Multiple Myeloma, RefractoryPhase 1LNA-i-miR221NCT04811898
A Dose Escalation Study of LNA-i-Mir-221 for Cancer Treatment
A Phase 1 study testing LNA-i-miR-221 in people with Multiple Myeloma, Refractory and Hepatocarcinoma, run by Azienda Ospedaliera Universitaria Mater Domini, Catanzaro at 1 site in Italy.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma, Refractory, Hepatocarcinoma, Advanced Solid Tumor
- What is being tested?
- LNA-i-miR-221
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteItaly
- Study dates
- 14 Jan 2019to 29 Dec 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
- Negative results on the following screening laboratory tests:
- urine or serum pregnancy test (for women of childbearing potential),
- 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:
- Post-menopause - defined as one year without menses or follicle-stimulating hormone (FSH) of >40 U/mL
- Surgical menopause - hysterectomy, bilateral oophorectomy, or bilateral tubal ligation
- 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.
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
Italy1 site
Center for Phase I Clinical Studies in Medical Oncology and Oncohematology - Translational Medical Oncology Unit, AOU MaterDomini and Magna Graecia University
Catanzaro, 88100
About this study
Official title: A Dose Escalation Phase I Study of LNA-i-miR-221 for the Treatment of Refractory Multiple Myeloma and Advanced Solid Tumors
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.
Read the detailed description
The LNA-i-miR-221 Phase I trial is a no-profit fully academic study on research funds and no external sponsor does exist. The study is a monocentric, open-label, phase I dose-finding to determine the safety, the maximum tolerated dose (MTD), and the recommended phase II dose of LNA-i-miR-221 (RP2D) using escalating doses; The secondary endopoints will be plasma and urinary pharmacokinetc (PK), efficacy as preliminary exploration of the antitumor activity, the disease control and the evaluation of biomonitoring activity. The study will include refractory MM and advanced solid tumors. In the last cohort, if 3 out of 3 or 5 out of 6 subjects do not experience DLT, no further dose escalation will be required and dose level 5 will be declared the MTD. At the end, further expansion will be performed to define RP2D, after a critical evaluation of trial data by SRC. LNA-i-miR-221 is a 13-mer antisense miR-221 inhibitor, which takes advantage of locked nucleic acid (LNA) technology and phosphorotioate (PS) backbone chemistry to increase affinity for miR-221 and nuclease resistance and represents a new frontier for chemically modified antisense oligonucleotides.
Participants will be assigned to 5 different cohorts, according to 5 different dose levels used. The cohorts will be defined with progressive numbers (1, 2, 3, 4, 5). Each cohort will be composed of 3 to 6 subjects. The dose level of LNA-i-miR-221 will be increased from one cohort to the next one. Independently from the assigned dose level, patients from each cohort will receive a total of 4 IV administrations as boluses. The treatment cycle will last 28 days. Each subject who will not experience any DLT (see DLT definition) will remain on the assigned dose level. In the case that MTD will be defined by the occurrence of DLT at the superior level, the MTD cohort will be considered for expansion to definitely assess the RP2D studies.
The treatment schedule (as amended and approved by AIFA on 1/15/2020) will be 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), for safety and toxicity evaluation, MTD assessment, PK and modulatory activity investigation in refractory MM and advanced solid cancer patients. No other investigational drug and/or standard antitumor chemotherapy will be allowed during the study.
The enrolled subject will require hospitalization to ensure adequate protocol adherence.
LNA-i-miR-221will be administered inpatient setting as intravenous infusion of 30 minutes. During infusion and the following two hours post infusion, patients will be continuously monitored for vital signs. Local healthy authority guidelines must be followed with regard to further observation and monitoring, if applicable. Following the first infusion, patients will be observed for at least 120 minutes for fever, chills, or other infusion-associated symptoms. If prior infusions were well tolerated (without any signs or symptoms of infusion reactions) subsequent doses of LNA-i-miR-221 will be administered in 30 minutes with a 120 minutes observation period after infusion.
The determination of LNA-i-miR-221 in human plasma and urine will be used for the pharmacokinetic evaluation. For each enrolled subject, 2-5 ml of blood samples will be drawn for the quantification of LNA-i-miR-221 before, after 15 min and at the end of infusion at the following time points: 0.5, 1, 2, 4, 6, 12 hours on days 1 and 2. On day 3 and 4, blood samples will be drawn before and at the end of infusion at the following time points: 1, 2, 4. At 24 hours (day 5) and 48 hours (day 6) after last administration blood samples will be drawn for the quantification of LNA-i-miR-221.
Urine pharmacokinetic samples (15-20 ml) will be collected at pre-dose and 6, 12 and 24 hours period postdose on day 1 of cycle of treatment. Aliquots (15-20 ml) of 24-hour urine will also be collected at post dosing time during the cycle of treatment (day 2, 3, 4 and 5).
The vials containing lyophilized LNA-i-miR-221 must be stored at +2-8°C, while the reconstituted solution must be manipulated rapidly in a safe and secure place below 25°C, with no access for unauthorized personnel. The solution can be reconstituted immediately before administration. All adverse events will be followed with appropriate medical management until resolved. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. For selected adverse events for which administration of the investigational drug was stopped, a rechallenge of the subject with the investigational drug may be conducted if considered both safe and ethical by the study coordinator.
All the safety data will be reviewed by an independent Safety Review Committee (SRC). Dose escalation to the next dose level will be allowed by SRC. In the last cohort, if 3 out of 3 or 5 out of 6 subjects do not experience DLT, no further dose escalation will be required and dose level 5 will be declared the MTD. At the end, further expansion will be performed to define RP2D, after a critical evaluation of trial data by SRC. At 30 (+/-1) days from the first dose of treatment, each enrolled patients will be evaluated for the end of treatment (EOT) visit in order to evaluate the efficacy and clinical benefit of LNA-i-miR-221 treatment based on RECIST V1.1 criteria. Only for patients with clinical benefit or radiological response/stable disease, the treatment will be offered until disease progression or if the patient withdraws consent. Out patients follow up will be continued every two months, until death.
Back-up blood samples will be collected for re-analysis in case of failure of the test measurement or for samples lost in transit. The samples will be appropriately stored and destroyed at study closure. Monitoring and auditing procedures defined/agreed by the External board (Sequre s.r.l. and Kilimo s.r l.) will be followed, in order to comply with GCP guidelines. This will include on-site checking of the case report forms (CRF) for completeness and clarity, cross-checking with source documents, and clarification of administrative matters.
Primary endpoints:
- To determine the safety, the maximum tolerated dose (MTD) and the RP2D of LNA-i-miR-221 using escalating doses in refractory multiple myeloma (MM) and advanced solid tumors for further investigations.
- To assess the safety and toxicity of LNA-i-miR-221
Secondary endpoints:
- PK analysis
- To preliminary explore the antitumor activity, the disease control, and the efficacy
- Biomodulatory activity A minimum/maximum number of 15/36 subjects will be enrolled in the study, according to expansion cohorts. All clinical data will be inserted on the Case Report Form (CRF) pages and all data can be extracted for the purpose of the ongoing analysis of the SRC and for statistical analysis.
- Being tested
- LNA-i-miR-221
- Keywords
- LNA-i-miR-221, Multiple Myeloma, Hepatocarcinoma, Advanced solid tumors, Phase I, Dose escalation, Safety, maximum tolerated dose (MTD), RP2D
- Medical subject headings
- Multiple Myeloma, Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LNA-i-miR-221Biological
LNA-i-miR-221, IV daily infusion on days 1-4 followed by 24 days washout (1 cycle lasting 28 days)
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: Biological: LNA-i-miR-221 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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.
Measured: 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
Measured: two years
Secondary outcomes (5)
To assess the Cmax of ascending doses of LNA-i-miR-221
Peak Plasma Concentration of LNA-i-miR-221
Measured: 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
plasma concentration-time profile of LNA-i-miR-221
Measured: During first 6 days of dosing
To assess the LNA-i-miR-221 clearance
the total body clearance of LNA-i-miR-221
Measured: During first 6 days of dosing
To assess LNA-i-miR-221 biological half-life
t½, LNA-i-miR-221 apparent half-life
Measured: During first 6 days of dosing
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
Measured: Tumor response will be assessed after 30 (+/-1) days from the start of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Mar 2021
- Study start14 Jan 2019
- Primary completion29 Dec 2021
- Study completion29 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Multiple Myeloma, RefractoryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Model description
- 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).
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliera Universitaria Mater Domini, Catanzaro
- Sponsor type
- University, hospital or other
- Collaborators
- Associazione Italiana per la Ricerca sul Cancro
- Responsible party
- Principal investigator, TASSONE PIERFRANCESCO, Azienda Ospedaliera Universitaria Mater Domini, Catanzaro
- Investigators
- Pierfrancesco Tassone, MD, Principal investigator, Translational Medical Oncology Unit, AOU MaterDomini and Magna Graecia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04811898
- Sponsor's protocol ID
- AOU-MD FIH-LNA-i-miR-221
- Other IDs
- 2017-002615-33, 2017
- Acronym
- LNA-i-miR221
- Status last verified
- Jan 2022
- First submitted
- 27 Feb 2021
- Last updated
- 1 Feb 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 32146420Di 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.
PubMed 31861748Gallo 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.
PubMed 27327137Franzoni 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.
PubMed 32659676Gulla 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.
PubMed 26527748Di 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.
PubMed 24586944Franzoni 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.
PubMed 29268195Di 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.
PubMed 23479461Di 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.
PubMed 26959615Santolla 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.
PubMed 29716623Calura 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.
PubMed 26496024Tassone 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.
PubMed 37365583
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Dose Escalation Phase I Study of LNA-i-miR-221 for the Treatment of Refractory Multiple Myeloma and Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT04811898
- Acronym / sponsor ID
- LNA-i-miR221 / AOU-MD FIH-LNA-i-miR-221
- Keywords
- LNA-i-miR-221, Multiple Myeloma, Hepatocarcinoma, Advanced solid tumors, Phase I, Dose escalation, Safety, maximum tolerated dose (MTD)
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Azienda Ospedaliera Universitaria Mater Domini, CatanzaroUniversity, hospital or other
- Collaborators
- Associazione Italiana per la Ricerca sul Cancro
- Study start
- 14 Jan 2019 (actual)
- Primary completion
- 29 Dec 2021 (actual)
- Study completion
- 29 Dec 2021 (actual)
- First posted
- 23 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The LNA-i-miR-221 Phase I trial is a no-profit fully academic study on research funds and no external sponsor does exist. The study is a monocentric, open-label, phase I dose-finding to determine the safety, the maximum tolerated dose (MTD), and the recommended phase II dose of LNA-i-miR-221 (RP2D) using escalating doses; The secondary endopoints will be plasma and urinary pharmacokinetc (PK), efficacy as preliminary exploration of the antitumor activity, the disease control and the evaluation of biomonitoring activity. The study will include refractory MM and advanced solid tumors. In the last cohort, if 3 out of 3 or 5 out of 6 subjects do not experience DLT, no further dose escalation will be required and dose level 5 will be declared the MTD. At the end, further expansion will be performed to define RP2D, after a critical evaluation of trial data by SRC. LNA-i-miR-221 is a 13-mer antisense miR-221 inhibitor, which takes advantage of locked nucleic acid (LNA) technology and phosphorotioate (PS) backbone chemistry to increase affinity for miR-221 and nuclease resistance and represents a new frontier for chemically modified antisense oligonucleotides.
Participants will be assigned to 5 different cohorts, according to 5 different dose levels used. The cohorts will be defined with progressive numbers (1, 2, 3, 4, 5). Each cohort will be composed of 3 to 6 subjects. The dose level of LNA-i-miR-221 will be increased from one cohort to the next one. Independently from the assigned dose level, patients from each cohort will receive a total of 4 IV administrations as boluses. The treatment cycle will last 28 days. Each subject who will not experience any DLT (see DLT definition) will remain on the assigned dose level. In the case that MTD will be defined by the occurrence of DLT at the superior level, the MTD cohort will be considered for expansion to definitely assess the RP2D studies.
The treatment schedule (as amended and approved by AIFA on 1/15/2020) will be 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), for safety and toxicity evaluation, MTD assessment, PK and modulatory activity investigation in refractory MM and advanced solid cancer patients. No other investigational drug and/or standard antitumor chemotherapy will be allowed during the study.
The enrolled subject will require hospitalization to ensure adequate protocol adherence.
LNA-i-miR-221will be administered inpatient setting as intravenous infusion of 30 minutes. During infusion and the following two hours post infusion, patients will be continuously monitored for vital signs. Local healthy authority guidelines must be followed with regard to further observation and monitoring, if applicable. Following the first infusion, patients will be observed for at least 120 minutes for fever, chills, or other infusion-associated symptoms. If prior infusions were well tolerated (without any signs or symptoms of infusion reactions) subsequent doses of LNA-i-miR-221 will be administered in 30 minutes with a 120 minutes observation period after infusion.
The determination of LNA-i-miR-221 in human plasma and urine will be used for the pharmacokinetic evaluation. For each enrolled subject, 2-5 ml of blood samples will be drawn for the quantification of LNA-i-miR-221 before, after 15 min and at the end of infusion at the following time points: 0.5, 1, 2, 4, 6, 12 hours on days 1 and 2. On day 3 and 4, blood samples will be drawn before and at the end of infusion at the following time points: 1, 2, 4. At 24 hours (day 5) and 48 hours (day 6) after last administration blood samples will be drawn for the quantification of LNA-i-miR-221.
Urine pharmacokinetic samples (15-20 ml) will be collected at pre-dose and 6, 12 and 24 hours period postdose on day 1 of cycle of treatment. Aliquots (15-20 ml) of 24-hour urine will also be collected at post dosing time during the cycle of treatment (day 2, 3, 4 and 5).
The vials containing lyophilized LNA-i-miR-221 must be stored at +2-8°C, while the reconstituted solution must be manipulated rapidly in a safe and secure place below 25°C, with no access for unauthorized personnel. The solution can be reconstituted immediately before administration. All adverse events will be followed with appropriate medical management until resolved. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. For selected adverse events for which administration of the investigational drug was stopped, a rechallenge of the subject with the investigational drug may be conducted if considered both safe and ethical by the study coordinator.
All the safety data will be reviewed by an independent Safety Review Committee (SRC). Dose escalation to the next dose level will be allowed by SRC. In the last cohort, if 3 out of 3 or 5 out of 6 subjects do not experience DLT, no further dose escalation will be required and dose level 5 will be declared the MTD. At the end, further expansion will be performed to define RP2D, after a critical evaluation of trial data by SRC. At 30 (+/-1) days from the first dose of treatment, each enrolled patients will be evaluated for the end of treatment (EOT) visit in order to evaluate the efficacy and clinical benefit of LNA-i-miR-221 treatment based on RECIST V1.1 criteria. Only for patients with clinical benefit or radiological response/stable disease, the treatment will be offered until disease progression or if the patient withdraws consent. Out patients follow up will be continued every two months, until death.
Back-up blood samples will be collected for re-analysis in case of failure of the test measurement or for samples lost in transit. The samples will be appropriately stored and destroyed at study closure. Monitoring and auditing procedures defined/agreed by the External board (Sequre s.r.l. and Kilimo s.r l.) will be followed, in order to comply with GCP guidelines. This will include on-site checking of the case report forms (CRF) for completeness and clarity, cross-checking with source documents, and clarification of administrative matters.
Primary endpoints:
- To determine the safety, the maximum tolerated dose (MTD) and the RP2D of LNA-i-miR-221 using escalating doses in refractory multiple myeloma (MM) and advanced solid tumors for further investigations.
- To assess the safety and toxicity of LNA-i-miR-221
Secondary endpoints:
- PK analysis
- To preliminary explore the antitumor activity, the disease control, and the efficacy
- Biomodulatory activity A minimum/maximum number of 15/36 subjects will be enrolled in the study, according to expansion cohorts. All clinical data will be inserted on the Case Report Form (CRF) pages and all data can be extracted for the purpose of the ongoing analysis of the SRC and for statistical analysis.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 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).
| Arm | Type | Receives |
|---|---|---|
| Experimental single arm | Experimental | Biological: LNA-i-miR-221Single group with 5 dose escalation for each cohort (0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg; 5 mg/kg) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (35 listed)
- 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.
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LNA-i-miR-221LNA-i-miR-221, IV daily infusion on days 1-4 followed by 24 days washout (1 cycle lasting 28 days) | Biological | Experimental single arm |
Primary outcome
Safety measured by adverse events To assess the toxicity of LNA-i-miR-221
Time frame: two years
To assess the safety and toxicity of LNA-i-miR-221
The maximum tolerated dose (MTD) of LNA-i-miR-221
Time frame: two years
The maximum tolerated dose (MTD) is the dose level below the dose level at which at least 2 out of 6 patients experience DLT.
The recommended phase II dose of LNA-i-miR-221 (RP2D)
Time frame: two years
recommended phase II dose of LNA-i-miR-221 (RP2D) using escalating doses for further evaluation
5 secondary outcomes
To assess the Cmax of ascending doses of LNA-i-miR-221
Time frame: 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
Time frame: During first 6 days of dosing
To assess the LNA-i-miR-221 clearance
Time frame: During first 6 days of dosing
To assess LNA-i-miR-221 biological half-life
Time frame: During first 6 days of dosing
To assess the efficacy of LNA-i-miR-221
Time frame: Tumor response will be assessed after 30 (+/-1) days from the start of treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2022.
- Background: PubMed 32146420Di 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: PubMed 31861748Di 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: PubMed 27327137Gallo 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: PubMed 32659676Franzoni 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: PubMed 26527748Gulla 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: PubMed 24586944Di 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: PubMed 29268195Franzoni 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: PubMed 23479461Di 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: PubMed 26959615Di 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: PubMed 29716623Santolla 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: PubMed 26496024Calura 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.
- Derived from this study: PubMed 37365583Tassone 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.
- Volume 4 of "The rules governing medicinal products in the European Union" for human and veterinary useLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pierfrancesco Tassone, MD principal investigator
Translational Medical Oncology Unit, AOU MaterDomini and Magna Graecia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LNA-i-miR-221 in people with Multiple Myeloma, Refractory and Hepatocarcinoma, run by Azienda Ospedaliera Universitaria Mater Domini, Catanzaro at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 35 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety measured by adverse events To assess the toxicity of LNA-i-miR-221 (time frame: two years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04811898, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2022.