A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors
Open accessAbstract
Purpose LY3022859 is an anti-TGFβRII IgG 1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK).Methods LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W.Results Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t 1/2 (4.37-7.80 h) and rapid clearance (CL ss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration.Conclusions The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines).Trial registration clinicaltrials.gov Identifier: NCT01646203.
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Soluble, high-affinity ligand traps prevent TGF-β binding to its receptors.
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- Authors
- Tolcher, A. W., Berlin, J. D., Cosaert, J., Kauh, J., Chan, E., Piha-Paul, S. A., Amaya, A., Tang, S., Driscoll, K., Kimbung, R., Kambhampati, S. R. P., Gueorguieva, I., & Hong, D. S.
- Affiliations
- South Texas Accelerated Research Therapeutics (US)
- Vanderbilt-Ingram Cancer Center (US)
- Merck KGaA, Darmstadt (Germany) (DE)
- Eli Lilly (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Tolcher, Anthony W.
- ORCID
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 2017-03-09
- Volume
- 79
- Issue
- 4
- Pages
- 673-680
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- PMC
- PMC5893148
- OpenAlex
- W2593598026
- Cited by
- 105
- References
- 19
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 17 · 2023: 11 · 2022: 18 · 2021: 16 · 2020: 11 · 2019: 5 · 2018: 6 · 2017: 1
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- TGF-beta inhibition, advanced solid tumors, dose-limiting toxicity, maximum tolerated dose, pharmacokinetics, cytokine release syndrome, infusion reactions, dose escalation
- MeSH terms
- Adult, Aged, Antibodies, Monoclonal, Antineoplastic Agents, Dose-Response Relationship, Drug, Female, Half-Life, Humans, Infusions, Intravenous, Male, Middle Aged, Neoplasms, Cohort Studies, Cytokines, Treatment Outcome, Receptors, Transforming Growth Factor beta, Maximum Tolerated Dose, Young Adult
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