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    Summary
    EudraCT Number:2010-019348-37
    Sponsor's Protocol Code Number:CLDE225X2104
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-11-09
    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 ConcernedFrance - ANSM
    A.2EudraCT number2010-019348-37
    A.3Full title of the trial
    A phase 1 study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway
    A.4.1Sponsor's protocol code numberCLDE225X2104
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameLDE225
    D.3.2Product code LDE225
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.1CAS number 1218778-77-8
    D.3.9.2Current sponsor codeLDE225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 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 nameLDE225
    D.3.2Product code LDE225
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.1CAS number 1218778-77-8
    D.3.9.2Current sponsor codeLDE225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 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 nameLDE225
    D.3.2Product code LDE225
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.1CAS number 1218778-77-8
    D.3.9.2Current sponsor codeLDE225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10066594
    E.1.2Term Medulloblastoma recurrent
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10039027
    E.1.2Term Rhabdomyosarcoma recurrent
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10066595
    E.1.2Term Neuroblastoma recurrent
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10065443
    E.1.2Term Malignant glioma
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10031296
    E.1.2Term Osteosarcoma recurrent
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10019823
    E.1.2Term Hepatoblastoma recurrent
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the MTD of LDE225 in children with advanced solid tumors (recurrent or refractory MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma) when administered on a continuous daily dosing schedule
    E.2.2Secondary objectives of the trial
    • To characterize the safety and tolerability of LDE225 in children with advanced solid
    tumors that are potentially dependent on the Hh signaling pathway.
    • To characterize the PK profile of LDE225 in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
    • To assess any preliminary antitumor activity of LDE225 in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
    • To assess the Hh gene expression signature and the mutational status of Hh pathway genes (ie, Smo, PTCH, SuFu) in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients aged >= 12 months and < 18 years
    • Histologically confirmed diagnosis of MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma, that has progressed despite treatment with standard therapies, or for which no standard treatments are available (patients with brainstem gliomas are excluded from this study).
    • Performance Status: Karnofsky performance status score >= 60% for patients >10 years of age (see Table 7-2), Lansky score >= 50 for patients <= 10 years of age (see Table 7-3)
    Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
    • Adequate renal function as defined by:
    • Serum creatinine <= 1.5 x upper limit of normal (ULN) for age, or
    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 1.17 mL/s/1.73 m2
    • Adequate liver function as defined by:
    • Bilirubin (sum of conjugated + unconjugated) <= 1.5 x ULN for age
    • Serum alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGOT) <= 5 x ULN for age
    • Serum albumin >= 20 g/L
    • Adequate bone marrow function as defined as:
    • Peripheral absolute neutrophil count (ANC) >= 1.0 x 109/L
    • Platelet count >= 80 x 109/L
    • Hemoglobin (Hgb) >= 90 g/L (may receive red blood cell [RBC] transfusions). Patients with a Hgb >= 80 g/L are eligible if their anemia is unequivocally related to recent surgery (rather than suspected bone marrow suppression).
    • For females of child-bearing potential (reproductive or child-bearing potential for this study will be defined as per local site practice): a negative pregnancy test <= 72 hours before starting study treatment is required. If sexually active, females of child bearing potential must use ‘highly effective’ methods of contraception for the study duration and for 3 months following the last dose of LDE225. Highly effective methods of contraception are defined in Section 5.1.
    • For males of reproductive potential: any sexually active male patient must use a condom while on study treatment and for 3 months following the last dose of LDE225. Reproductive or child-bearing potential for this study will be defined as per local site practice.
    • Written informed consent/assent before any study-specific procedures (routine procedures performed as part of standard clinical care are permitted). Consent will be obtained from parent(s) or legal guardians and the signature of at least 1 parent or guardian will be required. Investigators will also obtain assent of patients according to local, regional, or national guidelines.
    • All patients must consent to provide a tumor sample (archival or fresh) for analyses of expression of specific Hh pathway genes and mutations in Smo and PTCH. The tumor material submitted for these analyses may have been obtained at any time during the course of the patient’s disease. It is accepted that it may not be possible to obtain all samples before commencement of study-related treatment. It is also accepted that it may not be possible to obtain a sample for every patient (eg, if sufficient sample does not exist), and in this situation inclusion of the patient should be discussed with Novartis (as this may not make a patient ineligible).
    E.4Principal exclusion criteria
    • Systemic anticancer treatment (including biologic therapy/antibodies) within 2 weeks before first dose of study treatment (6 weeks for nitrosourea, mitomycin, and monoclonal antibodies).
    • Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months of first dose of study treatment.
    • Investigational agents within 2 weeks or <= 5x t1/2 (whichever is longer) before starting study drug.
    • Unresolved toxicity greater than CTCAE grade 1 from previous anticancer therapy or radiation therapy (excluding neurotoxicity, alopecia or other specifications in the eligibility criteria for this study), or incomplete recovery from previous surgery, unless agreed by Novartis and the Principal Investigator (PI) and documented.
    • Patients receiving treatment with medications that are known to be strong inhibitors or inducers of cytochrome P450 3A4/5 (CYP3A4/5) (listed in Post-text supplement 3), or are metabolized by CYP2B6 and CYP2C9, that have low therapeutic indices (listed in Post-Text-Supplement 3), that cannot be discontinued at least 1 week before start of study therapy, and for the duration of the study.
    • Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose must have been stabilized (or decreasing) for at least 7 days before start of study therapy.
    • Patients receiving treatment with enzyme-inducing anticonvulsants (listed in Post-Text-Supplement 3), that cannot be discontinued at least 1 week before start of study therapy, and for the duration of the study. Patients on non-enzyme-inducing anticonvulsants are eligible.
    • Major surgery, serious illness, or traumatic injury within 2 weeks of starting study therapy. Insertion of a gastric feeding tube (G-tube), 3rd ventriculostomy, ventriculoperitoneal (VP) shunt, and central venous access are not considered major surgery.
    • Patients anticipated to require major surgery during the first 2 cycles of treatment in this study.
    • Surgery for revision of an allograft within 3 months of starting study therapy.
    • Patients who require a nasogastric tube for drug administration (G-tubes are permitted)
    • Any concurrent severe and/or uncontrolled medical conditions (eg, uncontrolled diabetes, uncontrolled diarrhea, autoimmune disease including lupus, psoriasis, inflammatory bowel disease, severe infection, severe hypertension, severe cardiovascular disease, clinically significant ECG abnormalities) that in the investigator’s opinion could put the patient at greater risk for treatment-related toxicities or confound the interpretation of clinical outcomes.
    • Patients who have neuromuscular disorders that are associated with elevated CPK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
    • Impaired cardiac function or clinically significant heart disease, including any one of the following:
    • Clinically significant heart disease (eg, congestive heart failure, uncontrolled hypertension, history of labile hypertension, history of poor compliance with an antihypertensive regimen)
    • QTc interval corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec for males and > 470 msec for females on the screening ECG
    • A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
    • Angina pectoris within 3 months of study entry
    • Acute myocardial infarction within 3 months of study entry
    • Pregnant or breast-feeding females.
    • Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or C (testing is not mandatory for study entry).
    • Impairment of GI function or GI disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
    • Patients who in the investigators’ opinion may be unwilling, unable, or unlikely to comply with the requirements of the study protocol.
    E.5 End points
    E.5.1Primary end point(s)
    • Frequency of dose-limiting toxicities (DLTs) associated with daily administration of LDE225
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To define the maximum tolerated dose (MTD)
    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
    To determine the MTD of LDE225 in children
    E.7.2Therapeutic exploratory (Phase II) No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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.1.1.1In 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) Yes
    F.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    patients age >= 12 Months
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 24
    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)
    Expected normal treatment of that 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 Decision2010-12-24
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
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