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    Summary
    EudraCT Number:2014-001862-84
    Sponsor's Protocol Code Number:ISO-CC-005
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-01-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNorway - NOMA
    A.2EudraCT number2014-001862-84
    A.3Full title of the trial
    An Open-label, Multiple-site, Phase I/II Dose Cohort Trial of [6R] 5,10-Methylene Tetrahydrofolate (Modufolin®) in Combination with a Fixed Dose of 5-Fluorouracil (5-FU) alone or together with a Fixed Dose of Oxaliplatin or Irinotecan in Patients with Stage IV Colorectal Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Trial to Identify a Suitable Dose of Modufolin® to be Used in Combination with a Fixed Dose of 5-Fluorouracil Alone or Together with a Fixed Dose of Oxaliplatin in Colorectal Cancer Patients
    A.4.1Sponsor's protocol code numberISO-CC-005
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIsofol Medical AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIsofol Medical AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsofol Medical AB
    B.5.2Functional name of contact pointLouise Kvistgaard
    B.5.3 Address:
    B.5.3.1Street AddressArvid Wallgrens backe 20
    B.5.3.2Town/ cityGöteborg
    B.5.3.3Post codeSE-413 46
    B.5.3.4CountrySweden
    B.5.4Telephone number+46 (0)70 750 55 67
    B.5.6E-maillouise.kvistgaard@isofolmedical.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameModufolin® powder for solution for injection 100 mg
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNModufolin API
    D.3.9.2Current sponsor codeModufolin API
    D.3.9.3Other descriptive name(6R)-5,10-methylene-tetrahydrofolic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced metastatic colorectal cancer (stage IV)
    E.1.1.1Medical condition in easily understood language
    Colon cancer that has spread to other organs.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10010035
    E.1.2Term Colorectal cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To characterise the tolerability of Modufolin® in Stage IV CRC patients in terms of toxicity during eight (8) weeks of treatment with one (1) of two (2) dose levels of Modufolin® (30 and 60 mg/m2) in combination either with 5-FU (500 mg/m2) alone (Arm #1), with Oxaliplatin (85 mg/m2) and 5-FU (500 mg/m2) (Arm #2), or with Irinotecan (180 mg/m2) and 5-FU (500 mg/m2) (Arm #3)
    E.2.2Secondary objectives of the trial
    - To characterise all adverse events (AEs) and clinically significant abnormal laboratory test result changes regardless of attribution during the entire study period.
    - To evaluate tumour response and disease progression by means of Objective Response Rate (ORR) at the end of study participation.
    - To assess the level of overall inhibition of thymidylate synthase (TS) as reflected by change of deoxyuridine (dU) levels from before and 24 hours after administration of the combination treatment on Day 1 in Cycle #1 and in Cycle #4 in a subset of patients.
    - To determine the pharmacokinetic characteristics of methylenetetrahydrofolate (MTHF), methyl-tetrahydrofolate (methyl-THF), and tetrahydrofolate (THF) calculated from plasma samples in each cohort following Modufolin® administration on Day 1 in Cycle #1 and in Cycle #4.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Advanced metastatic colorectal (Stage IV) cancer verified by biopsy
    2) CT-scan or MRI of thorax, abdomen and pelvis; within four (< 4) weeks before start of chemotherapy
    3) Evaluable disease and one measurable site of disease according to RECIST 1.1 criteria (at least 10 mm for CT-scan or MRI)
    4) Male and female adults, age of 18 years or older
    5) WHO performance status 0 < 2, and life expectancy > 3 months
    6) Adequate haematological function:
    a) Haemoglobin (Hb) > 100 g/L,
    b) Absolute neutrophil count (ANC) > 1.5x109/L, and
    c) Platelets > 100x109/L
    7) Adequate renal and hepatic functions:
    a) Creatinine clearance > 50 mL/min,
    b) Total bilirubin < 1.5 times upper limit of normal (ULN),
    c) Aspartate transaminase (AST) and Alanine transaminase (ALT) < 3 times ULN (and < 5 times ULN in case of liver metastases)
    8) Negative pregnancy test for females of child bearing potential
    9) Willing and able to provide informed consent
    10) Using adequate contraceptive measures
    Female patients who have been post-menopausal for more than one year or female patients of childbearing potential using a highly efficient method of contraception (i.e. a method with less than 1% failure rate [e.g. sterilisation, hormone implants, hormone injections, some intrauterine devices, or vasectomised partner]).
    Male patients agreeing to use condoms during the study and for three months after the end of the study/last dose of the investigational medicinal product (IMP), or patients having a partner who is using a highly efficient method of contraception as described above.
    E.4Principal exclusion criteria
    1) Tumours other than colorectal adenocarcinomas (current or within the previous 5 years), with the exception for curatively treated non melanoma skin cancer or in situ carcinoma of the cervix.
    2) Adjuvant treatment of CRC within the last 12 months.
    3) Evidence of central nervous system metastases
    4) Unresolved bowel obstruction or sub-obstruction, uncontrolled Crohn’s disease or ulcerative colitis
    5) History of cardiac disease with a New Your Heart Association (NYHA) Class II or greater congestive heart failure, myocardial infarction or unstable angina in the past six (6) months prior to Day 1 of treatment and serious arrhythmias requiring medication for treatment
    6) Current severe chronic diarrhoea
    7) Current chronic infection or uncontrolled serious illness causing immunodeficiency
    8) Any current uncontrolled serious illness or medical condition
    9) Current major psychiatric disorder (e.g. major depression, psychosis)
    10) Participation in another clinical study with an IMP within one (1) month prior to inclusion
    11) Known intolerance to fluoropyrimidine therapy suggestive of dihydropyrimidine dehydrogenase deficiency
    12) Suspicion of hypersensitivity or allergy to the IMP, or to products chemically related to the IMP (i.e. folate derivatives)
    13) Female patients: currently pregnant or breast-feeding.
    E.5 End points
    E.5.1Primary end point(s)
    - Number and severity of dose limiting toxicity (DLT) associated with the administration of the administered chemotherapeutic agents or any other significant AEs at each Modufolin® dose level.
    - Number of patients with adjusted chemotherapeutic agent dose (i.e. 5-FU, Oxaliplatin and/or Irinotecan) due to presence of related toxicity in the individual treatment cohorts.
    E.5.1.1Timepoint(s) of evaluation of this end point
    8 weeks
    E.5.2Secondary end point(s)
    - Number and severity of AEs or clinically significant abnormal laboratory test result changes regardless of causal relationship
    - Determination of Objective Response Rate (ORR) after four (4) cycles of chemotherapy.
    - Deoxyuridine (dU) levels before and 24 hours after administration of the combination treatment on Day 1 in the first and in the last chemotherapy cycle of a subset of patients.
    - Plasma pharmacokinetics of 5,10- Methylene Tetrahydrofolate (MTHF), 5-Methyl Tetrahydrofolate (5-methyl-THF), and Tetrahydrofolate (THF), directly prior, and at 10 minutes, at 1, 2, and 4 hours in each cohort following Modufolin® administration on Day 1 in Cycle #1 and in Cycle #4
    E.5.2.1Timepoint(s) of evaluation of this end point
    8 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Modufolin® has been tested before, first time in combination with 5-FU, Oxilaplatin and Irinotecan
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    Last patient, last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 27
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-03
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-01-30
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