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Crizanlizumab is an anti–P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 “pain during infusion”), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was −0.88 (−14.7 to 13.3) and −0.93 (−2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months’ treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.

Background: SCD is an inherited blood disorder characterized by hemolytic anemia, endothelial damage and acutely painful VOCs that cause chronic and potentially life-threatening complications. P-selectin is an adhesion protein that plays a key role in the multicellular interactions leading to a VOC. The Phase II SUSTAIN study showed that crizanlizumab (SelG1), a humanized monoclonal anti-P-selectin antibody, reduced the annualized rate of VOCs leading to a healthcare visit by 45.3% vs placebo (P=0.01) in SCD patients (pts) [Ataga K et al. N Engl J Med 2017]. Aims: To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD; ex vivo P-selectin inhibition) of crizanlizumab (SEG101), as well as safety and efficacy in SCD pts with a history of VOCs. Methods: SOLACE-adults is a Phase II, multicenter, open-label PK-PD study that enrolled SCD pts aged 16-70 years who had experienced ≥1 VOC in the 12 months prior to study start (NCT03264989). Pts received crizanlizumab by intravenous infusion over 30 minutes at 5.0 mg/kg or 7.5 mg/kg on: Week 1, Day 1 (Wk1D1); Wk3D1; and then on D1 of every 4-wk cycle. PK and PD assessments were performed in all pts pre- and post-dose on days 1, 2, 4, 8, and 15 of the first dose (Wk1D1) and then on days 1, 2, 4, 8, 15, 22 and 29 of the fifth dose (Wk15D1). Adverse events (AEs) were evaluated based on MedDRA v22.1 and AE severity based on CTCAE v5.0. Pts were continuously monitored for VOCs, with the relevant medical and treatment information collected in case of occurrence. Results: A total of 57 pts were enrolled: 45 received crizanlizumab 5.0 mg/kg (female, n=25 [56%]; mean [SD] age, 32 [13] years) for a median of 65 (range, 6-90) wks and 12 received 7.5 mg/kg (female, n=6 [50%]; mean [SD] age, 27 [12] years) for a median of 43 (range, 9-49) wks. In the 5.0 and 7.5 mg/kg arms, respectively, 6 (13%) and 2 (17%) pts discontinued treatment, primarily because of patient decision (n=4; 9%) in the 5.0 mg/kg arm and because of death and AE (both n=1; 8%) in the 7.5 mg/kg arm. The most common AEs were headache (5.0 mg/kg, n=11 [24%]; 7.5 mg/kg, n=3 [25%]) and pyrexia (5.0 mg/kg, n=9 [20%]; 7.5 mg/kg, n=2 [17%]). Grade ≥3 AEs occurred in 18 (40%) pts in the 5.0 mg/kg arm and in 2 pts (17%) in the 7.5 mg/kg arm. Serious AEs were reported in 11 pts (24%) in the 5.0 mg/kg arm and in 1 pt (8%) in the 7.5 mg/kg arm; none were deemed drug-related. One pt in each of the 5.0 (2%) and 7.5 mg/kg (8%) arms discontinued treatment because of AEs. Infections, infusion-related reactions (IRR), bleeding events, and immunogenicity were AEs of special interest. Infections were reported in 20 (44%) and 3 (25%) pts in the 5.0 and 7.5 mg/kg arms, respectively; none were considered drug-related. Signs and symptoms indicative of IRRs were reported in 15 (33%) and 2 (17%) pts in the 5.0 and 7.5 mg/kg arms, respectively; none were grade 3/4 severity or led to treatment withdrawal. Bleeding events were rare, and none were deemed serious. No pts developed immunogenicity. For both doses, serum crizanlizumab concentrations increased to nearly maximum levels (Cmax) at the end of the 30-minute infusion, remaining steady for 6 hours post-infusion (Figure). For each dose, Cmax at wks 1 and 15 were similar (Table), indicating a lack of accumulation. The increase in exposure to crizanlizumab in the 5.0 and 7.5 mg/kg arms was almost dose-proportional. Ex vivo inhibition of P-selectin binding to its receptor was complete throughout the dosing interval for both crizanlizumab doses (Figure). Pre-dose PK and PD were consistent and stable throughout the study. The median (range) annualized rate of VOCs leading to a healthcare visit in the 5.0 mg/kg arm was 4.0 (1.0-25.0) at baseline and 2.8 (0.0-21.7) on treatment (median [range] absolute change from baseline, -0.97 [-14.4 to 17.7]). In the 7.5 mg/kg arm, the corresponding rates were 2.0 (1.0-9.0) and 1.8 (0.0-7.0) [median (range) absolute change from baseline, -0.80 (-3.7 to 1.0)]. Seven pts (16%) in the 5.0 mg/kg arm and 4 pts (33%) in the 7.5 mg/kg arm were VOC-free during the treatment period. Conclusions: No new safety signals were identified in this SCD population treated with crizanlizumab, with no apparent differences between the 5.0 and 7.5 mg/kg doses in the frequency and severity of AEs. For both doses, serum crizanlizumab concentrations rose to a near maximum level shortly after infusion. Consistent with results from the SUSTAIN trial, crizanlizumab reduced from baseline the annualized rate of VOCs leading to a healthcare visit. Disclosures Smith-Whitley: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees. Brown:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Imara, Inc: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Forma Therapeutics: Research Funding. Shah:Alexion: Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy. Tanaka:Novartis Institute for Biomedical Research: Current Employment, Current equity holder in publicly-traded company. Sanchez-Olle:NOVARTIS PHARMA AG: Current Employment. Albers:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Kanter:Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy; Medscape: Honoraria.

TPS9589 Background: The treatment of melanoma has improved markedly with the emergence of new immune therapies, and both anti-PD-1 monotherapy and the combination of the anti-PD-1 antibody nivolumab and anti-CTLA-4 therapy ipilimumab are now considered standard-of-care in the unresectable or metastatic (advanced) melanoma setting. However, many patients have primary or acquired resistance to these therapies, thereby underpinning the need for more effective approaches. IO102-IO103 is a potentially first-in-class, dual-antigen, immune-modulatory therapy targeting the key cancer immune resistance pathways mediated by IDO and PD-L1. The ability of IO102 and IO103 to respectively activate the specific T cells that recognize these checkpoint molecules and directly modulate immune regulation has previously been demonstrated both preclinically and in human clinical trials. A synergistic anti-tumor response upon treatment against both IDO and PD-L1 has also previously been demonstrated in a preclinical model where IDO and PD-L1 were expressed by different cells in the tumor microenvironment. Due to the distinctive mechanisms of action of IO102-IO103 and anti-PD-1 antibodies, there may be a further synergistic effect when treatment is combined. A previous Phase 1/2 trial investigating the use of IO102-IO103 plus nivolumab in patients with anti-PD-1-naïve metastatic melanoma has demonstrated promising anti-tumor activity with an overall response rate (ORR) of 80%, median progression-free survival (PFS) of 26 months and a manageable safety profile (NCT03047928; Kjeldsen et al, Nat Med 2021). Methods: This is a Phase 3, multicenter, open-label, randomized, 2-arm trial investigating the efficacy and safety of IO102-IO103 plus pembrolizumab versus pembrolizumab alone (EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254). Inclusion criteria include: adult patients with untreated, unresectable (Stage III), or metastatic (Stage IV) melanoma; > 6 months since last dose of (neo)adjuvant treatment with targeted or immune therapy (in those previously treated); and ≥1 measurable lesion by RECIST v1.1. Primary endpoint is PFS by blinded independent central review. Secondary endpoints include ORR, durable response rate, complete response rate, duration of response, time to response, disease control rate, overall survival, and safety/tolerability. Target enrollment is 300 patients at > 100 sites in 20 countries. Patients are randomized 1:1 to receive either pembrolizumab 200 mg intravenously (IV) every 3 weeks up to 2 years or pembrolizumab 200 mg IV every 3 weeks up to 2 years with dual-antigen IO103-IO102 85-85 µg and Montanide adjuvant subcutaneously on Day 1 and 8 of cycle 1 and 2 and on Day 1 of each cycle thereafter. Enrolment for the study is ongoing. Clinical trial information: EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254.

Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from 10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: 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; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

TPS3131Background: Birinapant is a bivalent SMAC mimetic with activity against multiple members of the inhibitor of apoptosis protein (IAP) family including cIAP1 and has demonstrated tolerability ...