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    Summary
    EudraCT Number:2009-009999-12
    Sponsor's Protocol Code Number:ISO-MC-091
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2010-01-13
    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 ConcernedSweden - MPA
    A.2EudraCT number2009-009999-12
    A.3Full title of the trial
    An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate and Pemetrexed Single Agent, given
    as Neoadjuvant Treatment in Patients with Resectable Rectal Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate and Pemetrexed Single Agent, given
    as Neoadjuvant Treatment in Patients with Resectable Rectal Cancer
    A.4.1Sponsor's protocol code numberISO-MC-091
    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 organisationEva Rongård
    B.5.2Functional name of contact pointSenior Clinical Manager
    B.5.3 Address:
    B.5.3.1Street AddressBiotech Center, Arvid 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)70924 94 25
    B.5.6E-maileva.rongard@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
    D.3.2Product code LMTH
    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)
    Intravenous use
    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-Methylenetetrahydrofolic acid
    D.3.9.4EV Substance CodeSUB96099
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 500
    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 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 Yes
    D.2.1.1.1Trade name Alimta
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameAlimta
    D.3.2Product code LY231514
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMETREXED
    D.3.9.1CAS number 137281-23-3
    D.3.9.2Current sponsor codeLY231514 disodium
    D.3.9.4EV Substance CodeSUB09655MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    Resectable Rectal Cancer
    E.1.1.1Medical condition in easily understood language
    Rectal Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10038045
    E.1.2Term Rectal cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the feasibility of Methylenetetrahydrofolate (Modufolin®) and Pemetrexed (Alimta®) single agent as neoadjuvant treatment in patients with resectable rectal cancer; and
    • To identify the optimal dose of Methylenetetrahydrofolate (Modufolin®) in combination with a fixed dose of Pemetrexed (Alimta® 500mg/m2) with the most advantageous safety and efficacy profile
    E.2.2Secondary objectives of the trial
    • To evaluate the pathological complete response rate;
    • To evaluate the prop. of patients who undergo sphincter saving surgery compared with those for whom anal sphincter system cannot be preserved;
    • To characterize all toxicities experienced by patients, regardless of attribution, from beginning of study treatment until the postop. visit;
    • To investigate the changes in the levels of mTHF in tumor tissue compared with normal tissue following completed treatment with Modufolin® and Alimta®;
    • To investigate whether there is a correlation between mTHF and Hcy levels in blood;
    • To evaluate whether the occurrence of folate gene polymorphisms and microarray signature profiles is correlated with the clin. outcomes and tox.profiles of patients;
    • To compare the PK parameters (i.e. exposure by means of AUC) of [6R] 5,10-mTHF, 5-formyl-THF, 5-methyl-THF and THF calculated from plasma samples conc. in patients receiving i.v. bolus injections of Modufolin® of either 200 or 500 mg/m2.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Protocol for Translational Research Studies Associated with the Extended Phase I/II Studies of
    Methylenetetrahydrofolate in Preoperative Rectal Cancer Patients ISO-MC-091 Final Protocol: version 2:1 2013-04-05

    Objectives/Hypothesis:
    A hypothesis has been put forward that tumor and normal hosts tissue have differential folate requirements, such that the supplemental amount of folate is sufficient to selectively protect the toxic effect of Pemetrexed in normal versus the tumor. Therefore, to address this hypothesis in this trial, attempts will be made to study how i.v. dosing of Methyleneterahydrofolate affects folate and homocysteine levels in blood, and in turn folates as reflected by the intracellular folates, such as mTHF and 5-methylTHF in the tumor and adjacent normal tissues, both before and after starting vitamin supplementation. It is hoped that understanding how folic acid modulate toxicity may allow future fine-tuning of the vitamin regimen.
    E.3Principal inclusion criteria
    1. Pathological or cytological diagnosis of adenocarcinoma of the rectum. Patients must have operable rectal cancer that is amenable to curative surgery.

    2. No prior therapy for rectal cancer.

    3. Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale. (See Protocol Attachment S091.2).

    4. Adequate organ function that includes the following indices:
    - adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and hemoglobin ≥9 g/dL.
    - hepatic: bilirubin ≤1.5 times the upper limit of normal (x ULN), alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤3.0 x ULN).
    - renal: calculated creatinine clearance (CrCl) ≥ 45 ml/min by using the standard Cockcroft and Gault formula (see Protocol Attachment S091.3). Creatinine clearance enrollment and dosing decisions may be made on the basis of either local lab values or central laboratory values (the central laboratory reports the calculated value directly). A patient may be enrolled on the basis of the local lab values.

    5. Patient compliance and geographic proximity that allow adequate follow-up.

    6. For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen during and for 3 months after treatment; must have a negative serum or urine pregnancy test (within 7 days before enrolment) and must not be lactating.
    For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.

    7. Estimated life expectancy of at least 12 weeks.

    8. Patients must sign an informed consent document.

    9. Patients must be at least 18 years of age.
    E.4Principal exclusion criteria
    1. Concurrent administration of any other anti-tumor therapy.

    2. Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.

    3. Serious concomitant systemic disorders (e.g., active infection including HIV, cardiac disease) that in the opinion of the investigator would compromise the patient's ability to complete the study.

    4. Have previously completed or withdrawn from this study or any other study investigating Pemetrexed.

    5. Are pregnant or breast-feeding.

    6. Second primary malignancy except for basal-cell carcinoma and in situ carcinoma of the cervix, that is clinically detectable at the time of consideration for study enrollment.

    7. History of significant neurological or mental disorder, including seizures or dementia.

    8. Inability to interrupt aspirin or other no steroidal anti-inflammatory drugs (NSAIDs) 2 days before, the day of and 2 days after administration of Pemetrexed. If a patient is taking an NSAID or salicylate with a long half-life (e.g., Naproxen, Piroxicam, Diflunisal, Nabumetone, Refexocib, Celecoxib) it should not be taken 5 days before, the day of and 2 days after administration of Pemetrexed.

    9. Presence of clinically relevant (i.e., detectable by physical examination) third-space fluid collection (e.g., ascites, pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry.

    10. Inability or unwillingness to be given Methylenetetrahydrofolate, vitamin B12 or Dexamethasone
    E.5 End points
    E.5.1Primary end point(s)
    • Feasibility by means of the ability to receive the total planned dose of Pemetrexed (i.e., 1500 mg/m2) administered over a period of no more than 9 weeks
    • Optimal dose of Methylenetetrahydrofolate (Modufolin®), identified by determining the concentration of Deoxyuridine in blood (surrogate marker for inhibition of thymidylate synthase) and by monitoring of Pemetrexed-related toxicity.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of treatment phase.
    E.5.2Secondary end point(s)
    • Pathological response rate (pCR);
    • Time to objective progressive disease (TOPD);
    • Proportion of patients with sphincter saving surgery;
    • Characterization (frequency and severity) of all reported or observed toxicities regardless of attribution, including postoperative complications (e.g. bleeding, anastomosis leakage, serious infection), from beginning of study treatment until the postoperative visit;
    • mTHF levels in tumor and. normal tissue, before and after treatment with study drugs;
    • mTHF and Hcy levels in blood;
    • Tracing of folate gene polymorphisms and micro array signature profiles;
    • The following PK parameters will be calculated on Day1 (Modufolin® combo with Alimta®) and Day15 (Modufolin® alone) after cycle 1 and 3:
    - C10min from plasma concentration of [6R] 5,10-methylene-THF, 5-methyl-THF and THF, and of 5-formyl-THF if data permits;
    - AUC(0-1h) and AUC(0-1h)/Dose, calculated from plasma concentration of [6R] 5,10-methylene-THF, 5-methyl-THF and THF, and of 5-formyl-THF if data permits;
    - AUC(0-2h) and AUC(0-2h)/Dose, calculated from plasma concentration of [6R] 5,10-methylene-THF, 5-methyl-THF and THF;
    - AUC(0-4h) and AUC(0-4h)/Dose calculated from plasma concentration of [6R] 5,10-methylene-THF, 5-methyl-THF and THF.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety end points will be evaluated continously. The dose of Methylenetetrahydrofolate, which diminish the side effects of Pemetrexed, will be evaluated during the dose-finding part of the study. The TOPD from the date of study enrollment to the date of objectively determined progressive disease. Other end-points after end of assessment/treatment.
    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
    PK of two different doses to be compared
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.5The trial involves multiple Member States No
    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 is currently estimated to Q1 2015.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months9
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state70
    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)
    Subjects will be treated according to routine treatment 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 Decision2010-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-02-01
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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