A Dose Escalation Study of LNA-i-Mir-221 for Cancer Treatment

Summary

The LNA-i-miR-221 Phase I trial has been designed as a monocentric open label dose escalation study which received written approval by the Competent Authority and independent Ethics Committee (IEC). LNA-i-miR-221 will be investigated for safety and tolerability in patients, men and women age ≥18 yrs, affected by Refractory-MM and advanced solid tumors.

Timeline

Start

2019-01-14

Primary completion

2021-12-29

Completion

2021-12-29

Publications

• Background Di Martino MT, Arbitrio M, Caracciolo D, Scionti F, Tagliaferri P, Tassone P. Dose-Finding Study and Pharmacokinetics Profile of the Novel 13-Mer Antisense miR-221 Inhibitor in Sprague-Dawley Rats. Mol Ther Nucleic Acids. 2020 Jun 5;20:73-85. doi: 10.1016/j.omtn.2020.01.036. Epub 2020 Feb 8.
• Background Di Martino MT, Arbitrio M, Fonsi M, Erratico CA, Scionti F, Caracciolo D, Tagliaferri P, Tassone P. Allometric Scaling Approaches for Predicting Human Pharmacokinetic of a Locked Nucleic Acid Oligonucleotide Targeting Cancer-Associated miR-221. Cancers (Basel). 2019 Dec 19;12(1):27. doi: 10.3390/cancers12010027.
• Background Gallo Cantafio ME, Nielsen BS, Mignogna C, Arbitrio M, Botta C, Frandsen NM, Rolfo C, Tagliaferri P, Tassone P, Di Martino MT. Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates. Mol Ther Nucleic Acids. 2016 Jun 21;5(6). doi: 10.1038/mtna.2016.36.
• Background Franzoni S, Morbioli L, Turtoro A, Solazzo L, Greco A, Arbitrio M, Tagliaferri P, Tassone P, Di Martino MT, Breda M. Development and validation of bioanalytical methods for LNA-i-miR-221 quantification in human plasma and urine by LC-MS/MS. J Pharm Biomed Anal. 2020 Sep 5;188:113451. doi: 10.1016/j.jpba.2020.113451. Epub 2020 Jun 29.
• Background Gulla A, Di Martino MT, Gallo Cantafio ME, Morelli E, Amodio N, Botta C, Pitari MR, Lio SG, Britti D, Stamato MA, Hideshima T, Munshi NC, Anderson KC, Tagliaferri P, Tassone P. A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res. 2016 Mar 1;22(5):1222-33. doi: 10.1158/1078-0432.CCR-15-0489. Epub 2015 Nov 2.
• Background Di Martino MT, Gulla A, Gallo Cantafio ME, Altomare E, Amodio N, Leone E, Morelli E, Lio SG, Caracciolo D, Rossi M, Frandsen NM, Tagliaferri P, Tassone P. In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. PLoS One. 2014 Feb 21;9(2):e89659. doi: 10.1371/journal.pone.0089659. eCollection 2014.
• Background Franzoni S, Vezzelli A, Turtoro A, Solazzo L, Greco A, Tassone P, Di Martino MT, Breda M. Development and validation of a bioanalytical method for quantification of LNA-i-miR-221, a 13-mer oligonucleotide, in rat plasma using LC-MS/MS. J Pharm Biomed Anal. 2018 Feb 20;150:300-307. doi: 10.1016/j.jpba.2017.12.027. Epub 2017 Dec 15.
• Background Di Martino MT, Gulla A, Cantafio ME, Lionetti M, Leone E, Amodio N, Guzzi PH, Foresta U, Conforti F, Cannataro M, Neri A, Giordano A, Tagliaferri P, Tassone P. In vitro and in vivo anti-tumor activity of miR-221/222 inhibitors in multiple myeloma. Oncotarget. 2013 Feb;4(2):242-55. doi: 10.18632/oncotarget.820.
• Background Di Martino MT, Rossi M, Caracciolo D, Gulla A, Tagliaferri P, Tassone P. Mir-221/222 are promising targets for innovative anticancer therapy. Expert Opin Ther Targets. 2016 Sep;20(9):1099-108. doi: 10.1517/14728222.2016.1164693. Epub 2016 Mar 21.
• Background Santolla MF, Lappano R, Cirillo F, Rigiracciolo DC, Sebastiani A, Abonante S, Tassone P, Tagliaferri P, Di Martino MT, Maggiolini M, Vivacqua A. miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling. J Exp Clin Cancer Res. 2018 May 2;37(1):94. doi: 10.1186/s13046-018-0767-6.
• Background Calura E, Bisognin A, Manzoni M, Todoerti K, Taiana E, Sales G, Morgan GJ, Tonon G, Amodio N, Tassone P, Neri A, Agnelli L, Romualdi C, Bortoluzzi S. Disentangling the microRNA regulatory milieu in multiple myeloma: integrative genomics analysis outlines mixed miRNA-TF circuits and pathway-derived networks modulated in t(4;14) patients. Oncotarget. 2016 Jan 19;7(3):2367-78. doi: 10.18632/oncotarget.6151.
• Tassone P, Di Martino MT, Arbitrio M, Fiorillo L, Staropoli N, Ciliberto D, Cordua A, Scionti F, Bertucci B, Salvino A, Lopreiato M, Thunarf F, Cuomo O, Zito MC, De Fina MR, Brescia A, Gualtieri S, Riillo C, Manti F, Caracciolo D, Barbieri V, Di Paola ED, Di Francesco AE, Tagliaferri P. 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. J Hematol Oncol. 2023 Jun 26;16(1):68. doi: 10.1186/s13045-023-01468-8.

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