E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Squamous cell cancer or adenocarcinoma, including primary cancer of the liver, of the gastrointestinal tract or cancer of unknown origin |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017985 |
E.1.2 | Term | Gastrointestinal neoplasm malignant |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
· Safety profile of Repos MBZ.
· Anti-tumour efficacy: tumour response rate and prolongation of time to tumour progression (TTP) according to RECIST 1.1. |
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E.2.2 | Secondary objectives of the trial |
· The single dose pharmacokinetic (PK) profile of Repos MBZ.
· The steady state PK profile of Repos MBZ.
· Repos MBZ induced changes in blood cytokines and immune cells.
· Overall survival.
· Change in tumour load and TTP according to irRECIST |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. -
7. Pharmacological treatment attempt considered reasonable.
8. Females of childbearing potential should use adequate contraception throughout the study;
a. Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation (oral, intravaginal or transdermal)
b. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)
c. Intrauterine device (IUD)
d. Intrauterine hormone-releasing system (IUS)
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Sexual abstinence
9. Signed informed consent. |
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E.4 | Principal exclusion criteria |
1. Anti-tumour therapy within 3 weeks prior to study drug administration day 1.
2. Ongoing infection or other major recent or ongoing disease that, according to the Investigator’s assessment, 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.:
a. neutrophils ≤ 1,3 x 109/l
b. platelets ≤ 100 x 109/l
c. bilirubin > 1.5 x ULN
d. ALAT > 5 x ULN
e. GFR <50 ml/min (calculated from P-creatinine)
f. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety:
· Number of AEs probably or possibly related to the study drug, graded according to CTCAE 4.03
· Changes in lab parameters and vital sign over time vs baseline
Efficacy:
· Best overall radiological response according to RECIST 1.1.
· Time to tumour progression on Repos MBZ compared with time to progression on the treatment just preceding participation in this protocol. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety:
Continuously during treatment and up to 0-30 days after treatment stop.
Efficacy:
Every 8 weeks during study / until progress. |
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E.5.2 | Secondary end point(s) |
· Cmax, Tmax and T1/2 after single dose Repos MBZ.
· Number of patients that reach the steady state S-mebendazole target concentration of 300 ng/ml (accepted range 250 – 350 ng/ml), time to reach this concentration and S-mebendazole concentration variation over time.
· Immunological changes induced by mebendazole from baseline, as reflected in cytokines and immune cells in blood
· Overall survival from start of treatment phase to death from any cause.
· Best overall radiological response according to irRECIST 1.1. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK-parameters will be assesed weekly until target concentration is reached . Then PK will be assessed every 4 weeks.
Survival will be followed up until time to death. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |