ALBERT

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: Background: Panobinostat is a histone deacetylase inhibitor that has shown promising results in cutaneous T-cell lymphoma (CTCL). Objectives: An open-label, multicenter, Phase II study is being conducted with a primary objective of establishing the efficacy and safety of the pan-deacetylase inhibitor, panobinostat (LBH589), for patients (pts) with relapsed/refractory CTCL with Stage IB–IVA mycosis fungoides (MF) or Sézary syndrome (SS). Methods: Inclusion criteria include adequate organ function, no clinically significant cardiovascular abnormalities (QTcF ≤ 450 ms, ECOG PS ≤2), failure of ≥2 prior systemic therapies, and no prior HDAC inhibitor treatment. Pts were grouped as having bexarotene therapy (Group [Gr] 1) or bexarotene naïve (Gr 2). Panobinostat was administered at a dose of 20 mg orally on Days 1, 3, 5, weekly, every 28 days until progression or unacceptable toxicity. Response was based on a composite score, including skin assessment with the modified Severity-Weighted Assessment Tool (mSWAT) and systemic disease assessed by CT scan. Results: To date, 95 pts (Gr 1=62; Gr 2=33) have enrolled with median age of 58 yrs [range 25–88]: 58 male, 37 female; 70 MF, 25 SS. Median prior treatment regimens are 4 and 3 for Gr 1 and 2, respectively. Most pts were ≥Stage IIB at study entry (Gr 1=42; Gr 2=26) and received 1–17+ (median=3) treatment cycles of panobinostat. In Gr 1, 11/62 pts have had confirmed skin responses by SWAT, including 2 complete skin responses. Confirmatory CT scans are pending for 2 patients. In Gr 2, 4/33 pts had confirmed skin and CT scan responses. Common AEs (〉20%; all grades, regardless of causality) included diarrhea, thrombocytopenia, nausea, pruritus, fatigue, and asthenia, and Grade 3/4 AEs (〉2%, regardless of causality) included thrombocytopenia, neutropenia, pruritus, diarrhea, and hypophosphatemia. Of 4,542 ECGs analyzed, 2 pts have had QTcF 〉480 ms; 4 had QTcF 〉60 ms increase from baseline. Conclusions: Panobinostat continues to demonstrate encouraging clinical activity with a manageable safety profile in pts with CTCL. Per predefined criteria, Group 2 enrollment to Stage 2 is open. Updated efficacy and safety data will be presented.

Description: Background: CTCL represents a rare group of non-Hodgkin lymphomas with substantial negative impact on patient (pt) quality of life and mortality in advanced-stage disease. Mycosis fungoides (MF), the most common subtype of CTCL, and the rarer leukemic variant Sézary syndrome (SS) are distinct subtypes of CTCL. Mogamulizumab is a first-in-class, defucosylated monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), which is highly expressed on malignant T-cells in CTCL. Primary results from the MAVORIC study (data cut-off December 2016), a phase 3 trial comparing mogamulizumab to FDA-approved vorinostat in adults with relapsed/refractory MF/SS, showed mogamulizumab significantly prolonged median progression-free survival compared with vorinostat (7.7 vs 3.1 months, P351 d was defined as cut-off for long-term exposure. Baseline characteristics across exposure groups are shown in the Table. Significant trends were observed for baseline Eastern Cooperative Oncology Group performance status (ECOG PS; P=0.04), disease type (P=0.03), and blood involvement (defined as ≥B1 per Olsen et al J Clin Oncol 2011; P351 d of exposure to mogamulizumab were drug eruption (9/45 [20%]), thrombocytopenia (5/45 [11%]), stomatitis (4/45 [9%]), and anemia (4/45 [9%]). Conclusions: This follow-up analysis of the phase 3 MAVORIC study demonstrated mogamulizumab treatment of pts with MF/SS for approximately 1 year was not associated with an increased safety risk. Significant long-term clinical benefit was observed in pts with blood involvement at baseline, regardless of CCR4 expression status. A higher proportion of pts who had long-term (〉351 days) exposure attained confirmed global response versus those who had less exposure. Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Tsianakas:Kyowa Kirin: Research Funding. Musiek:Seattle Genetics: Honoraria; Kyowa Kirin: Honoraria; Actelion: Other: Scientific Advisory Committee . Ortiz-Romero:Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding; Actelion: Consultancy; 4SC: Consultancy. Poligone:Johnson and Johnson: Research Funding; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding; Mallinckrodt: Speakers Bureau; Stemline Therapeutics: Honoraria; Seattle Genetics: Honoraria. Duvic:Clinical Care Options: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huron Consulting Group: Consultancy; Taiwan Liposome Company LTD: Consultancy; Rhizen Pharma: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; UT MD Anderson Cancer Center: Employment; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: Speaker/Preceptor; Guidepoint Global: Consultancy; Jonathan Wood & Associates: Other: Speaker; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Evidera, Inc.: Consultancy; Kiniksa Pharmaceuticals: Consultancy; MEDACorp: Consultancy; The Lynx Group: Consultancy; Spatz Foundation: Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Allos: Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals, Inc.: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Array Biopharma: Consultancy, Honoraria; Oncoceuticals: Research Funding; Tetralogics: Research Funding. Elmets:NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Association: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Leo Pharma: Other: Data and Safety Monitoring Board. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Kim:miRagen: Research Funding; Forty Seven Inc: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding.

Description: Introduction Cutaneous T-cell lymphoma (CTCL), a heterogeneous group of rare non-Hodgkin's lymphomas, is characterized by infiltration of malignant clonally expanded T lymphocytes in the skin and is very challenging to treat at advanced stages. Around 65% of the CTCL cases are mycosis fungoides (MF), which usually starts as indolent disease with accumulation of neoplastic resident memory T lymphocytes in the skin, evolving from patch to plaque and later to tumor stage with poor prognosis. Sézary syndrome (SS) involves erythroderma in the skin, malignant circulating clone, and lymphadenopathy. The CTCL pathogenesis is incompletely understood but suggests a complex interplay between neoplastic T cells and the tumor microenvironment. Glycoengineered ARGX-110 potently blocks CD70/CD27 signaling, which is thought to inhibit evasion of tumor immune surveillance as well as tumor cell proliferation and survival. The ARGX-110 effector functions, i.e., complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and enhanced antibody-dependent cellular cytotoxicity (ADCC), efficiently kill CD70-expressing tumor cells. With only limited expression in normal tissues and strong expression on tumor cells, CD70 is a very attractive target for antibody-based therapy in cancer. The role of CD70 and treatment with ARGX-110 was further investigated as part of a Phase 1/2 study in advanced CTCL patients. Methods As part of a non-randomized, open-label, multicenter Phase 1/2 study (NCT01813539), a total of 27 patients with CD70-expressing advanced CTCL of different subtypes and stages were included for determination of the optimal dose, to evaluate exploratory efficacy and safety, and to characterize pharmacokinetics and biomarkers of drug activity (immunohistochemistry [IHC] staining for drug- and disease-related markers, profiling of malignant and non-malignant immune cells by flow cytometry, quantitative polymerase chain reaction [qPCR] and Nanostring). ARGX-110 was administered intravenously at 1 (N=11) or 5 mg/kg (N=16) every three weeks (Q3W). Adverse events were graded according to NCI-CTCAE v. 4.03. Results ARGX-110 was safe and well tolerated at both 1 and 5 mg/kg in heavily treated CTCL patients with a median age of 67 years (range: 25-84 years). At cut-off (26th June 2018), a total of 110 treatment-emergent adverse events (TEAE) were reported in 27 patients of which 12 were grade 3-5; 40 events in 18 patients were considered drug-related by the investigator. The most common TEAE was pyrexia (7 events in 5 patients), and infusion-related reactions (IRRs) was the most common drug-related TEAE. The best response was 1 complete response (CR), 5 partial response (PR), and 7 stable disease (SD) in 26/27 patients evaluable for response, meaning overall response (ORR) in 23% of the patients and disease stabilization in 27% of the patients. The mean duration on the study was around 4.8 months. Two patients were still on the study at cut-off: 1 patient (subcutaneous panniculitis-like T-cell lymphoma, 24 months) with CR and 1 SS patient with PR (6.5 months). Pharmacokinetics (PK) revealed a mean half-life of 8-12 days, in line with previously published data. The 5 mg/kg dose was chosen as the recommended phase 2 dose (RP2D) based on PK and immunogenicity data. IHC staining for drug- and disease-specific markers showed results in line with clinical reduction of modified Severity Weighted Assessment Tool (mSWAT) and regression from plaque to patch stages. Molecular and cellular profiling indicated a complex interplay between the tumor and the microenvironment, in which CD70/CD27 plays a role. Conclusions ARGX-110 was safe and well tolerated at both dose levels (1 and 5 mg/kg) in advanced CD70-expressing CTCL patients. Clinical anti-tumor activity in patients with various types of CTCL was observed after treatment with ARGX-110, indicating ARGX-110 as a safe and promising treatment option for advanced CTCL. Disclosures Bagot: Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Maerevoet:Karyopharm: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant. Zinzani:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: 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, Speakers Bureau. Morschhauser:Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Ribrag:Incyte Corporation: Consultancy; Amgen: Research Funding; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Servier: Consultancy, Honoraria; pharmamar: Other: travel; argenX: Research Funding; BMS: Consultancy, Honoraria, Other: travel; MSD: Honoraria. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Hultberg:argenx: Employment. Gandini:argenx: Employment. Moshir:argenx: Employment. Delahaye:argenx: Employment. Zabrocki:argenx: Employment. Silence:argenx: Consultancy. Van Rompaey:argenx: Employment. De Haard:argenx: Employment. Leupin:argenx: Employment.

Description: GA101 is a third generation, glycoengineered type II IgG1 anti-CD20 monoclonal antibody (Mab) with enhanced ADCC and superior caspase-independent apoptosis induction in comparison to other anti-CD20 antibodies, including rituximab which is a type I antibody. We compared the antitumor efficacy of GA101 and rituximab in established RL human lymphoma xenografts in SCID beige mice. One million exponentially growing RL cells were injected SC, yielding fast growing xenografts. GA101 was given twice weekly at 3 dosages (10, 30 and 100 mg/kg), whereas Rituximab was given at fixed dose of 30 mg/kg twice weekly. Both Mabs were administered as intravenous injections, for a total of 5 injections. GA101 was dose-related active against RL xenografts in terms of tumor growth inhibition (TGI). TGI was calculated using NCI formula and showed values of 25, 75 and 85% for the 10, 30 and 100 mg/kg dosages of GA101 respectively while the 30 mg/kg dose of rituximab induced a TGI of 43% only. Both higher doses of 30 and 100 mg/kg significantly inhibited the growth of RL tumors and resulted in some complete tumor remissions (10–30 %). The antitumor activity of Rituximab against RL xenografts was inferior to equivalent dosing of GA101. Toxicity of GA101 with these regimens was excellent with no toxic deaths and no significant modification of body weight. In a separate series of experiments rituximab 30 mg/kg and GA101 30 mg/kg administered once weekly i.v. for 4 weeks were combined or not to cyclophosphamide 50 mg/kg administered once weekly intraperitoneally for 4 weeks. This study confirmed the previous observation that the new anti CD20 GA101 was more active than rituximab administered at similar doses on established RL tumors. TGI values were 79, 35% and 93% for GA101, rituximab and cyclophosphamide administered as single agents when compared to untreated controls. When groups receiving combined therapy were compared to the groups receiving the corresponding single agent Mab, cyclophosphamide increased antitumor efficacy with TGI values of 83 and 94% for rituximab and GA101, respectively. Thus using a suboptimal dose of the classical antilymphoma alkylating agent cyclophosphamide, the combination of either antibody with cyclophosphamide was more active than either agent alone, and the most active combination was GA101 with cyclophosphamide. These results show that GA101 is more active than rituximab on RL xenografts at similar doses, both administered as a single agent or in combination with cyclophosphamide. In the SCID mice model it is not expected that a major contribution to antitumor efficacy comes from the interaction of glycoengineered Mab with murine FcgRIV receptors. Complementary experiments with cobra venom factor, which is used for in vivo complement inhibition, suggest that rituximab antitumor effect was strongly dependent on complement dependent cytotoxicity while GA101 remained active when complement was depleted.

Description: Abstract 2467 GA101, a novel glycoengineered type II IgG1 antibody against CD20, has shown a direct and immune effector cell-mediated cytotoxicity in numerous B-cell disorders. Chronic Lymphocytic Leukemia (CLL) is the most common hematologic malignancy in the western world. Since circulating mature B-CLL cells express high levels of antiapoptotic proteins that are implicated in the survival mechanism, we investigated whether the effects of GA101 compared to rituximab, induces apoptosis in these cells and what mechanism underlies GA101-mediated cytotoxicity. CLL cells were isolated from peripheral blood samples by density gradient centrifugation and B lymphocytes were purified by a negative selection method using the EasySep® B Cell Enrichment Cocktail. Cell viability was measured flow cytometrically by annexinV binding. We assessed the mitochondrial transmembrane potential (ΔΨm) by staining with 3,3-dihexyloxacarbocyanine iodide (DiOC6[3]), the generation of reactive oxygen species by staining with Dihydroethidine (DHE) as well as cytochrome c release. Moreover, the expression of several apoptosis-regulating proteins, including the Bcl-2 family proteins (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak and Bad) and the activation of the caspase cascade were evaluated by immunoblotting on 34 fresh peripheral blood B-CLL specimens. We showed that GA101 initiates an early extensive cell death. The average decrease of viability of freshly isolated and purified CLL cells 24 hours post-treatment with 10μg/ml of anti CD20 antibodies were 37.6% for GA101 (n=11) and 28.8% for Rituximab (n=11). The GA101-induced cell death was paralleled by a rapid loss of mitochondrial membrane potential accompanied with the production of ROS and cytochrome c release that occurred significantly as early as 3 hours post-treatment. However, rituximab was unable to initiate a loss of ΔΨm and the production of ROS. The use of antioxidants such as N-acetyl cysteine and L-ascorbic acid were unable to circumvent either the GA101-induced cell death or the loss of ΔΨm. However, the preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone), a broad caspase inhibitor, abolished the exposure of phosphatidylserine residues, the generation of reactive oxygen species and reversed the loss of ΔΨm. Furthermore no change was observed in the expression level of Bcl2 pro-survival family members, while GA101 induced the pro-apoptotic proteins such as Bax and Bak and caused cleavage of the active form of caspase 9 and 3 and the proteolytic cleavage of PARP, in 5 out of 9 patients studied. Altogether, these data show that GA101 induced-cell death in B-CLL cells, unlike what has been observed in cell lines, is mediated by a caspase-dependent mechanism involving the loss of ΔΨm and the generation of ROS. Ongoing studies aim to analyze the role, the conformational changes and the cellular redistribution of Bax and Bak in response to GA101 and the modifications of other apoptosis-related proteins in CLL cells. Disclosures: No relevant conflicts of interest to declare.