A Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin.

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Cancer of the Gastrointestinal Tract, Cancer of Unknown Origin

Intervention / Treatment
-----------------
* Drug: ReposMBZ


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 1.1. 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. Exclusion Criteria: 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 ≥ 2. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm study<br>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. | Drug: ReposMBZ<br>* Capsules 50mg, 100mg, 200mg<br>* Other names: Mebendazole;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) probably or possibly related to ReposMBZ | AEs graded according to CTCAE 4.03. | 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. | 
| Changes in plasma Albumin over time | Blood Chemistry (plasma): Albumin (g/L) | 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. | 
| Changes in C-reactive protein (CRP) over time | Blood chemistry (plasma): CRP (mg/L) | 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. | 
| Changes in plasma Sodium, Potassium, Calcium and Glucose over time | Blood chemistry (plasma): Sodium, Potassium, Calcium, Glucose (mmol/L) | 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. | 
| Changes in plasma Bilirubin over time | Blood chemistry (plasma): Bilirubin (µmol/L) | 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. | 
| Changes in plasma ALAT (alanine aminotransferase), ASAT (aspartate aminotransferase), LDH (lactate dehydrogenase), ALP (alkaline phosphatase) over time | Blood chemistry (plasma): ALAT, ASAT, LDH, ALP (µkat/L) | 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. | 
| Changes in Haemoglobin over time | Haematology: Haemoglobin (g/L) | 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. | 
| Changes in red, white and platelet blood cell count over time | Haematology: RBC (red blood cell count), White blood cells with differential count and platelets (absolute count/L) | 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. | 
| Changes in Activated Partial Thromboplastin Time (APTT) over time | Coagulation (plasma): APTT (s) | 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. | 
| Changes in Prothrombin complex (PK/INR) over time | Coagulation (plasma): Prothrombin complex (INR) | 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. | 
| Changes in blood pressure over time | Systolic and diastolic blood pressure (mmHg) Weight (kg) | 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. | 
| Changes in heart rate over time | Supine heart rate (beats per minute) | 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. | 
| Changes in body temperature over time. | Body temperature (Celsius degrees) | 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. | 
| Tumour response: CT/MRI assessed according to RECIST 1.1 | Best overall radiological response Time to tumour progression (TTP) compared with TTP on the treatment just preceding this protocol. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The peak serum concentration (Cmax) of ReposMBZ after single dose administration. | Cmax will be used to decide the starting dose in the treatment phase. | Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours. | 
| Area under the serum concentration versus time curve (AUC) for ReposMBZ | Analysis of serum concentration after single dose administration of 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. | Cmax will be used to adjust the dose until target S-mebendazole level is reached and to show the individual variation of S-mebendazole concentration over time | 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. | Number of patients that reach the steady state S-mebendazole target concentration. | From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase. | 
| Time to reach the steady state S-mebendazole target concentration after repeated dose administration.. | Time from first dose in treatment phase until target S-mebendazole concentration is reached | From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase. | 
| Systemic immune activation. | Change of cytokine levels in blood, evaluated by cytokine array. | From baseline up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study). | 
| Immune cell activation. | Up-regulation of activation markers compared to baseline, evaluated by flow cytometry. | From baseline and up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study). | 
| Overall survival. | Months of survival from first dose until death of any cause. | From date of first dose ReposMBZ to date of death, assessed up to 24 months (end of study). | 
| Change in tumour load and TTP according to irRECIST | Best over all radiological response according to irRECIST 1.1. | 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). |