This is a Phase I, FIH, open-label, multi-site, dose escalation trial with expansion cohorts to evaluate safety and preliminary efficacy of claudin 6 (CLDN6) chimeric antigen receptor T cells (CAR-T) with or without CLDN6 ribonucleic acid lipoplexes (RNA-LPX) in patients with CLDN6-positive relapsed or refractory advanced solid tumors.
CLDN6 CAR-T is used as a general term to refer to CLDN6 CAR-T cells from the manual and automated manufacturing processes. The trial consists of two parts. The trial began using a manual CLDN6 CAR-T production process. Part 1 is a CLDN6 CAR-T dose escalation in lymphodepleted patients until the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CLDN6 CAR-T are defined. Dose escalation with CLDN6 CAR-T cells from the automated manufacturing process follows an accelerated titration design, as opposed to the classical 3+3 trial design used for the dose escalation with CLDN6 CAR-T manufactured with the manual process. In addition, an optional de-escalation dose level may be explored to further evaluate clinical safety and efficacy of CLDN6 CAR-T manufactured with the automated process. Part 2 is a vaccine-modulated dose escalation using a bifurcated design until the MTD and/or RP2D of CLDN6 CAR-T + CLDN6 RNA-LPX are defined. The trial started with a CLDN6 encoding uridine containing RNA formulated in lipoplexes (CLDN6 uRNA-LPX). In order to optimize CAR-T cell persistence in patients, an alternative RNA-LPX, CLDN6 modRNA-LPX, will be tested once the RP2D dose for CLDN6 CAR-T ± CLDN6 RNA-LPX is identified. The planned trial duration per patient in the main trial is 25 months. Patients exposed to genetically engineered therapies may be at risk of delayed adverse events. Therefore, after patients complete or prematurely discontinue participation in the main trial, they will be asked to participate in a long-term follow-up (LTFU) trial to assess long-term safety and efficacy for up to 15 years. Patients will be asked to re-consent to participate in this LTFU period.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
214
administered as an intravenous (i.v.) infusion.
administered as an i.v. injection at protocol-specified intervals.
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
COMPLETEDCharité - Universitätsmedizin Berlin - Campus Benjamin Franklin
Berlin, Germany
RECRUITINGUniversitätsklinikum Köln AÖR-Centrum für Integrierte Onkologie (CIO)-Studienzentrum der Klinik I für Innere Medizin (CTU Cologne)
Cologne, Germany
RECRUITINGUniversitätsklinikum Erlangen - Hämatologie & Intrinsische Onkologie - Medizinische Klinik 5
Erlangen, Germany
RECRUITINGUniversitätsklinikum Hamburg Eppendorf - II Medizinische Klinik und Poliklinik
Hamburg, Germany
RECRUITINGMedizinische Hochschule Hannover - Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
Hanover, Germany
RECRUITINGNationales Centrum für Tumorerkrankungen (NCT) Heidelberg
Heidelberg, Germany
RECRUITINGUniversitätsmedizin Mainz - III Medizinische Klinik und Poliklinik
Mainz, Germany
RECRUITINGUniversitätsklinikum Regensburg - Klinik und Poliklinik für Innere Medizin III
Regensburg, Germany
RECRUITINGHe Nederlands Kanker Instituut (The Netherlands Cancer Institute) - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL)
Amsterdam, Netherlands
RECRUITING...and 2 more locations
Occurrence of treatment-emergent adverse events (TEAEs) including ≥ Grade 3, serious, fatal TEAEs by relationship
Time frame: up to 25 months
Occurrence of dose reduction and discontinuation of investigational medicinal product (IMP) due to TEAEs
Time frame: up to 25 months
Occurrence of dose-limiting toxicity (DLT) during the DLT evaluation period
Time frame: Day 1 to day 28
Change from baseline in the levels and kinetics of soluble immune factors measured by cytokine multiplex assay
Systemic effects in patients will be assessed (e.g., tumor necrosis factor, interferon (IFN)-γ, interleukin (IL)-2, IL-10, soluble IL-2Rα, interferon-gamma-induced- protein (IP)-10, IL-12, IFN-α, IL-6, soluble IL-6R).
Time frame: Baseline up to 25 months
Objective response rate
Defined as the proportion of patients in whom a complete response (CR) or partial response (PR) (per response evaluation criteria in solid tumors version 1.1 \[RECIST v1.1\] or defined by tumor marker change from baseline when RECIST evaluation is not feasible) is observed as best overall response
Time frame: up to 25 months
Disease control rate
Defined as the proportion of patients in whom a CR or PR or stable disease (SD) per RECIST v1.1 or defined by tumor marker change from baseline when RECIST evaluation is not feasible (SD assessed at least 6 weeks after the first dose) is observed as best overall response
Time frame: up to 25 months
Duration of response
Defined as the time from first objective response (CR or PR per RECIST v1.1 or first response defined by tumor marker change from baseline when RECIST evaluation is not feasible) to first occurrence of objective progressive disease (PD) or death from any cause, whichever occurs first
Time frame: up to 25 months
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