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    Summary
    EudraCT Number:2013-001280-23
    Sponsor's Protocol Code Number:ISO-MTX-003
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-07-21
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2013-001280-23
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase I/II Clinical Trial to Identify the Modufolin® Dose with Most Favorable Safety Prospect and Confirmed Ability to Mitigate High-Dose Methotrexate Induced Toxicity during Treatment of Osteosarcoma Patients
    Otevřená, multicentrická klinická studie fáze I/II za účelem identifikace dávky Modufolinu® s nejuspokojivějším bezpečnostním profilem a potvrzenou schopností snížit toxicitu způsobenou vysokými dávkami metotrexátu u pacientů během léčby osteosarkomu
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to identify an appropriate Modufolin® dose with respect to safety and ability to mitigate high-dose Methotrexate induced toxicity in osteosarcoma patients.
    Klinické hodnocení pro identifikaci vhodné dávky léčivého přípravku Modufolin® s ohledem na bezpečnost a schopnost zmírnit toxicitu vyvolanou vysokými dávkami metotrexátu u pacientů s osteosarkomem
    A.3.2Name or abbreviated title of the trial where available
    Investigation of Modufolin® as rescue therapy for osteosarcoma patients treated with HDMTX
    A.4.1Sponsor's protocol code numberISO-MTX-003
    A.5.4Other Identifiers
    Name:N/ANumber:N/A
    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 organisationSkåne University Hospital
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressDepartment of Oncology/SUS
    B.5.3.2Town/ cityLund
    B.5.3.3Post codeSE-221 85
    B.5.3.4CountrySweden
    B.5.4Telephone number+46(0)46177507
    B.5.5Fax number+46(0)46176080
    B.5.6E-mailmikael.eriksson@med.lu.se
    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®
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Lyophilisate 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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    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 nameCalcium Folinate
    D.3.4Pharmaceutical form 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 INNCALCIUM FOLINATE
    D.3.9.1CAS number 1492-18-8
    D.3.9.2Current sponsor codeCalcium Folinate
    D.3.9.4EV Substance CodeSUB06054MIG
    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
    Rescue after High Dose Methotrexate therapy in Osteosarcoma patients.
    E.1.1.1Medical condition in easily understood language
    Rescue after High Dose Methotrexate therapy in Osteosarcoma patients.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10061814
    E.1.2Term Detoxification
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To characterize safety in terms of toxicity during HDMTX treatment and folate rescue therapy with either Modufolin® or Calcium Folinate.
    • To identify the recommended dose of Modufolin® for further assessment.
    E.2.2Secondary objectives of the trial
    • To examine the feasibility of Modufolin® as folate rescue therapy for HDMTX treatment in osteosarcoma patients previously treated with Calcium Folinate as rescue therapy.
    • To characterize all AEs and laboratory test result changes regardless of attribution during the entire study period.
    • To study the pharmacokinetic profiles of [6R] 5,10-MTHF, 5-formyl-THF, 5-methyl-THF, and THF in plasma.
    • To study the pharmacokinetic profile of S-MTX.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have histological evidence of osteosarcoma including metastatic osteosarcoma.
    2. Patients must be eligible for high-dose methotrexate treatment (HDMTX) according to the MAP treatment schedule described in the study protocol (see Appendix 1) and fulfill all of the criteria below prior to first course of HDMTX in the study.
    a. Serum MTX: ≤ 0.1µmol/L
    b. Neutrophils: ≥ 0.25 x 109/L
    c. Platelets: ≥ 50 x 109/L
    d. Serum bilirubin: ≤ 1.25 x ULN
    e. GFR ≥ 70 mL/min/1.73 m2
    f. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator.
    3. Patients must be enrolled in HDMTX course 1, 3 or 5 of the MAP treatment schedule (see Appendix 1).
    4. Patients enrolled in HDMTX course 3 or 5 must have a history of successful advancement from first to second HDMTX course within the previous MAP cycle, i.e. fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle:
    a. Serum MTX: ≤ 0.1µmol/L
    b. Neutrophils: ≥ 0.25 x 109/L
    c. Platelets: ≥ 50 x 109/L
    d. Serum bilirubin: ≤ 1.25 x ULN
    e. GFR ≥ 70 mL/min/1.73 m2
    f. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator.
    5. Patients enrolled in HDMTX course 3 or 5 must have a history of successful advancement to next MAP cycle after end of previous MAP cycle, i.e. fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle:
    a. Serum MTX: ≤ 0.1µmol/L
    b. Neutrophils: ≥ 0.75 x 109/L
    c. Platelets: ≥ 75 x 109/L
    d. Serum bilirubin: ≤ 1.25 x ULN
    e. GFR ≥ 70 mL/min/1.73 m2
    f. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator.
    6. Patients must be 12-40 years of age. The age limit may be lowered to 6-40 years for enrolment in Cohort 2 (only) and if recommended by the
    DSMB.
    7. Sexually active females of childbearing potential: Must be surgically sterile, or compliant with a contraceptive regimen during and for six (6) months after last MTX dose in MAP regimen; must have a negative serum or urine pregnancy test (within seven (7) days before study enrolment) and must not be lactating.
    8. Sexually active males: Must be surgically sterile or compliant with a contraceptive regimen during and for six (6) months after last MTX dose in MAP regimen.
    9. Patient, parent(s), or guardian(s), as appropriate, is/are willing and able to provide signed informed consent.
    10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures specified in the protocol.
    11. Patients who have undergone surgical resection of their tumor must have recovered from their surgery and be eligible to continue on the MAP regimen; any post-operative complications should be resolved to NCI CTCAE v4.0 Grade 1 or better.
    E.4Principal exclusion criteria
    1. Involvement in another clinical trial within 30 days before enrolment in the study.
    2. Hypersensitivity to Calcium Folinate.
    3. Previous treatment with glucarpidase.
    4. Known serious concomitant systemic disorders (e.g., active infection including HIV, liver dysfunction, cardiac disease) that, in the opinion of the investigator, would compromise the patient's ability to complete the study
    E.5 End points
    E.5.1Primary end point(s)
    • Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0.
    • Identification of the recommended Modufolin® dose selected for further assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Safety - Continously during the study
    • Recommended dose - At Follow-up visit
    E.5.2Secondary end point(s)
    • Number of administered HDMTX courses with Modufolin rescue classified as having met the criteria for successful advancement at scheduled time according to Definition A and/or Definition B.
    • Number of administered MAP cycles with Modufolin rescue classified as having met the criteria for successful advancement from first to second HDMTX course within the same MAP cycle at scheduled time according to Definition A.
    • Number of administered MAP cycles with Modufolin rescue classified as having met the criteria for successful advancement to next MAP cycle at scheduled time according to Definition B.
    • Time (hours) to successful MTX elimination (Definition C).
    • Number of HDMTX courses in which the dose of study drug was increased.
    • Number of HDMTX courses in which the frequency of study drug administration was increased.
    • Number of HDMTX courses in which the hydration was increased.
    • Number of HDMTX courses with delayed early MTX elimination (Definition E).
    • Number of HDMTX courses with delayed late MTX elimination (Definition F).
    • Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D excretion toxicities as listed in the MTX-toxicity management instructions (see Appendix 2), i.e. delayed elimination of MTX, increased serum creatinine or occurrence of events of mucositis oral or bone marrow hypocellular.
    • Characterization (frequency and severity) of all reported AEs regardless of attribution per NCI CTCAE v4.0 and laboratory test result changes of clinical relevance during the entire study period.
    • Study PK parameters from plasma such as AUC, AUClast, C5min, t1/2, λz, MRT, CL, Vz and Vss calculated for [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF, if data permits.
    • Study PK parameters from serum such as AUC, AUClast, C5min, t1/2, λz, MRT, CL, Vz and Vss calculated for MTX.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Successful advancement - Eight (8) days after start of HDMTX administration of each HDMTX course
    • Successful MTX elimination - start at HDMTX administration of each HDMTX course
    • Safety - continously during the entire study period.
    • PK assessments - Day 2 and Day 3 of each HDMTX course
    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 Yes
    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
    PK/PD
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial 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
    Last visit of the last subject
    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 months40
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months42
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 18
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 18
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18
    F.1.3Elderly (>=65 years) No
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 18
    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)
    All subjects will recieve treatment according to routine care of the specific condition.
    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 Decision2014-09-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-01-03
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