IKKb-matured, RNA-loaded Dendritic Cells for Metastasised Uveal Melanoma

Phase I Vaccination Trial in Metastatic Uveal Melanoma Using IKKb-matured Dendritic Cells Loaded With Autologous Tumor-RNA + RNA Coding for Defined Antigens and Driver Mutations

A Phase I vaccination trial in patients suffering from recently diagnosed metastatic uveal melanoma not cureable with local therapy and needing systemic therapy. IKKb-matured Dendritic Cells loaded with autologous tumor-RNA + RNA coding for defined antigens and driver mutations will be added to a standard therapy chosen by the tumor board (either checkpoint blockade or chemotherapy).

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma, Uveal Metastatic
• Intervention / Treatment: Biological: Vaccination with IKKb matured Dendritic Cells

Detailed Description

Intravenous infusion of 7.5 to 30 mio DCIKKb at 9 vaccination time points (week 1, 3, 7, 13, 19, 25, 31, 37 and 42) and in intervals of 2, 4, and 6 intervals of 6 weeks) is scheduled; the first 4 patients will receive reduced doses for the first 4 vaccinations, namely 7.5 mio (1st and 2nd vaccination) and 15 mio (3rd and 4th vaccination) DC followed by the full dose of 30 mio for subsequent vaccinations. Patients number 5 to 8 will receive initially reduced doses of 15 mio (1st and 2nd vaccination) DC for the first 2 vaccinations, and the full dose of 30 mio for subsequent vaccinations. Patients number 8 to 12 will receive the full dose of 30 mio cells from vaccination 1 onwards provided that no major side effects occurred. Patients will be vaccinated in a staggered approach by selectively decelerating release of the vaccine.

DCIKKb = autologous, monocyte-derived DC that are matured with the standard cocktail (TNF-alpha, IL-1 beta, IL-6 and PGE2) and IKKb-RNA loaded by electroporation with 1) autologous PCR-amplified total tumor mRNA, 2) RNA coding for defined tumor associated antigens (TAA) namely gp100, tyrosinase, PRAME, MAGE-A3, IDO) and 3) RNA coding for driver mutations (GNAQ/GNA11Q209 or R183, or the less frequently occurring SF3B1R625, CYSLTR2L129Q or PLCB4D630) by electroporation; RNAs for selected TAAs are in stock and will be transfected into the DCs only if expressed in the individual tumor of a patient (shown by RNA sequencing of the tumor); RNAs for selected driver mutations are in stock and will be loaded into the DCs only if the respective mutation is found (proven by exome and RNA sequencing) in the individual tumor.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • University Hospital Erlangen Dept. of Dermatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed unresectable stage IV metastatic uveal melanoma as per AJCC staging system 2014, 7th edition (updated 2018) not curable with local therapy modalities
• WHO performance status of 0, 1 or 2
• age from 18 and ≤ 75 years
• negative pregnancy test
• signed informed consent

Exclusion Criteria:

• Major serious illness
• evidence for HIV-1, HIV-2, HTLV-1, HBV or HCV infection
• active autoimmune disease requiring immunosuppressive therapy
• splenectomy or radiation therapy of the spleen
• organ allografts
• pregnancy
• lactation
• psychiatric disorders
• severe organic brain syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DC IKKb; Vaccination with IKKb matured RNA loaded Dendritic Cells	Biological: Vaccination with IKKb matured Dendritic Cells; IKKb matured autologous monocyte derived dendritic cells loaded with RNAs; intravenous Infusion with a dose escalation starting with 7.5 mio Dendritic Cells for the first vaccination up to 30 mio cells per vaccination; Other Names: Dendritic Cell vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of DCIKKb	Assesment of side effects using the Common Toxicity Criteria (CTC v4.0)	1 year
Tolerability of DCIKKb	Assesment of Quality of life using Quality of life EORTC QLQ-C30, Version 2	1 year
Dose-limiting toxicities (DLTs) of DCIKKb	Assesment of side effects using the Common Toxicity Criteria (CTC v4.0)	1 year
Maximum tolerated dose (MTD) of DCIKKb	Assesment of side effects using the Common Toxicity Criteria (CTC v4.0)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prolongation of median overall survival	Assesment of survival	2 years
Prolongation of overall survival (OS) after 1 and 2 years	Assesment of survival	2 years
Induction of antigen specific CD8+ T cells and / or CD4+ T cells against TAA and mutated drivers	Assesment of immune responses	2 years

Collaborators and Investigators

• Sponsor: Hasumi International Research Foundation
• Investigators: Principal Investigator: Beatrice Schuler-Thurner, MD, University Hospital Erlangen Germany

Publications and helpful links

General Publications

• Pfeiffer IA, Hoyer S, Gerer KF, Voll RE, Knippertz I, Guckel E, Schuler G, Schaft N, Dorrie J. Triggering of NF-kappaB in cytokine-matured human DCs generates superior DCs for T-cell priming in cancer immunotherapy. Eur J Immunol. 2014 Nov;44(11):3413-28. doi: 10.1002/eji.201344417. Epub 2014 Sep 16.
• Gerer KF, Erdmann M, Hadrup SR, Lyngaa R, Martin LM, Voll RE, Schuler-Thurner B, Schuler G, Schaft N, Hoyer S, Dorrie J. Preclinical evaluation of NF-kappaB-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination. Ther Adv Med Oncol. 2017 Jul;9(7):451-464. doi: 10.1177/1758834017712630. Epub 2017 Jun 13.
• Schuler-Thurner B, Bartz-Schmidt KU, Bornfeld N, Cursiefen C, Fuisting B, Grisanti S, Heindl LM, Holbach L, Keseru M, Knorr H, Koch K, Kruse F, Meiller R, Metz C, Meyer-ter-Vehn T, Much M, Reinsberg M, Schliep S, Seitz B, Schuler G, Susskind D, Viestenz A, Wagenfeld L, Zeschnigk M. [Immunotherapy of uveal melanoma: vaccination against cancer. Multicenter adjuvant phase 3 vaccination study using dendritic cells laden with tumor RNA for large newly diagnosed uveal melanoma]. Ophthalmologe. 2015 Dec;112(12):1017-21. doi: 10.1007/s00347-015-0162-z. German.
• Koch EAT, Schaft N, Kummer M, Berking C, Schuler G, Hasumi K, Dorrie J, Schuler-Thurner B. A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKbeta-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma. Front Immunol. 2022 Feb 4;13:785231. doi: 10.3389/fimmu.2022.785231. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2020
• Primary Completion (Anticipated): January 30, 2023
• Study Completion (Anticipated): January 30, 2024

Study Registration Dates

• First Submitted: April 1, 2020
• First Submitted That Met QC Criteria: April 3, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2022
• Last Update Submitted That Met QC Criteria: March 16, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: local treatment not sufficient; systemic treatment indicated
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: DERMA-ER-DC 09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No