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

NCT04811898 | Completed Phase 1 DMC

• 2 other identifiers: AOU-MD FIH-LNA-i-miR-2212017-002615-33
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Multiple Myeloma, Refractory; Hepatocarcinoma; Advanced Solid Tumor

Keywords

LNA-i-miR-221; Multiple Myeloma; Hepatocarcinoma; Advanced solid tumors; Phase I; Dose escalation; Safety; maximum tolerated dose (MTD); RP2D

Outcome Measures

Primary Outcomes (3)

• Safety measured by adverse events To assess the toxicity of LNA-i-miR-221

  To assess the safety and toxicity of LNA-i-miR-221

  two years

• The maximum tolerated dose (MTD) of LNA-i-miR-221

  The maximum tolerated dose (MTD) is the dose level below the dose level at which at least 2 out of 6 patients experience DLT.

  two years

• The recommended phase II dose of LNA-i-miR-221 (RP2D)

  recommended phase II dose of LNA-i-miR-221 (RP2D) using escalating doses for further evaluation

  two years

Secondary Outcomes (5)

• To assess the Cmax of ascending doses of LNA-i-miR-221

  During first 6 days of dosing

• To assess the Area under the plasma concentration versus time curve (AUC) of ascending doses of LNA-i-miR-221

  During first 6 days of dosing

• To assess the LNA-i-miR-221 clearance

  During first 6 days of dosing

• To assess LNA-i-miR-221 biological half-life

  During first 6 days of dosing

• To assess the efficacy of LNA-i-miR-221

  Tumor response will be assessed after 30 (+/-1) days from the start of treatment

Study Arms (1)

Experimental single arm

EXPERIMENTAL

Single group with 5 dose escalation for each cohort (0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg; 5 mg/kg)

Biological: LNA-i-miR-221

Interventions

LNA-i-miR-221 BIOLOGICAL

LNA-i-miR-221, IV daily infusion on days 1-4 followed by 24 days washout (1 cycle lasting 28 days)

Experimental single arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women age ≥18 yrs
• Diagnosis of symptomatic multiple myeloma with measurable disease, i.e. detectable monoclonal component (MC) in the serum and/or urine.
• Patients with evidence of refractory disease according to IMWG criteria, who are either not suitable for bone marrow transplantation procedures or have relapsed after bone marrow transplantation and have failed at least three prior lines of therapy (10) (i.e. patients with lack of response or patients whose disease progresses on or within 60 days after the completion of last treatment).
• Histologically diagnosed stromal or epithelial solid tumors (clinically diagnosed HCC according to AASLD/EASLD guidelines).
• Patients with inoperable tumor(s) and no applicable curative therapy, not amenable to loco-regional therapy and/or codified standard systemic treatment, as established in the context of internationally accepted treatment guidelines for the various types of tumors that will be enrolled. One measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Life expectancy of at least three months according to physician evaluation
• ECOG 0-2
• Screening hematology, clinical chemistries, coagulation and urine analyses are not clinically significant and the following criteria are met:
• Platelets \>75,000/mm3
• ANC \>1000/mm3
• Hemoglobin \> 8 g/dL
• Total and direct bilirubin \< 2.5 mg/dl (except for clearly documented Gilbert's Syndrome)
• ALT and AST \< 5 x ULN
• International normalized ratio (INR) \<2.3 or prothrombin time (PT) \<6 seconds above control
• Serum creatinine WNL and estimated by the Cockcroft-Gault formula or measured creatinine clearance rate \> 40 ml/min

You may not qualify if:

• Pregnancy,
• breastfeeding
• Subjects who participated to any other investigational drug trial within 30 days before enrollment to this trial
• Severe liver dysfunction (Child-Pugh Class C or hepatic encephalopathy).
• Serious medical or psychiatric illness, that may affect the correct participation to the trial
• Concurrent social conditions (e.g. drug/alcohol abuse issue), that would potentially affect the correct participation to the trial New York Heart Association (NYHA) Class III or IV
• cardiac disease, myocardial infarction within the past 6 months, unstable and/or symptomatic arrhythmia, or evidence of ischemia on ECG
• Patients with active infections requiring systemic therapy are ineligible
• Patients HIV positive or acquired immunodeficiency syndrome-related illness are ineligible
• History of other malignancies within 3 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or breast, low grade, early stage localized prostate cancer treated surgically with curative intent (TNM stage of T1a or T1b)
• ECOG\>2

Sponsors & Collaborators

• Azienda Ospedaliera Universitaria Mater Domini, Catanzaro: lead
• Associazione Italiana per la Ricerca sul Cancro: collaborator

Study Sites (1)

Center for Phase I Clinical Studies in Medical Oncology and Oncohematology - Translational Medical Oncology Unit, AOU MaterDomini and Magna Graecia University

Catanzaro, 88100, Italy

Location

Related Publications (12)

• 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.

  PMID: 32146420 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.

  PMID: 31861748 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.

  PMID: 27327137 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.

  PMID: 32659676 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.

  PMID: 26527748 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.

  PMID: 24586944 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.

  PMID: 29268195 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.

  PMID: 23479461 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.

  PMID: 26959615 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.

  PMID: 29716623 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.

  PMID: 26496024 BACKGROUND

• 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.

  PMID: 37365583 DERIVED

Related Links

• Volume 4 of "The rules governing medicinal products in the European Union" for human and veterinary use

MeSH Terms

Conditions

Multiple Myeloma; Carcinoma, Hepatocellular

Interventions

LNA-i-miR-221

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Pierfrancesco Tassone, MD

  Translational Medical Oncology Unit, AOU MaterDomini and Magna Graecia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: None (Open Label)
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medical Oncology, Magna Graecia University, Catanzaro, Italy

Model Details: monocentric, open label, phase I dose-escalation to determine the safety, the maximum tolerated dose (MTD) and the recommended phase II dose of LNA-i-miR-221 (RP2D) in a minimum/maximum number of 15/36 subjects affected by MM and advanced solid tumors. LNA-i-miR-221 will be administered IV daily infusion on days 1-4 followed by 24 days washout (1 cycle lasting 28 days) with a modified 3+3 Fibonacci dose escalation design, with 5 different dose levels for each cohort (0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg; 5 mg/kg).

Study Record Dates

• First Submitted: February 27, 2021
• First Posted: March 23, 2021
• Study Start: January 14, 2019
• Primary Completion: December 29, 2021
• Study Completion: December 29, 2021
• Last Updated: February 1, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)