Clinical trial NCT03628079: A Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin.
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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Cancer of the Gastrointestinal Tract
Cancer of Unknown Origin
Lead sponsor: Repos Pharma
Sponsor class: INDUSTRY
Collaborators: name: Uppsala University
name: Uppsala University Hospital
First posted: 2018-08-14
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of adverse events (AEs) probably or possibly related to ReposMBZ
timeFrame: 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.
measure: Changes in plasma Albumin over time
timeFrame: 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.
measure: Changes in C-reactive protein (CRP) over time
timeFrame: 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.
measure: Changes in plasma Sodium, Potassium, Calcium and Glucose over time
timeFrame: 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.
measure: Changes in plasma Bilirubin over time
timeFrame: 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.
measure: Changes in plasma ALAT (alanine aminotransferase), ASAT (aspartate aminotransferase), LDH (lactate dehydrogenase), ALP (alkaline phosphatase) over time
timeFrame: 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.
measure: Changes in Haemoglobin over time
timeFrame: 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.
measure: Changes in red, white and platelet blood cell count over time
timeFrame: 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.
measure: Changes in Activated Partial Thromboplastin Time (APTT) over time
timeFrame: 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.
measure: Changes in Prothrombin complex (PK/INR) over time
timeFrame: 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.
measure: Changes in blood pressure over time
timeFrame: 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.
measure: Changes in heart rate over time
timeFrame: 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.
measure: Changes in body temperature over time.
timeFrame: 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.
measure: Tumour response: CT/MRI assessed according to RECIST 1.1
timeFrame: 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 outcomes:
measure: The peak serum concentration (Cmax) of ReposMBZ after single dose administration.
timeFrame: Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours.
measure: Area under the serum concentration versus time curve (AUC) for ReposMBZ
timeFrame: Pre-dose, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours.
measure: The Cmax serum concentration of ReposMBZ after repeated dose administration.
timeFrame: 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.
measure: Target S-mebendazole concentration after repeated dose administration.
timeFrame: From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase.
measure: Time to reach the steady state S-mebendazole target concentration after repeated dose administration..
timeFrame: From first dose in treatment phase and assessed up to 16 weeks after start of treatment phase.
measure: Systemic immune activation.
timeFrame: From baseline up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
measure: Immune cell activation.
timeFrame: From baseline and up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
measure: Overall survival.
timeFrame: From date of first dose ReposMBZ to date of death, assessed up to 24 months (end of study).
measure: Change in tumour load and TTP according to irRECIST
timeFrame: 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 outcomes:
measure: Association between ReposMBZ efficacy and properties of the diagnostic tumour tissue (optional)
timeFrame: Assessed up to 24 months (end of study).
measure: Comparison of diagnostic tissue and a fresh tumour biopsy after 4 weeks of treatment at the target S-mebendazole concentration (optional).
timeFrame: Collected up to 20 weeks after start of treatment phase, assessed up to 24 months (end of study).
measure: Association between S-mebendazole and efficacy and safety
timeFrame: 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).
Locations:
city: Uppsala
country: Sweden
facility: Dept of oncology, University Hospital
Study officials:
References: