedule will be compared to placebo using a Hochberg procedure. The first patient was randomized on 12/11/2012. Clinical trial information: NCT01687387.

Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if > 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin < 1.5 ULN, and ALT / AST < 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

Background Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma.Design and Methods We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression.Results In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide.Conclusions Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: NCT00452569)

UNLABELLED:Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma. We report a 9-year follow-up of a French multicenter nonrandomized phase II study that evaluated the effect of oral thalidomide in 120 patients with advanced multiple myeloma. Independent predictors of survival were response to last therapy, performance status, serum β(2)-microglobulin level, platelet count, and response at day 60 of treatment. BACKGROUND:Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma. PATIENTS AND METHODS:We report the 9-year follow-up of a French multicenter, nonrandomized, phase II study that evaluated the effect of oral thalidomide in advanced multiple myeloma. Thalidomide was started at 200 mg/d and increased to 400 mg/d at day 15. RESULTS:One hundred twenty patients were enrolled in 2 months at 33 centers. The overall response rate was 31.7% (38/120) on day 60. Overall survival rates were 47.5% (95% confidence interval [CI], 38.6-56.4), 25.0% (95% CI, 17.3-32.7), 11.7% (95% CI, 5.9-17.4), and 7.5% (95% CI, 2.8-12.2) at 1, 3, 6, and 9 years, respectively. Independent predictors of short survival at 1, 3, 6, and 9 years were multiple myeloma refractory to last therapy, performance status ≥ 2, serum β(2)-microglobulin level ≥ 3.5 mg/L, platelet count < 152 × 10(9)/L, and nonresponse at day 60 (Cox proportional hazards regression model). CONCLUSION:Our study identified 5 independent unfavorable prognostic factors associated with short survival. These prognostic factors were very robust, allowing the prediction of patient survival not only during the first year but also during 3, 6, and even 9 years after the beginning of treatment.

Abstract Abstract 4058 Introduction: Multiple myeloma (MM) cells upregulate MHC class I antigens which serve as ligands to inhibitory Killer Immunoglobulin-like Receptors (KIR) as a means of evading natural killer (NK) cell immunity. IPH2101 is a human, IgG4 monoclonal antibody against common inhibitory KIR that prevents KIR-ligand interaction and augments NK cell cytotoxicity against MM. A prior, single-agent, phase I study of IPH2101 demonstrated acceptable safety and tolerability with 34% of heavily pretreated patients achieving disease stabilization. Lenalidomide expands and activates NK cells, thus, pairing this agent with IPH2101 may represent a novel, steroid-free therapeutic option. Our preclinical data suggest that IPH2101 and lenalidomide combine to enhance NK cell function against MM. Herein, interim results of a phase I clinical trial of IPH2101 and lenalidomide are presented. Methods: A 3+3 design includes dose escalation over 4 planned cohorts: Cohort 1 = IPH2101 0.2mg/kg & lenalidomide 10mg, Cohort 2 = IPH2101 0.2mg/kg & lenalidomide 25mg, Cohort 3 = IPH2101 1mg/kg & lenalidomide 25mg, Cohort 4 = IPH2101 2mg/kg & lenalidomide 25mg. A 6-patient extension cohort is planned at the maximally tolerated dose. Lenalidomide is administered orally days 1–21 and IPH2101 is given intravenously on day 1 of a 28-day cycle for 4 cycles. Responding patients may continue therapy for 4 additional cycles and are maintained on lenalidomide alone thereafter. The primary objective of the study is to determine the safety and tolerability of IPH2101 and lenalidomide with secondary endpoints including: response rate, progression-free survival, pharmacodynamics, pharmacokinetics, and biologic correlates. Adult patients with relapsed MM following one or two lines of prior therapy are eligible to participate. Prior exposure to lenalidomide is allowed; however, patients must not have been resistant to, or intolerant of, lenalidomide. Patients must have measurable disease, ECOG performance status 0–2, and adequate organ function and bone marrow reserve. Thromboprophylaxis is mandatory for all patients. Results: To date, n=13 patients have been enrolled in the first 3 cohorts who have received a median number of 4 cycles of therapy to date (range 1–8). Adverse events have been generally low grade and self-limited. Two potential dose-limiting toxicities (DLT) have been observed (cohort 1 and cohort 3). Both patients experienced grade 3 infusion reactions associated with pyrexia and transient, grade 4 leucopenia following cycle 1, day 1 treatment. Clinical cytokine release syndrome was observed, and high levels of IFN-gamma, IL-6, TNF-alpha, and MIP-1beta were documented. Infusion reactions were treated with supportive care, including intravenous fluids and anti-pyretics; steroids were not administered. Leucopenia resolved without intervention, and both patients were subsequently treated in cycle 2 without recurrence of DLT. Both patients appear to have disproportionally greater KIR binding of IPH2101 on T cells relative to NK cells. Cohort 1 was expanded to n=6 patients without recurrence and expansion of cohort 3 is ongoing. An amendment is now included for pre-medication of patients with an anti-pyretic and anti-histamine prior to dosing. Co-administration of lenalidomide does not appear to alter the IPH2101 pharmacodynamic profile observed in the prior, single-agent phase I study. To date, responses include: 1 (unconfirmed) complete response, 3 partial responses, 2 minor responses and 1 stable disease. Conclusions: In addition to direct anti-MM effects, lenalidomide promotes NK cell activation, and IPH2101 prevents inhibitory signaling to augment NK cell immunity against MM. Results suggest the combination has activity with manageable toxicity in relapsed MM. At present, ongoing unconfirmed complete response has been > 12 months and ongoing partial responses have been > 18 months, > 8 months, and > 1 month in duration. This combination may represent the first steroid-free, “dual immunotherapy” for MM and further development is justified. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without dexamethasone, IPH2101 not FDA approved yet. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment.

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.

Abstract Abstract 959 Introduction: The OPTIMUM trial was designed to compare the efficacy of single-agent Thalidomide (THAL) with high-dose Dexamethasone (DEX) in patients with relapsed refractory (RR) multiple Myeloma (MM) and to determine the optimal dose of THAL in these patients. Methods: Patients with RRMM who had progressed after 1-3 lines of prior therapy were eligible for this multinational, randomized, open label phase III study. Patients were randomized to either daily THAL 100mg (THAL 100), 200mg (THAL 200) or 400mg (THAL 400), or DEX (40mg daily on days 1-4, 9-12 and 17-20 of each 28 day cycle for four cycles. From cycle 5 onwards, the dosing schedule was reduced to 40mg daily on days 1-4 of each cycle). All patients received study medication until disease progression or for a maximum of 12 cycles. Anticoagulant prophylaxis was not given routinely. Stratification factors included number of prior lines of therapy (1 versus > 1), prior autologous stem cell transplantation (ASCT) and International Staging System (ISS) score (Stage I+II versus III). The primary endpoint was time-to-progression (TTP) validated by an Independent Review Committee (IRC). Secondary endpoints included response rate, clinical benefit, survival, quality of life and safety. Planned accrual was 496 patients in order to detect a significant difference of 3 months in median TTP between the arms with 82% power at a two-sided significance level of 0.05. Results: Between Apr 2006 and Feb 2008, 499 patients were randomized by 68 sites in 15 countries from Europe, Asia and South Africa. Median age was 64 years (range 33-86); 73% of patients had ISS Stage I+II; 56.7% had received one prior therapy, 29.7% had received 2 and 12.8% had received 3 prior lines; 14.4% of patients had received prior bortezomib. Patients who had received prior thalidomide or lenalidomide were not included in this trial. Based on IRC-confirmed disease progressions during the treatment phase of the study, median TTP in the THAL 400 and in the DEX groups were 9.9 versus 6.0 months (hazard ratio, 0.64; p=0.017). Median TTP of the THAL 100 and THAL 200 arms were 6.7 and 7.3 months, respectively. IRC-validated complete and partial response rates according to EBMT criteria were 20.7% with THAL 100, 18.0% with THAL 200, 21.5% with THAL 400, and 24.6% with DEX. However, duration of response (DOR) showed a clear benefit for patients responding to THAL in comparison to DEX (median DOR in months: THAL 100: 12.7, p=0.046; THAL 200: 13.1, p=0.005; THAL 400: 11.6, p=0.016; DEX: 6.5). There was no difference in one year overall survival between the groups (80%, 83%, 82% and 80% for THAL 100, THAL 200, THAL 400 and DEX, respectively). During the study treatment period, the median of average daily drug dose in the THAL 100, THAL 200, THAL 400 and DEX groups were 99.5 mg, 198.2 mg, 255.5 mg and 40 mg, and the median treatment duration was 185, 179, 195, and 144 days, respectively. 60.2% of patients treated with THAL 400 had at least one treatment emergent AE (TEAE) ≥ Grade 3 compared to 39.5% with DEX. Thalidomide caused more frequent nervous system events (16.4 versus 2.4%), ≥ Grade 3 blood and lymphatic system disorders (14.8 versus 4.8%) and general disorders (12.5 versus 8.1%). Infections ≥ Grade 3 were more frequent with DEX (10.5% versus 8.6%). However, since TEAE of Grade 4 or higher were similar between both groups (12.5 versus 11.3%), the higher number of grade 3/4 events in the THAL 400 arm is due to an increase in grade 3 but not grade 4 TEAE with THAL 400 versus DEX. Venous thromboembolic events were uncommon in both groups (1.6% with DEX versus none with THAL 400). Patients treated with lower doses of THAL showed a more favorable safety profile. TEAEs of grade 3 or higher occurred in only 38.2 and 32.0% of the patients treated in the THAL 200 and 100 arms, respectively. Conclusion: This study is the first trial to evaluate the single agent activity of THAL in RRMM patients in a randomized controlled setting. Patients treated with THAL showed longer disease control in terms of TTP and DOR compared to high-dose DEX. The results confirm that THAL is a good treatment option for these patients with a dose dependent safety profile. Disclosures: Kropff: Celgene, ORTHO BIOTECH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: In Europe, thalidomide is not approved for the treatment of relapsed multiple myeloma. . Robak:Celgene: Consultancy, Research Funding. Hajek:Janssen-Cilag: Honoraria. Liebisch:Celgene, ORTHO BIOTECH: Honoraria. Blade:Janssen-Cilag: Honoraria; Celgene: Honoraria. Caravita:Celgene: Honoraria. Pattou:Celgene: Employment. Lucy:Celgene: Employment, Equity Ownership. Kueenburg:Celgene: Employment. Glasmacher:Celgene: Employment, Equity Ownership. Zerbib:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.