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    Summary
    EudraCT Number:2010-021719-18
    Sponsor's Protocol Code Number:KS-2009-003
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-10-05
    Trial 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 ConcernedGermany - BfArM
    A.2EudraCT number2010-021719-18
    A.3Full title of the trial
    Phase I/II study on cytarabine and idarubicine combined with escalating doses of clofarabine as induction therapy in patients with acute myeloid leukemia and high risk for induction failure (CIARA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Dose-finding study of the substance clofarabine in combination with fixed doses of cytarabine and idarubicine as therapy for patients with acute myeloid leukemia and high risk for treatment failure (CIARA)
    A.3.2Name or abbreviated title of the trial where available
    AMLSG 17-10
    A.4.1Sponsor's protocol code numberKS-2009-003
    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 SponsorHannover Medical School
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGenzyme Europe BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation
    B.5.2Functional name of contact pointClARA clinical trial information
    B.5.3 Address:
    B.5.3.1Street AddressCarl-Neuberg-Str. 1
    B.5.3.2Town/ cityHannover
    B.5.3.3Post code30625
    B.5.3.4CountryGermany
    B.5.4Telephone number+49511532 3021
    B.5.5Fax number+495115328041
    B.5.6E-mailganser.arnold@mh-hannover.de
    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 Yes
    D.2.1.1.1Trade name Evoltra® 1mg/ml Konzentrat zur Herstellung einer Infusionslösung
    D.2.1.1.2Name of the Marketing Authorisation holderGenzyme Europe BV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameClofarabine
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNCLOFARABINE
    D.3.9.1CAS number 123318-82-1
    D.3.9.4EV Substance CodeSUB21902
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.2.5The 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 nameCytarabine
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNCYTARABINE
    D.3.9.1CAS number 147-94-4
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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: 3
    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.2.5The 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 nameIdarubicin
    D.3.4Pharmaceutical form Solution for injection/infusion
    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 INNIDARUBICINE
    D.3.9.1CAS number 58957-92-9
    D.3.9.4EV Substance CodeSUB08111MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    Patients with acute myeloid leukemia (AML) and high risk for induction failure
    E.1.1.1Medical condition in easily understood language
    high risk blood cancer
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    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
    Evaluation of tolerability and safety of escalating doses of clofarabine in combination with cytarabine and idarubicine in the therapy of previously untreated patients with AML and high risk for induction failure
    E.2.2Secondary objectives of the trial
    •Definition of the recommended dose level of the combination of clofarabine, cytarabine and idarubicine for upcoming phase III trials in the therapy of previously untreated patients with AML and high risk for induction failure
    •Evaluation of the efficacy of escalating doses of clofarabine in combination with cytarabine and idarubicine in the therapy of previously untreated patients with AML and high risk of induction failure
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with newly diagnosed acute myeloid leukemia according to WHO classification and aged ≥ 18 years eligible for an intensive induction chemotherapy with high risk for induction failure and for whom currently no molecularly targeted therapy is available:
    • absence of a t(15;17), t(8;21), inv(16)/t(16;16) and the respective fusion transcripts PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11
    • absence of an activating FLT3-mutation (FLT3-ITD or TKD - mutation)
    • absence of an NPM1 exon12 mutation
    2. Written informed consent
    3. No previous cytotoxic chemotherapy for the treatment of AML (exception: oral hydroxyurea for up to 5 days during screening/baseline to control hyperleukocytosis)
    4. Adequate renal and hepatic functions as indicated by the following laboratory values:
    • Serum creatinine </= upper limit of normal (ULN) or glomerular filtration rate (GFR) > 60 mL/min/1.73 m2, respectively
    • Serum bilirubine </= 1.5 x ULN
    • Aspartate aminotransferase (AST/SGOT) /alanine aminotransferase (ALT/SGPT) </= 2.5 x ULN
    • Alkaline phosphatase (ALP) </= 2.5 x ULN
    5. Capable of understanding the investigational nature, potential risks and benefits of the study
    6. Women of childbearing potential must have a negative serum pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to start of IMP treatment
    7. Female patients must meet one of the following criteria:
    • For female patients > = 50 years of age at the day of inclusion: Menopause since at least 1 year
    • Female patients < 50 years of age at the day of inclusion who meet all of the following criteria:
    • menopause since at least 1 year
    • serum FSH levels > 40 MIU/mL
    • serum estrogen levels < 30 pg/mL or negative estrogen test
    • 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy
    • Correct use of two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide. In case the patient takes hormone preparations for suppression of menstruation during the period of aplasia, a suitable and effective method of contraception has to be discussed with the investigator and used by the patient
    • General sexual abstinence from the time of screening/baseline, during the study until a minimum of 90 days after the last administration of study medication
    • Having only female sexual partners
    • Monogamous relationship with sterile male partner
    8. Male patients must meet one of the following criteria:
    • 6 weeks after surgical sterilization by vasectomy
    • Correct use of two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide.
    • General sexual abstinence from the time of screening/baseline during the study until a minimum of 90 days after the last administration of study medication
    • Having only male sexual partners
    • Monogamous relationship with sterile female partner
    E.4Principal exclusion criteria
    1. Current concomitant chemotherapy, radiation therapy or immunotherapy not defined in the study protocol
    2. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of oral hydroxyurea. The patient must have recovered from all non-hematological acute toxicities from any previous therapy
    3. Participation in a clinical trial within 30 days before inclusion in this study or concurrent to this study.
    4. Bleeding disorder independent of AML
    5. Patients with uncontrolled systemic fungal, bacterial, viral or other infection (defined as persistent disease signs/symptoms without improvement despite appropriate antibiotics or other treatment)
    6.Patients with clinically relevant heart disease such as:
    •History of acute myocardial infarction within the last 6 months
    •Heart failure NYHA grade III or IV due to myocardial infarction or other causes
    •Acute inflammatory heart disease
    •Unstable atrial fibrillation or other hemodynamically relevant arrythmias
    7. HIV infection
    8. Patients who have received cumulative doses of ≥ 360mg/m2 of doxorubicin or its equivalent to other anrthracyclines, e.g. 900mg/m2 of daunorubicin, 450mg of pegylated liposomal doxorubicin hydrochloride, 225mg/m2 idarubicin or 140mg/m2 mitoxantrone
    9. Pregnant or lactating women
    10. Any significant concurrent disease, illness, psychiatric disorder or history of serious organ dysfunction that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
    11. Diagnosis of another malignancy, unless the patient is disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions:
    • Myelodysplastic syndrome (MDS) in patients with AML after MDS according to the WHO classification
    • Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed.
    12. Known hypersensitivity to any of the IMPs
    E.5 End points
    E.5.1Primary end point(s)
    Maximal tolerable dose (MTD) of clofarabine in combination with cytarabine and idarubicine in the therapy of previously untreated AML and high risk for induction failure
    E.5.1.1Timepoint(s) of evaluation of this end point
    MTD will be defined on the basis of the occurrence of dose-limiting toxicities (DLTs) measured within 14 days after start of the first induction cycle (max. 42 days after start of the first induction cycle in case of hematological DLTs)
    E.5.2Secondary end point(s)
    1. Rate of complete remission after two cycles of induction therapy
    2. Relapse-free, event-free and overall survival
    3. Blast reduction in the bone marrow after the first induction cycle
    4. Duration of aplasia
    5. Therapy-associated morbidity and mortality
    6. Course of molecular and cytogenetic markers during chemotherapy
    7. Fraction of patients who receive an alloSCT in CR1
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. 3 months
    2. 2 years
    3. max. 42 days after start of the first induction cycle
    4. max. 42 days after start of the first induction cycle
    5. 2 years
    6. 3 months
    7. 2 years
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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
    Dose-finding study of clofarabine in combination with cytarabine and idarubicine
    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 No
    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 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 concerned6
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    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 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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state60
    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)
    see protocol; 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 Decision2011-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-23
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