Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced/Metastatic Solid Tumors or Lymphomas
| Autor: | Funda Meric-Bernstam, Randy F. Sweis, F. Stephen Hodi, Wells A. Messersmith, Robert H.I. Andtbacka, Matthew Ingham, Nancy Lewis, Xinhui Chen, Marc Pelletier, Xueying Chen, Jincheng Wu, Thomas W. Dubensky, Sarah M. McWhirter, Thomas Müller, Nitya Nair, Jason J. Luke |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Agonist Cancer Research medicine.medical_specialty Lymphoma Maximum Tolerated Dose medicine.drug_class Gastroenterology Proinflammatory cytokine Lesion Pharmacokinetics Neoplasms Internal medicine medicine Humans Adverse effect Merkel cell carcinoma business.industry Neoplasms Second Primary medicine.disease Sting Oncology Chills Immunotherapy medicine.symptom business |
| Zdroj: | Clinical Cancer Research. 28:677-688 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers. Patients and Methods: Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule. Results: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation. Conclusions: MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study; however, evidence of systemic immune activation was seen. |
| Databáze: | OpenAIRE |
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