A Dose Escalation Phase I Study of LNA-i-miR-221 for the Treatment of Refractory Multiple Myeloma and Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 17
- 试验地点
- 2
- 主要终点
- Safety measured by adverse events To assess the toxicity of LNA-i-miR-221
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
None (Open Label)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Life expectancy of at least three months according to physician evaluation
- •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.
排除标准
- •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)
结局指标
主要结局
Safety measured by adverse events To assess the toxicity of LNA-i-miR-221
时间窗: two years
To assess the safety and toxicity of LNA-i-miR-221
The maximum tolerated dose (MTD) of LNA-i-miR-221
时间窗: 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)
时间窗: two years
recommended phase II dose of LNA-i-miR-221 (RP2D) using escalating doses for further evaluation
次要结局
- To assess the efficacy of LNA-i-miR-221(Tumor response will be assessed after 30 (+/-1) days from the start of treatment)
- 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 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)
研究者
TASSONE PIERFRANCESCO
Professor of Medical Oncology, Magna Graecia University, Catanzaro, Italy
Azienda Ospedaliera Universitaria Mater Domini, Catanzaro