Advanced Solid Tumor Clinical Trial
— LNA-i-miR221Official title:
A Dose Escalation Phase I Study of LNA-i-miR-221 for the Treatment of Refractory Multiple Myeloma and Advanced Solid Tumors
Verified date | January 2022 |
Source | Azienda Ospedaliera Universitaria Mater Domini, Catanzaro |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 17 |
Est. completion date | December 29, 2021 |
Est. primary completion date | December 29, 2021 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: - 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: 1. Platelets >75,000/mm3 2. ANC >1000/mm3 3. Hemoglobin > 8 g/dL 4. Total and direct bilirubin < 2.5 mg/dl (except for clearly documented Gilbert's Syndrome) 5. ALT and AST < 5 x ULN 6. International normalized ratio (INR) <2.3 or prothrombin time (PT) <6 seconds above control 7. Serum creatinine WNL and estimated by the Cockcroft-Gault formula or measured creatinine clearance rate > 40 ml/min - Negative results on the following screening laboratory tests: 1. urine or serum pregnancy test (for women of childbearing potential), 2. human immunodeficiency virus (HIV) antibody. - For men and women of childbearing potential, willingness to utilize adequate contraception and not become pregnant (or have their partner become pregnant) during the full course of the study. - For female study participants, adequate birth control methods will be defined as: intrauterine device or double barrier contraception, i.e., condom plus diaphragm, condom or diaphragm plus spermicidal gel /foam - For males study participants, adequate birth control methods will be defined as: double barrier contraception, i.e., condom plus diaphragm; condom or diaphragm plus spermicidal gel/foam. Note: Females who are not of childbearing potential must meet one of the following criteria: 1. Post-menopause - defined as one year without menses or follicle-stimulating hormone (FSH) of >40 U/mL 2. Surgical menopause - hysterectomy, bilateral oophorectomy, or bilateral tubal ligation 3. 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) - Voluntary written informed consent released before any study related procedure is performed. The consent may be withdrawn by the subject at any time without prejudice to future medical care. Exclusion Criteria: - 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 |
Country | Name | City | State |
---|---|---|---|
Italy | Center for Phase I Clinical Studies in Medical Oncology and Oncohematology - Translational Medical Oncology Unit, AOU MaterDomini and Magna Graecia University | Catanzaro |
Lead Sponsor | Collaborator |
---|---|
Azienda Ospedaliera Universitaria Mater Domini, Catanzaro | Associazione Italiana per la Ricerca sul Cancro |
Italy,
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. — View Citation
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. — View Citation
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). pii: E27. doi: 10.3390/cancers12010027. — View Citation
Di Martino MT, Gullà 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. — View Citation
Di Martino MT, Gullà 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. — View Citation
Di Martino MT, Rossi M, Caracciolo D, Gullà 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. Review. — View Citation
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. — View Citation
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. — View Citation
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. Erratum in: Mol Ther Nucleic Acids. 2016 Jul 19;5(7):e336. — View Citation
Gullà 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. — View Citation
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. — View Citation
* Note: There are 11 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 | To assess the Cmax of ascending doses of LNA-i-miR-221 | Peak Plasma Concentration of LNA-i-miR-221 | During first 6 days of dosing | |
Secondary | To assess the Area under the plasma concentration versus time curve (AUC) of ascending doses of LNA-i-miR-221 | plasma concentration-time profile of LNA-i-miR-221 | During first 6 days of dosing | |
Secondary | To assess the LNA-i-miR-221 clearance | the total body clearance of LNA-i-miR-221 | During first 6 days of dosing | |
Secondary | To assess LNA-i-miR-221 biological half-life | t½, LNA-i-miR-221 apparent half-life | During first 6 days of dosing | |
Secondary | To assess the efficacy of LNA-i-miR-221 | Preliminary assessment of the clinical benefit and antitumoral activity of LNA-i-miR-221 based on RECIST V1.1 criteria | Tumor response will be assessed after 30 (+/-1) days from the start of treatment |
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