Offene Phase 1/2a Studie mit Erstanwendung am Menschen zur Bewertung der Sicherheit, Durchführbarkeit und Wirksamkeit wiederholter Dosen mit personalisierter VB10.NEO oder VB10.NEO und Bempegaldesleukin (NKTR-214)-Immuntherapie

Offene Phase 1/2a Studie mit Erstanwendung am Menschen zur Bewertung der Sicherheit, Durchführbarkeit und Wirksamkeit wiederholter Dosen mit personalisierter VB10.NEO oder VB10.NEO und Bempegaldesleukin (NKTR-214)-Immuntherapie bei Patienten mit lokal fortgeschrittenem oder metastasierendem Melanom, nicht-kleinzelligem Bronchialkarzinom (NSCLC), klarzelligem Nierenzellkarzinom, Urothelkarzinom oder Plattenzellkarzinom des Kopf-Hals-Bereiches, die unvollständig auf die derzeitige Standardtherapie mit Immun-Checkpoint-Blockade ansprechen.

This open-label first-in-human phase 1/2a study is designed to evaluate the safety, feasibility and efficacy of multiple dosing with individualised VB10.NEO or VB10.NEO and bempegaldesleukin (NKTR-214) immunotherapy in combination, in patients with locally advanced or metastatic solid tumours including melanoma, non-small cell lung cancer (NSCLC), clear-cell renal carcinoma (RCC), urothelial cancer or squamous cell carcinoma of the head and neck (SCCHN), who did not reach complete responses with current standard of care (checkpoint inhibitor [CPI]). The study will be conducted in 2 parts. Part A will evaluate the safety, feasibility, immunogenicity and efficacy of individualised VB10.NEO immunotherapy alone or in combination with NKTR-214. The expansion in part B will further explore efficacy and safety of individualised VB10.NEO immunotherapy in selected types of cancer. The use of the combination of VB10.NEO and NKTR-214 is not foreseen for the expansion in part B. Part A includes patients with either of the 5 indicated tumour entities to receive VB10.NEO (arms 1-5A), and patients with SCCHN to receive a combination of VB10.NEO and NKTR-214 (arm 5B). Approximately 50 patients in total will be enrolled in this part, with a maximum of 10 patients treated per study arm. The expansion part B will be opened after at least 12 patients have been enrolled and analysed in part A. Tumour entity-specific expansion cohorts can only be opened once the safety criteria (overarching) and immunogenicity criteria (per tumour entity) have been met and regulatory approval to proceed into part B has been obtained (interim analysis). This implies that at least 12 patients in total have completed week 10 (visit 8) of part A, the Independent Data Safety Monitoring Board (IDSMB) recommends continuation of the study (safety) and at least 2 patients out of at least 6 patients in 1 study arm have a neoantigen-specific immune response on at least 1 occasion after the first vaccination. Part B can be started with up to 3 tumour-specific expansion cohorts. For each cohort, a maximum of 17 patients can be enrolled. Once the ninth patient has reached week 26 (visit 12) (stage 1), a futility analysis takes place. The futility analysis will evaluate the tumour entity-specific clinically relevant response rate in accordance with Simon’s Optimal Two-Stage Design. If no (0) patients in this cohort show a response, further enrolment in the specific expansion cohort will be terminated. If there are 1 or more patients with a response in the specific cohort, additional patients will be accrued until the total number of 17 is reached in this cohort (stage 2). With up to 17 patients in each cohort, a maximum of 51 patients will be enrolled in part B of this study. To characterise potential changes in the neoepitope expression pattern and tissue-based immunological parameters before and after VB10.NEO or the combination of VB10.NEO and NKTR-214, patients will be asked to provide optional biopsies at different time points. The investigator will decide which tumour lesions are most suitable and whether biopsies need to be computerised tomography (CT)-guided to secure high-quality material. To minimize radiation burden to the patients, CT-guided biopsies are restricted to a maximum of 5 biopsies during this study. An up to 24-month follow-up period will follow the treatment period and patients will be followed until discontinuation for safety or any other reason, or death from any cause.