e-Article
Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study.
Document Type
Article
Author
Tassone, Pierfrancesco; Di Martino, Maria Teresa; Arbitrio, Mariamena; Fiorillo, Lucia; Staropoli, Nicoletta; Ciliberto, Domenico; Cordua, Alessia; Scionti, Francesca; Bertucci, Bernardo; Salvino, Angela; Lopreiato, Mariangela; Thunarf, Fredrik; Cuomo, Onofrio; Zito, Maria Cristina; De Fina, Maria Rosanna; Brescia, Amelia; Gualtieri, Simona; Riillo, Caterina; Manti, Francesco; Caracciolo, Daniele
Source
Subject
*NUCLEIC acids
*CANCER patients
*MICRORNA
*ANTINEOPLASTIC agents
*NON-coding RNA
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Language
ISSN
1756-8722
Abstract
Background: We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation. Methods: In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0–2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33). Results: Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3–4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose. Conclusions: The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898). [ABSTRACT FROM AUTHOR]