EUROCODES: BACKGROUND & APPLICATIONS: Elaboration of maps for climatic and seismic actions for structural design with the Eurocodes

Activities for promotion of policies for sustainable construction in the Balkan region Guidance for countries adopting the Eurocodes State-of-the-art material to elaborate maps for seismic and climatic actions for structural design Experience of the non-EU Balkan countries on elaboration of these mapsJRC.E.4 - Safety and Security of Building

Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented

Abstract CT244: A Phase 1/2 study evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

Abstract Background While Bruton's Tyrosine Kinase (BTK) inhibitors approved for CLL/SLL (ibrutinib, acalabrutinib) can mediate durable responses in some patients, relapses are seen primarily as a result of acquired mutations in BTK enzyme and/or phospholipase C gamma 2. Adoptive cell transfer of IOV-2001, a polyclonal and nongenetically modified autologous T-cell infusion product, is being investigated as a therapy option for CLL/SLL patients who are progressing or have progressed on ibrutinib or acalabrutinib. Methods IOV-CLL-01 (NCT04155710) is a First in Patient, Phase 1/2, open-label, multi-cohort, dose-finding study designed to evaluate the safety and efficacy of IOV-2001, in patients with CLL/SLL (Table 1). 50 ml of blood obtained from patients is used to generate Peripheral Blood Lymphocytes (PBLs). PBLs are result of expansion of T-cells in a 9-day manufacturing process at a centralized GMP facility. The product is then cryopreserved and sent back to the treatment center for infusion to the patient. IOV-2001 is a one-time administration cell therapy which involves a preparative regimen of lymphodepleting chemotherapy consisting of cyclophosphamide IV 500 mg/m2 and fludarabine IV 30 mg/m2 for 3 days followed by 2 days of rest. IOV-2001 is administered as a single infusion, followed by up to 6 doses of IL-2. Key eligibility includes diagnosed CLL/SLL patients (18 to 70 years of age) with radiographically measurable disease; and ECOG PS of 0-1, along with specifics per Table 1. The primary objective for Phase 1 is to determine the RP2D, and for Phase 2 is to evaluate the Investigator-assessed efficacy of IOV-2001 at RP2D followed by IL-2. Table 1.Overview of IOV-CLL-2001PhaseStudy PopulationCohort Test Product, Dose Regimen, and Route of AdministrationPhase 1CLL / SLL that has relapsed or is relapsing on ibrutinib or acalabrutinibDose-finding with IOV-2001 dose de-escalation guided by DLT observations:-Cohort 1a: IOV-2001, followed by ≤6 doses of SC low-dose IL-2 (9 MIU) every 8-12 hours-Cohort 1b: IOV-2001, followed by ≤6 doses of IV high-dose (600,000 IU/kg) every 8-12 hoursPhase 2IOV-2001 RP2D dose, followed by ≤6 doses of the selected IL-2 dose:-Cohort 2: with del(17p) and/or TP53 mutation-Cohort 3: without del(17p) and/or TP53 mutation Citation Format: Meixiao Long, Jennifer Woyach, Javier Pinilla-Ibarz, Deborah M. Stephens, Alex Cacovean, Rana Fiaz, Zelanna Goldberg, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, John C. Byrd. A Phase 1/2 study evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT244.</jats:p

Abstract CT169: A phase II, multicenter study to assess the efficacy and safety of autologous tumor infiltrating lymphocytes (LN-144) for treatment of patients with metastatic melanoma

Abstract Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) has been employed for years in hundreds of patients with metastatic melanoma and other solid tumors, demonstrating durable and complete responses, even in heavily pretreated patients. Despite the approvals of checkpoint-directed therapies, metastatic melanoma remains an unmet need due to progression subsequent to administration of checkpoints, as well as due to intolerance. The C-144-01 study will enroll metastatic melanoma patients who progressed on anti-PD-1 and BRAF inhibitors if BRAF mutation positive. This phase II trial utilizes a central GMP facility for the manufacture of LN-144 in either a non-cryopreserved generation-1 (Gen-1), or cryopreserved generation-2 (Gen-2) investigational TIL infusion product. The Gen-2 manufacturing process reduces the time required for manufacture of TIL product to 22 days. The process development of cryopreservation for the final LN-144 infusion product incorporates dramatic improvements in the flexibility of scheduling, distribution and delivery required for commercial use. C-144-01 (NCT02360579) is a global phase 2 multicenter, open-label study evaluating the efficacy and safety of autologous TIL (LN-144) therapy for the treatment of patients with advanced metastatic melanoma. The study consists of three treatment cohorts: 30 patients in Cohort 1 will receive a single dose of Gen-1, non-cryopreserved LN-144; 30 patients in Cohort 2 will receive a single dose of Gen-2, cryopreserved LN-144; and up to 10 eligible patients from either Cohort 1 or Cohort 2 may enter a third cohort (Cohort 3) for re-treatment with a second dose of LN-144. The investigational LN-144 TIL infusion product for all cohorts is prepared at the central GMP facility using lymphocytes that are extracted from a surgically-resected sample of patient tumor. LN-144 infusion is preceded by a non-myeloablative lymphodepletion regimen of cyclophosphamide and fludarabine and followed by IL-2 for up to 6 doses. Patients ≥ 18 years of age must have progressive, unresectable metastatic melanoma (Stage IIIc or Stage IV) following ≥1 line of prior systemic therapy including immune checkpoint inhibitors and BRAF-targeted therapy (if BRAF mutation-positive). A minimum of 2 tumor lesions are required: 1 for resection and TIL manufacture and 1 for assessment of response by RECIST 1.1 criteria. Other major eligibility criteria include: adequate bone marrow, cardiac, liver, pulmonary, and renal function; ECOG PS of 0 or 1. Efficacy is being assessed as a function of ORR, CR rate, DOR, DCR, and PFS per RECIST 1.1 and OS. Assessment of safety data will be descriptive and based on the summarization of TEAEs, SAEs, AEs leading to discontinuation from treatment and the study, vital signs, physical examinations, and clinical laboratory tests. Citation Format: Amod Sarnaik, Brendan Curti, Diwakar Davar, Omid Hamid, Jose Lutzky, Melissa Wilson, Harriet Kluger, Jason Chesney, Kevin Kim, Giao Phan, Sajeve Thomas, Eric Whitman, Bente Larsen, Sam Suzuki, Nancy Samberg, Igor Gorbatchevsky, Maria Fardis, John M. Kirkwood. A phase II, multicenter study to assess the efficacy and safety of autologous tumor infiltrating lymphocytes (LN-144) for treatment of patients with metastatic melanoma [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 CT169

Abstract CT008: Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up

Abstract Background Beneficial treatment options are limited for advanced melanoma patients who progress after or do not respond to immune checkpoint inhibitors (ICI) and targeted therapies. Lifileucel is an adoptive cell therapy using tumor-infiltrating lymphocytes (TIL), that has shown efficacy in patients with advanced melanoma who have progressed on/after anti-PD-1therapy (Sarnaik et al., ASCO 2020). We present the 28-month (mos) follow-up data here. Methods C-144-01 (NCT02360579) is a global Phase 2 open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on anti-PD-1 therapy and BRAF/MEK inhibitors, if BRAF V600 mutant. We report on Cohort 2 (N = 66) patients who have received lifileucel. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved and shipped back to sites in a 22-day process. Therapy consisted of one week of nonmyeloablative lymphodepletion using cyclophosphamide (60 mg/kg on Day -7, -6) and fludarabine (25 mg/m2 on Day -5 through -1), a single infusion of lifileucel, and up to six doses of IL-2 doses (600,000 IU/kg/dose). Objective response rate (ORR) was based on RECIST v1.1 as assessed by investigators. Data cutoff was December 14, 2020. Results Baseline characteristics: 3.3 mean prior therapies (100% anti-PD-1; 80% anti-CTLA-4; 23% BRAF/MEK inhibitor), high baseline tumor burden (106 mm mean target lesion sum of diameters), 42% liver/brain lesions, 40.9% had LDH &amp;gt; ULN. Median time from last therapy to tumor harvest was 2.2 mos and 58% of the tumors resected were extra-nodal or non-skin/subcutaneous. ORR by Investigator was 36.4% (3 CR, 21 PR). One patient converted from a PR to CR at 24 mo after lifileucel therapy. Median time to first response was 1.4 mos (range: 1.3-5.6 mos). Median duration of response (mDOR) was still not reached at median follow-up of 28 mos (DOR range: 2.2-35.2 mos). No new safety risks have been identified for lifileucel during the long-term follow-up. Exploratory analyses of product-specific characteristics, including levels of phenotypic markers of T-cell lineage, memory subset, youth, activation/exhaustion, or trafficking did not demonstrate association with response. Conclusions Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 28 mo of median study follow up in heavily pretreated advanced melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAF V600 mutant. Citation Format: Jason Alan Chesney, James M. Larkin, John M. Kirkwood, Jeffrey S. Weber, Nikhil I. Khushalani, Karl Lewis, Theresa M. Medina, Harriet M. Kluger, Sajeve S. Thomas, Evidio Domingo-Musibay, Judit Oláh, Eric D. Whitman, Salvador Martin-Algarra, Philippa G. Corrie, Jose Lutzky, Omid Hamid, Wen Shi, Xiao Wu, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Amod A. Sarnaik. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT008.</jats:p

Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1

2518 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status (TPS < 5%) were among responders. Mean cells infused was 28 x10 9 . Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT02360579