Back to resultsA Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin. (RepoMeb)
Primary Purpose
Cancer of the Gastrointestinal Tract, Cancer of Unknown Origin
Status
Terminated
Phase
Phase 1
Locations
Sweden
Study Type
Interventional
Intervention
ReposMBZ
Sponsored by
About this trial
This is an interventional treatment trial for Cancer of the Gastrointestinal Tract
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.
Sites / Locations
- Dept of oncology, University Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Single arm study
Arm Description
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.
Outcomes
Primary Outcome Measures
Incidence of adverse events (AEs) probably or possibly related to ReposMBZ
AEs graded according to CTCAE 4.03.
Changes in plasma Albumin over time
Blood Chemistry (plasma): Albumin (g/L)
Changes in C-reactive protein (CRP) over time
Blood chemistry (plasma): CRP (mg/L)
Changes in plasma Sodium, Potassium, Calcium and Glucose over time
Blood chemistry (plasma): Sodium, Potassium, Calcium, Glucose (mmol/L)
Changes in plasma Bilirubin over time
Blood chemistry (plasma): Bilirubin (µmol/L)
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)
Changes in Haemoglobin over time
Haematology: Haemoglobin (g/L)
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)
Changes in Activated Partial Thromboplastin Time (APTT) over time
Coagulation (plasma): APTT (s)
Changes in Prothrombin complex (PK/INR) over time
Coagulation (plasma): Prothrombin complex (INR)
Changes in blood pressure over time
Systolic and diastolic blood pressure (mmHg) Weight (kg)
Changes in heart rate over time
Supine heart rate (beats per minute)
Changes in body temperature over time.
Body temperature (Celsius degrees)
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.
Secondary Outcome Measures
The peak serum concentration (Cmax) of ReposMBZ after single dose administration.
Cmax will be used to decide the starting dose in the treatment phase.
Area under the serum concentration versus time curve (AUC) for ReposMBZ
Analysis of serum concentration after single dose administration of ReposMBZ.
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
Target S-mebendazole concentration after repeated dose administration.
Number of patients that reach the steady state S-mebendazole target concentration.
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
Systemic immune activation.
Change of cytokine levels in blood, evaluated by cytokine array.
Immune cell activation.
Up-regulation of activation markers compared to baseline, evaluated by flow cytometry.
Overall survival.
Months of survival from first dose until death of any cause.
Change in tumour load and TTP according to irRECIST
Best over all radiological response according to irRECIST 1.1.
Full Information
NCT ID
NCT03628079
First Posted
June 17, 2018
Last Updated
January 18, 2020
Sponsor
Repos Pharma
Collaborators
Uppsala University, Uppsala University Hospital
1. Study Identification
Unique Protocol Identification Number
NCT03628079
Brief Title
A Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin.
Acronym
RepoMeb
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2020
Overall Recruitment Status
Terminated
Why Stopped
Lack of effect
Study Start Date
May 25, 2018 (Actual)
Primary Completion Date
January 16, 2019 (Actual)
Study Completion Date
January 16, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Repos Pharma
Collaborators
Uppsala University, Uppsala University Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer of the Gastrointestinal Tract, Cancer of Unknown Origin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Single arm study
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ReposMBZ
Other Intervention Name(s)
Mebendazole
Intervention Description
Capsules 50mg, 100mg, 200mg
Primary Outcome Measure Information:
Title
Incidence of adverse events (AEs) probably or possibly related to ReposMBZ
Description
AEs graded according to CTCAE 4.03.
Time Frame
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.
Title
Changes in plasma Albumin over time
Description
Blood Chemistry (plasma): Albumin (g/L)
Time Frame
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.
Title
Changes in C-reactive protein (CRP) over time
Description
Blood chemistry (plasma): CRP (mg/L)
Time Frame
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.
Title
Changes in plasma Sodium, Potassium, Calcium and Glucose over time
Description
Blood chemistry (plasma): Sodium, Potassium, Calcium, Glucose (mmol/L)
Time Frame
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.
Title
Changes in plasma Bilirubin over time
Description
Blood chemistry (plasma): Bilirubin (µmol/L)
Time Frame
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.
Title
Changes in plasma ALAT (alanine aminotransferase), ASAT (aspartate aminotransferase), LDH (lactate dehydrogenase), ALP (alkaline phosphatase) over time
Description
Blood chemistry (plasma): ALAT, ASAT, LDH, ALP (µkat/L)
Time Frame
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.
Title
Changes in Haemoglobin over time
Description
Haematology: Haemoglobin (g/L)
Time Frame
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.
Title
Changes in red, white and platelet blood cell count over time
Description
Haematology: RBC (red blood cell count), White blood cells with differential count and platelets (absolute count/L)
Time Frame
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.
Title
Changes in Activated Partial Thromboplastin Time (APTT) over time
Description
Coagulation (plasma): APTT (s)
Time Frame
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.
Title
Changes in Prothrombin complex (PK/INR) over time
Description
Coagulation (plasma): Prothrombin complex (INR)
Time Frame
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.
Title
Changes in blood pressure over time
Description
Systolic and diastolic blood pressure (mmHg) Weight (kg)
Time Frame
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.
Title
Changes in heart rate over time
Description
Supine heart rate (beats per minute)
Time Frame
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.
Title
Changes in body temperature over time.
Description
Body temperature (Celsius degrees)
Time Frame
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.
Title
Tumour response: CT/MRI assessed according to RECIST 1.1
Description
Best overall radiological response Time to tumour progression (TTP) compared with TTP on the treatment just preceding this protocol.
Time Frame
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 Measure Information:
Title
The peak serum concentration (Cmax) of ReposMBZ after single dose administration.
Description
Cmax will be used to decide the starting dose in the treatment phase.
Time Frame
Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours.
Title
Area under the serum concentration versus time curve (AUC) for ReposMBZ
Description
Analysis of serum concentration after single dose administration of ReposMBZ.
Time Frame
Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours.
Title
The Cmax serum concentration of ReposMBZ after repeated dose administration.
Description
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
Time Frame
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.
Title
Target S-mebendazole concentration after repeated dose administration.
Description
Number of patients that reach the steady state S-mebendazole target concentration.
Time Frame
From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase.
Title
Time to reach the steady state S-mebendazole target concentration after repeated dose administration..
Description
Time from first dose in treatment phase until target S-mebendazole concentration is reached
Time Frame
From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase.
Title
Systemic immune activation.
Description
Change of cytokine levels in blood, evaluated by cytokine array.
Time Frame
From baseline up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
Title
Immune cell activation.
Description
Up-regulation of activation markers compared to baseline, evaluated by flow cytometry.
Time Frame
From baseline and up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
Title
Overall survival.
Description
Months of survival from first dose until death of any cause.
Time Frame
From date of first dose ReposMBZ to date of death, assessed up to 24 months (end of study).
Title
Change in tumour load and TTP according to irRECIST
Description
Best over all radiological response according to irRECIST 1.1.
Time Frame
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 Pre-specified Outcome Measures:
Title
Association between ReposMBZ efficacy and properties of the diagnostic tumour tissue (optional)
Description
Genetic changes and infiltration of immune cells, grade, molecular subtype, gene and protein expression and tumour infiltration and subtypes of macrophages and lymphocytes.
Time Frame
Assessed up to 24 months (end of study).
Title
Comparison of diagnostic tissue and a fresh tumour biopsy after 4 weeks of treatment at the target S-mebendazole concentration (optional).
Description
Changes in the properties analysed in the archived tissue (baseline) and the fresh biopsy.
Time Frame
Collected up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
Title
Association between S-mebendazole and efficacy and safety
Description
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.
Time Frame
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).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
Dept of oncology, University Hospital
City
Uppsala
ZIP/Postal Code
75185
Country
Sweden
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin.
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