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Publications

Journal Article Clinical Trial, Phase I Multicenter Study Ppublish

PubMed: 40152791 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.

Clin Cancer Res 31(12):2358-2369

Authors: Oliver Bechter, Carmen Loquai, Stephane Champiat, Jean-Francois Baurain, Jean-Jacques Grob, Jochen Utikal, Sylvie Rottey, Alfonso Berrocal, Jessica C Hassel, Ana Arance, Miguel F Sanmamed, Marye Boers-Sonderen, Brian Gastman, Christoffer Gebhardt, Brant Delafontaine, Ugur Sahin, Özlem Türeci, Patrick Brueck, Giovanni Abbadessa, Rahul Marpadga, Helen Lee, Yue Yang, Barbara Buday, Gianfranco Di Genova, Hong Wang, Binfeng Xia, Joon Sang Lee, Céleste Lebbe

Affiliations

  • Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
  • Department of Dermatology, University Medical Centre Mainz and Hospital Bremen-Ost, Gesundheit Nord gGmbH, Bremen, Germany.
  • Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Melanoma Clinic at King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium.
  • APHM Timone France, Aix-Marseille University, Marseille, France.
  • German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany.
  • Drug Research Unit Ghent, Ghent University Hospital, Ghent, Belgium.
  • Hospital Universitario General de Valencia, Valencia, Spain.
  • Department of Dermatology and National Center for Tumor Diseases (NCT), Medical Faculty Heidelberg, Heidelberg University, NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
  • Hospital Clínic de Barcelona and IDIBAPS, Barcelona, Spain.
  • Department of Medical Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
  • Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio.
  • Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
  • BioNTech SE, Mainz, Germany.
  • Sanofi, Cambridge, Massachusetts.
  • Sanofi, Budapest, Hungary.
  • AP-HP Dermato-oncology and CIC, Cancer Institute AP-HP, Nord Paris cité, INSERM U976, Saint Louis Hospital, Université Paris Cite, Paris, France.

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.

MeSH

Cytokines, Neoplasms, Rna, Messenger, Therapeutics