Clinical trial NCT04335890: IKKb-matured, RNA-loaded Dendritic Cells for Metastasised Uveal Melanoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Melanoma, Uveal Metastatic
Keywords: local treatment not sufficient
systemic treatment indicated
Lead sponsor: Hasumi International Research Foundation
Sponsor class: OTHER
First posted: 2020-04-07
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety of DCIKKb
timeFrame: 1 year
measure: Tolerability of DCIKKb
timeFrame: 1 year
measure: Dose-limiting toxicities (DLTs) of DCIKKb
timeFrame: 1 year
measure: Maximum tolerated dose (MTD) of DCIKKb
timeFrame: 1 year
Secondary outcomes:
measure: Prolongation of median overall survival
timeFrame: 2 years
measure: Prolongation of overall survival (OS) after 1 and 2 years
timeFrame: 2 years
measure: Induction of antigen specific CD8+ T cells and / or CD4+ T cells against TAA and mutated drivers
timeFrame: 2 years
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: University Hospital Erlangen Dept. of Dermatology
state: Bavaria
Study officials:
affiliation: University Hospital Erlangen, Germany
name: Beatrice Schuler-Thurner, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.