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Clinical Trial
. 2025 Jun 13;31(12):2358-2369.
doi: 10.1158/1078-0432.CCR-24-1983.

A Phase I, First-in-Human, Dose-Escalation, Expansion Trial of Cytokine-Encoding Synthetic mRNA Mixture Alone or with Cemiplimab in Advanced Solid Tumors

Oliver Bechter  1 , Carmen Loquai  2 , Stephane Champiat  3 , Jean-Francois Baurain  4 , Jean-Jacques Grob  5 , Jochen Utikal  6 , Sylvie Rottey  7 , Alfonso Berrocal  8 , Jessica C Hassel  9 , Ana Arance  10 , Miguel F Sanmamed  11 , Marye Boers-Sonderen  12 , Brian Gastman  13 , Christoffer Gebhardt  14 , Brant Delafontaine  7 , Ugur Sahin  15 , Özlem Türeci  15 , Patrick Brueck  15 , Giovanni Abbadessa  16 , Rahul Marpadga  16 , Helen Lee  16 , Yue Yang  16 , Barbara Buday  17 , Gianfranco Di Genova  16 , Hong Wang  16 , Binfeng Xia  16 , Joon Sang Lee  16 , Céleste Lebbe  18
Affiliations
Clinical Trial

A Phase I, First-in-Human, Dose-Escalation, Expansion Trial of Cytokine-Encoding Synthetic mRNA Mixture Alone or with Cemiplimab in Advanced Solid Tumors

Oliver Bechter et al. Clin Cancer Res. .

Abstract

Purpose: We investigated SAR441000 (mixture of four mRNAs encoding IL-12, single-chain IFN-α-2b, GM-CSF, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors.

Patients and methods: SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a predefined dose level with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine MTD or maximum administered dose, overall safety, tolerability, and objective response rate of SAR441000.

Results: We enrolled 77 patients previously treated with anticancer therapies [escalation monotherapy: N = 21; escalation combination: N = 15; and expansion combination (PD-1-refractory melanoma): N = 41]. The maximum administered dose at dose level 8 was 4,000 µg. The most common grade ≥3 treatment-related adverse events was fatigue in the escalation phase (monotherapy: 28.6% and combination therapy: 66.7%) and injection-site pain (31.7%) in the expansion phase. In combination therapy, one patient in the escalation phase and two patients in the expansion phase achieved partial responses. At 4,000 μg (highest dose) across all cohorts, the maximum fold change in plasma cytokine concentration was the highest and lowest for IFN-α-2 (74.9-fold) and IL-15 (1.96-fold), respectively. Increased blood IFN-γ and inducible protein-10 levels were observed for most patients.

Conclusions: Intratumoral administration of SAR441000 in combination with cemiplimab was generally well tolerated with antitumor activity in the locoregional disease setting. Anecdotal evidence of pharmacodynamic immunomodulatory effect and distant noninjected lesion antitumor response was observed, without significant effects in patients with advanced solid tumors previously treated with anti-PD-1 therapies.

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Conflict of interest statement

C. Loquai reports personal fees from Bristol Myers Squibb, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, and BioNTech outside the submitted work. S. Champiat reports nonfinancial support and other support from Sanofi-Aventis during the conduct of the study, as well as personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Ose Immunotherapeutics, Roche, SOTIO, AccessTrial, Alderaan Biotechnology, Astellas, Avacta, BeiGene, BioNTech, Celanese, Domain Therapeutics, Eisai, Ellipses Pharma, Genmab, Immunicom, Inc., Janssen, Mariana Oncology, Merck KGaA, Mima Health, MSD, Nanobiotix, NetCancer, NextCure, Novartis, Oncovita, Pierre Fabre, Seagen, Servier, Takeda, TATUM Bioscience, Tollys, and UltraHuman8 and other support from AbbVie, Amgen, Boehringer Ingelheim, Bolt Biotherapeutics, Centessa Pharmaceuticals, Cytovation, Eisai, GlaxoSmithKline, ImCheck Therapeutics, Immunocore, Molecular Partners AG, MSD, Ose Immunotherapeutics, Pierre Fabre, Replimune, Roche, Sanofi-Aventis, Seagen, SOTIO A.S, and Transgene outside the submitted work. J.-J. Grob reports personal fees from Bristol Myers Squibb, Sanofi, MSD, and Novartis during the conduct of the study, as well as personal fees from Bristol Myers Squibb, Sanofi, MSD, and Novartis outside the submitted work. S. Rottey reports grants from MSD and Ipsen, as well as other support from Bristol Myers Squibb and Ipsen outside the submitted work. A. Berrocal reports grants and personal fees from Bristol Myers Squibb, MSD, Novartis, and Pierre Fabre and grants from Pfizer outside the submitted work. J.C. Hassel reports other support from Sanofi during the conduct of the study, as well as personal fees from Bristol Myers Squibb, Delcath, MSD, Novartis, Immunocore, Sanofi, and Sun Pharma and grants from Bristol Myers Squibb, Sanofi, and Sun Pharma outside the submitted work. A. Arance Fernandez reports other support from Almirall Hermal, BioNTech, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Roche outside the submitted work. M.F. Sanmamed reports grants from Roche and personal fees from MSD and Catalym outside the submitted work. B. Gastman reports holding a position in Iovance Biotherapeutics since this work’s completion and that it has no overlap with this work, as well as being on the advisory board for various companies that make anti–PD-1. C. Gebhardt reports personal fees from Almirall Hermal, Amgen, Beiersdorf, BioNTech, Bristol Myers Squibb, Immunocore, Janssen, MSD, Pierre Fabre, Roche, and Sun Pharma, grants and personal fees from Delcath, Novartis, Regeneron, and Sanofi, nonfinancial support from Sciomics, and personal fees and nonfinancial support from Sysmex outside the submitted work. B. Delafontaine reports other support from Sanofi during the conduct of the study, as well as nonfinancial support from Sanofi outside the submitted work. U. Sahin reports personal fees from BioNTech outside the submitted work, as well as a patent for WO2017059902A1 issued to BioNTech. Ö. Türeci reports personal fees from BioNTech during the conduct of the study; a patent for mRNA technology pending, issued, and licensed; and being cofounder and chief medical officer of BioNTech. P. Brueck reports other support from BioNTech outside the submitted work. G. Abbadessa reports employment with and share ownership at Sanofi. H. Lee reports other support from Sanofi during the conduct of the study, as well as other support from Sanofi outside the submitted work. Y. Yang reports personal fees from Sanofi during the conduct of the study, as well as personal fees from Sanofi outside the submitted work. J.S. Lee reports other support from Sanofi outside the submitted work. C. Lebbé reports personal fees from Bristol Myers Squibb, MSD, Pierre Fabre, and Regeneron outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
A, Study design schema. B, Patient disposition. CSCC, cutaneous squamous cell carcinoma; EWOC, escalation with overdose control; HNSCC, head and neck squamous cell carcinoma; MAD, maximum administered dose; N/n, number of patients; RD, recommended dose.
Figure 2.
Figure 2.
Patient disease status with confirmed BOR per RECIST 1.1 in expansion combination therapy (SAR441000 plus cemiplimab)*. *, Patients were allowed to continue treatment beyond RECIST 1.1–defined disease progression based on the investigator’s discretion.
Figure 3.
Figure 3.
A, Plasma exposure of mRNA-expressed (PK) and downstream (PDy) cytokines. B, Plasma concentration of downstream cytokines IFN-γ and IP-10 after intratumoral injection at multiple timepoints (C1D1, C1D8, and C3D1) in expansion combination cohort. If the value was less than the lower limit of quantification (LLoQ), it was imputed as LLoQ/2, and if the value was more than the upper limit of quantification (ULoQ), it was imputed as ULoQ. C, cycle; D, day; N, number of patients; n (%), number and percentage of patients with max FC ≥5; T0, 0 hour; T6, 6 hours.
Figure 4.
Figure 4.
PDy effects in the tumor of an iPR patient with melanoma from the combination escalation phase. A, Posttreatment increase in CD3+ and CD8+ T cells in both injected and noninjected lesions. B, Percentage of positive cells/total nucleated cells (tumor plus immune cells) of the exemplified patient. C, TCR repertoire analysis in peripheral blood of the same patient. C, cycle; CD, cluster of differentiation; D, day; SCR, screening.
See this image and copyright information in PMC

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