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

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

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.

Study Overview

• Status: Terminated
• Conditions: Cancer of the Gastrointestinal Tract; Cancer of Unknown Origin
• Intervention / Treatment: Drug: ReposMBZ

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, 75185
    • Dept of Oncology, University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. At least 18 years of age.
2. Histologically confirmed diagnosis of squamous cell cancer or adenocarcinoma, including primary cancer of the liver, of the gastrointestinal tract or cancer of unknown origin.
3. Measurable disease according to RECIST 1.1.
4. Defined time to tumour progression on the standard/experimental treatment preceding the trial treatment.
5. Locally advanced or metastatic disease not amenable to standard treatment, i.e. progress on standard therapy or observed/expected intolerance to standard therapy.
6. - (removed via Amendment 1)
7. Pharmacological treatment attempt considered reasonable.

8. Females of childbearing potential should use adequate contraception throughout the study;

   1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal)
   2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)
   3. Intrauterine device (IUD)
   4. Intrauterine hormone-releasing system (IUS)
   5. Bilateral tubal occlusion
   6. Vasectomized partner
   7. Sexual abstinence
9. Signed informed consent.

Exclusion Criteria:

1. Anti-tumour therapy within 3 weeks prior to study drug administration day
2. Ongoing infection or other major recent or ongoing disease that, according to the investigator, poses an unacceptable risk to the patient.
3. WHO performance status ≥ 2.
4. Child-Pugh B or C liver function status if hepatocellular carcinoma.

5. Inadequate laboratory parameters reflecting major organ function i.e.:

   1. neutrophils ≤ 1,3 x 109/l
   2. platelets ≤ 100 x 109/l
   3. bilirubin > 1.5 x upper limit of normal (ULN)
   4. Alanine aminotransferase (ALAT) > 5 x ULN
   5. Glomerular filtration rate (GFR) <50 ml/min (calculated from P-creatinine)
   6. Prothrombin complex/INR outside normal range
6. Current active participation in any other interventional clinical study.
7. Contraindications to the investigational product, e.g. known or suspected hypersensitivity or inability to oral drug administration.
8. Pregnancy or lactation.
9. Lack of suitability for participation in the study, e g expected difficulties to follow the protocol procedures, as judged by the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: ReposMBZ; Capsules 50mg, 100mg, 200mg; 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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between ReposMBZ efficacy and properties of the diagnostic tumour tissue (optional)	Genetic changes and infiltration of immune cells, grade, molecular subtype, gene and protein expression and tumour infiltration and subtypes of macrophages and lymphocytes.	Assessed up to 24 months (end of study).
Comparison of diagnostic tissue and a fresh tumour biopsy after 4 weeks of treatment at the target S-mebendazole concentration (optional).	Changes in the properties analysed in the archived tissue (baseline) and the fresh biopsy.	Collected up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
Association between S-mebendazole and efficacy and safety	Mean S-mebendazole concentration during treatment phase in relation to safety (CTCAE 4.03 grade 3 and 4 toxicity) and efficacy (tumour response and TTP) respectively.	From date of first dose until date of first documented progression or date of death, whichever comes fist, assessed up to 24 months (end of study).

Collaborators and Investigators

• Sponsor: Repos Pharma
• Collaborators: Uppsala University; Uppsala University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2018
• Primary Completion (Actual): January 16, 2019
• Study Completion (Actual): January 16, 2019

Study Registration Dates

• First Submitted: June 17, 2018
• First Submitted That Met QC Criteria: August 8, 2018
• First Posted (Actual): August 14, 2018

Study Record Updates

• Last Update Posted (Actual): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 18, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Gastrointestinal Diseases; Neoplastic Processes; Neoplasm Metastasis; Carcinoma; Gastrointestinal Neoplasms; Neoplasms, Unknown Primary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiparasitic Agents; Antinematodal Agents; Anthelmintics; Mebendazole
• Other Study ID Numbers: RP-2017-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No