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Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors
Open accessPublished version of a preprint
Abstract
Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ “trap.” Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.
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“Initial dose escalation studies of galunisertib or other TβRI kinase inhibitors mandated monitoring for cardiotoxicity due to heart valve dysplasia that was observed in rats and dogs receiving high doses of drug340,341.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [340]
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Metadata
- Authors
- Strauss, J., Heery, C. R., Schlom, J., Madan, R. A., Cao, L., Kang, Z., Lamping, E., Marté, J. L., Donahue, R. N., Grenga, I., Cordes, L., Christensen, O., Mahnke, L., Helwig, C., & Gulley, J. L.
- Affiliations
- National Institutes of Health (US)
- 7EMD Serono, Billerica, Massachusetts.
- Merck KGaA, Darmstadt (Germany) (DE)
- Corresponding author
- Gulley, James L.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2018-03-14
- Volume
- 24
- Issue
- 6
- Pages
- 1287-1295
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7985967
- OpenAlex
- W2781947653
- Cited by
- 406
- References
- 35
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 48 · 2023: 40 · 2022: 81 · 2021: 73 · 2020: 64 · 2019: 26 · 2018: 20
- FWCI
- 17.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HHSN261200800001C)
- National Cancer Institute (HHSN261200800001E), ZIABC010945)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- bifunctional fusion protein, PD-L1, TGF-β trap, TGF-β1, TGF-beta2, TGF-beta3, advanced solid tumors, maximum tolerated dose, safety, pharmacokinetics, immunogenicity, cervical cancer, pancreatic cancer, anal cancer, carcinoid tumor, dose escalation
- MeSH terms
- Antineoplastic Agents, Immunological, Adult, Aged, Combined Modality Therapy, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Neoplasms, Transforming Growth Factor beta, Treatment Outcome, Antibodies, Bispecific, Retreatment, Molecular Targeted Therapy, B7-H1 Antigen
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