To Evaluate the Safety and Efficacy of ADP-TILIL7 in Patients With Locally Advanced or Metastatic Melanoma

Synopsis: Over the last decade treatment for malignant melanoma (MM) has seen remarkable progress particularly with checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). The combination of these inhibitors has elevated the 5-year overall survival (OS) from 5 % to 50 %. However, many patients still lack a durable response. Results from a Phase III trial, conducted in part at CCIT-DK, have illuminated the promising potential of adoptive cell therapy utilizing tumor infiltrating lymphocytes (TILs) in the treatment of malignant melnaoma. In this trial, 168 patients were randomly assigned to receive either standard anti-CTLA-4 treatment or TILs. The outcomes revealed a notably superior overall response rate (ORR) and a higher number of complete responses (CR) among those treated with TILs. In this phase I study the investigators intend to treat 10 subjects with locally advanced or metastatic MM. Included subjects undergo surgical removal of tumor tissue for TIL manufacturing. During TIL manufacture, the investigators will genetically modify the TILs, and enable them to produce Interleukin-7 (IL-7). This modification is anticipated to confer additional functionality to the TILs enhancing their proliferation and persistence. The lentiviral vector used to integrate the IL-7 gene to the TILs is manufactured and provided by the British/American biotechnological company, Adaptimmune. The genetically modified TILs are therefore called ADP-TILIL7. Lymphodepleting (LD) chemotherapy is administered 7 days prior to ADP-TILIL7 infusion. ADP-TILIL7 infusion is followed by high dose (HD) Interleukin (IL-2) for a maximum of 6 doses or until tolerance. Purpose: The primary objective of this study is to evaluate the tolerability and safety of treatment with ADP-TILIL7. The secondary objective is to assess the clinical effect of the treatment by use of the objective response rate (using RECIST 1.1). Overall survival (OS), progression-free survival (PFS), duration of response (DoR) and disease control rate (DCR) will be determined. In addition to this replication competent lentivirus (RCL) will be monitored. Exploratory objectives are to characterize the tumor and tumor microenvironment pre- and post infusion, ex by genomic profiling of tumor tissue to investigate the mutational landscape. Furthermore, the expression of tumor-associated immunerelated markers, including markers of phenotype and frequency of tumor infiltrating blood-derived cells. The investigators want to characterize subjects' peripheral blood which includes, but is not limited to, the phenotype and funcitionality of transduced TILs and non-transduced TILs, as well as the pharmacodynamic changes in whole blood and serum pre- and post infusion, which might include gene expression, TCR/B-cell receptor repertoire, cytokines and soluble markers. All this the investigators want to explore to understand factors that can influence response or resistance to ADP-TILIL7 therapy. Study design: This is a phase I, First-in-human, study. Ten (10) subjects with locally advanced or metastatic MM will be included and treated at the Department of Oncology, Herlev Hospital. Subjects can be referred from other oncology centers. Subjects will undergo a comprehensive screening process to confirm subjects' eligibility before enrollment. Included subjects will undergo surgical tumor removal for the subsequent manufacturing of TIL's. TheTIL manifacturing process is expected to take approximately 4-6 weeks. During TIL manufacture, a subset of the TILs will be transduced with genetic material encoding the production of IL-7. Lymphodepleting chemotherapy, Cyclophosphamide and Fludarabine phosphate, will be administered for 7 days prior to ADP-TILIL7 infusion. ADP-TILIL7 infusion is followed by high-dose IL-2 for a maximum of 6 doses or until tolerance. After the end of treatment, the subjects will be followed with clinical- and imaging controls for up to 15 years. The inclusion period is set to commence in early 2024, with the goal of enrolling all ten patients within a span of three years. The study's completion is defined as the moment when the last subject reaches and complete the 12 months follow-up visit. The study ends once all treated subjects complete 15 years of follow-up, passes away or withdraw from the study. The study will be monitored by the Good Clinical Practice (GCP)-unit of the Capital Region of Denmark. The Danish Medicines Agency, The GCP-unit, and Adaptimmune are allowed to audit this trial. Population: This study targets subjects aged 18 to 75, histologically confirmed with malignant melanoma who have experienced progression following at least one line of immune checkpoint inhibitor in the advanced or metastatic setting. Eligibility is contigent on meeting specific inclusion criteria, including acceptable performance status, kidney- and liver function, and the absence of major co-morbidities. Crucially, treatment will proceed only for the subjects with successful manufacturing of TILs. Previous clinical trials have demonstrated a success rate of TIL manufacturing from malignant melanoma exceeding 90%. Toxicity: The amount of toxicity caused by ADP-TILIL7 is not known. The systemic treatment with IL-7 infusion has been used in treatment of several malignancies and HIV and as an adjunct to allogeneic stem cell transplantation. In these studies, IL-7 has exhibited a generally well-tolerated safety profile. At CCIT-DK investigators boast substantial experience in treating subjects with TILs that have not been genetically modified. TIL therapy has generally been well-tolerated, with most adverse events expected to be associated with chemotherapy and high-dose IL-2 treatment. Dosing in the first three subjects will be staggered. Each subject will have safely completed a minimum observation period of 14 days from the ADP-TILIL7 infusion before lymphodepletion of the next subject commences. Toxicity assessment, including evaluation of treatment limiting toxicity (TLTs), will be performed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The TLT observation period will be during the first 21 days following the ADP-TILIL7 infusion. Evaluation of clinical response: Subjects enrolled in the study will undergo comprehensive clinical evaluations during treatment and hospitalization as well as 6, 12 and 24 weeks post-treatment with ADP-TILIL7. Thereafter clinical evaluation will take place every 3 months the first two years (year 1-2), every 6 months year 3-5, followed by evaluations every 12 months year 6-15. Diagnostic imaging, preferably PET/CT scans, will be conducted before the treatment initiation, and in conjunction with the clinical evaluations, commencing 6 weeks post-TIL treatment. Immunological response evaluation: Blood samples for research purposes will be systematically collected at Baseline, pre- and post-TIL infusion (day 0), during IL-2 (up to a maximum 3 days), before discharge and at week 6, week 12 and the final collection 12 months post-ADP-TILIL7/progressive disease/withdrawal whichever occurs first. Blood samples for research purposes will be selectively collected, contigent upon feasibility as assessed by the investigator. Biopsies from metastatic tumor tissue will be systematically obtined at key time points: before treatment initiation, 6 weeks post-treatment and, if applicable and deemed safe, in case of disease progression.