A Phase 2a TDM-guided Clinical Study on the Safety and Efficacy of Mebendazole in Patients With Advanced Gastrointestinal Cancer or Cancer of Unknown Origin
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Changes in body temperature over time.
研究概览
简要总结
This study will evaluate the safety and efficacy of mebendazole (ReposMBZ) in patient with advanced gastrointestinal cancer or cancer of unknown origin. All patients will be given ReposMBZ for 16 weeks continuous treatment, individually dosed based on the serum concentration of mebendazole.
详细描述
Mebendazole has been used extensively during long time for local gut helminthic infections at low dose but also at considerably higher doses during months to years against invasive echinococcus infections. Recent research has now clearly indicated that mebendazole has anticancer effect. Given these observations and the experience of excellent tolerance to mebendazole the current clinical trial protocol is based on the repositioning strategy to more extensively investigate whether mebendazole could be developed into a useful anticancer drug.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •At least 18 years of age.
- •Histologically confirmed diagnosis of squamous cell cancer or adenocarcinoma, including primary cancer of the liver, of the gastrointestinal tract or cancer of unknown origin.
- •Measurable disease according to RECIST 1.
- •Defined time to tumour progression on the standard/experimental treatment preceding the trial treatment.
- •Locally advanced or metastatic disease not amenable to standard treatment, i.e. progress on standard therapy or observed/expected intolerance to standard therapy.
- •(removed via Amendment 1)
- •Pharmacological treatment attempt considered reasonable.
- •Females of childbearing potential should use adequate contraception throughout the study;
- •Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal)
- •Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)
- •Intrauterine device (IUD)
- •Intrauterine hormone-releasing system (IUS)
- •Bilateral tubal occlusion
- •Vasectomized partner
- •Sexual abstinence
- •Signed informed consent.
排除标准
- •Anti-tumour therapy within 3 weeks prior to study drug administration day
- •Ongoing infection or other major recent or ongoing disease that, according to the investigator, poses an unacceptable risk to the patient.
- •WHO performance status ≥
- •Child-Pugh B or C liver function status if hepatocellular carcinoma.
- •Inadequate laboratory parameters reflecting major organ function i.e.:
- •neutrophils ≤ 1,3 x 109/l
- •platelets ≤ 100 x 109/l
- •bilirubin > 1.5 x upper limit of normal (ULN)
- •Alanine aminotransferase (ALAT) > 5 x ULN
- •Glomerular filtration rate (GFR) <50 ml/min (calculated from P-creatinine)
- •Prothrombin complex/INR outside normal range
- •Current active participation in any other interventional clinical study.
- •Contraindications to the investigational product, e.g. known or suspected hypersensitivity or inability to oral drug administration.
- •Pregnancy or lactation.
- •Lack of suitability for participation in the study, e g expected difficulties to follow the protocol procedures, as judged by the Investigator.
研究组 & 干预措施
Single arm study
ReposMBZ 100 mg capsule by mouth followed by 8h PK sampling to decide the initial daily dose.
Treatment: Repos MBZ capsules by mouth twice daily for 16 weeks, daily dose 50mg-4g, based on the serum level of mebendazole.
干预措施: ReposMBZ (Drug)
结局指标
主要结局
Changes in body temperature over time.
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Body temperature (Celsius degrees)
Incidence of adverse events (AEs) probably or possibly related to ReposMBZ
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
AEs graded according to CTCAE 4.03.
Changes in plasma Albumin over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Blood Chemistry (plasma): Albumin (g/L)
Changes in plasma Sodium, Potassium, Calcium and Glucose over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Blood chemistry (plasma): Sodium, Potassium, Calcium, Glucose (mmol/L)
Changes in red, white and platelet blood cell count over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Haematology: RBC (red blood cell count), White blood cells with differential count and platelets (absolute count/L)
Tumour response: CT/MRI assessed according to RECIST 1.1
时间窗: From date of first dose ReposMBZ until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 24 months (end of study).
Best overall radiological response Time to tumour progression (TTP) compared with TTP on the treatment just preceding this protocol.
Changes in C-reactive protein (CRP) over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Blood chemistry (plasma): CRP (mg/L)
Changes in plasma Bilirubin over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Blood chemistry (plasma): Bilirubin (µmol/L)
Changes in plasma ALAT (alanine aminotransferase), ASAT (aspartate aminotransferase), LDH (lactate dehydrogenase), ALP (alkaline phosphatase) over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Blood chemistry (plasma): ALAT, ASAT, LDH, ALP (µkat/L)
Changes in Haemoglobin over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Haematology: Haemoglobin (g/L)
Changes in Activated Partial Thromboplastin Time (APTT) over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Coagulation (plasma): APTT (s)
Changes in blood pressure over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Systolic and diastolic blood pressure (mmHg) Weight (kg)
Changes in Prothrombin complex (PK/INR) over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Coagulation (plasma): Prothrombin complex (INR)
Changes in heart rate over time
时间窗: From date of first dose, up to 30 days after last dose of ReposMBZ or start of new treatment, whatever comes first, assessed up to 20 weeks after start of treatment phase.
Supine heart rate (beats per minute)
次要结局
- Change in tumour load and TTP according to irRECIST(From date of first dose ReposMBZ until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 24 months (end of study).)
- Area under the serum concentration versus time curve (AUC) for ReposMBZ(Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours.)
- The Cmax serum concentration of ReposMBZ after repeated dose administration.(Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours (only up to the time point for Cmax after single dose), assessed up to 16 weeks after start of treatment phase.)
- Target S-mebendazole concentration after repeated dose administration.(From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase.)
- The peak serum concentration (Cmax) of ReposMBZ after single dose administration.(Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours.)
- Time to reach the steady state S-mebendazole target concentration after repeated dose administration..(From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase.)
- Systemic immune activation.(From baseline up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).)
- Immune cell activation.(From baseline and up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).)
- Overall survival.(From date of first dose ReposMBZ to date of death, assessed up to 24 months (end of study).)