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    Summary
    EudraCT Number:2014-000316-34
    Sponsor's Protocol Code Number:CCLR457X2101
    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:2015-01-07
    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 number2014-000316-34
    A.3Full title of the trial
    A phase I/II multicenter, open-label study of CLR457 administered orally
    in adult patients with advanced solid malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase I/II multicenter, open-label study of CLR457, administered orally
    in adult patients with advanced solid malignancies
    A.4.1Sponsor's protocol code numberCCLR457X2101
    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 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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma S.A.S.
    B.5.2Functional name of contact pointInformation&Communication Médicale
    B.5.3 Address:
    B.5.3.1Street Address2-4 rue Lionel Terray
    B.5.3.2Town/ cityRueil-Malmaison
    B.5.3.3Post code92500
    B.5.3.4CountryFrance
    B.5.4Telephone number+33155476600
    B.5.5Fax number+33155476100
    B.5.6E-mailicm.phfr@novartis.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 nameCLR457
    D.3.2Product code CLR457
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeCLR457
    D.3.9.4EV Substance CodeSUB130961
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 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 nameCLR457
    D.3.2Product code CLR457
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeCLR457
    D.3.9.4EV Substance CodeSUB130961
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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 nameCLR457
    D.3.2Product code CLR457
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeCLR457
    D.3.9.4EV Substance CodeSUB130961
    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) 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 solid malignancies
    E.1.1.1Medical condition in easily understood language
    Patients bearing solid tumor of breast, endometrium, lung or others as applicable
    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 LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    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
    1. To estimate the MTD or RP2D of CLR457 (dose escalation phase)
    2. To investigate the anti-tumor activity of CLR457 (Phase II)
    E.2.2Secondary objectives of the trial
    1. To characterize the safety and tolerability of CLR457 treatment
    2. To determine the single and multiple dose PK profile of CLR457
    3. To further investigate the anti-tumor activity of CLR457
    4. To assess the PI3K pathway inhibition by CLR457
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent must be obtained prior to any screening procedures
    2. Patient (male or female) ≥ 18 years of age
    3. Phase I: Patients with advanced/metastatic solid tumors, with measurable or non measurable disease as determined by modified RECIST version 1.1 who have progressed despite standard therapy or be intolerant of standard therapy, or for whom no standard therapy exists, who have tumors harboring one of the following: confirmed PIK3CA mutation or amplification, PTEN loss of function, EGFR mutation, cMET activation and/or HER2 overexpression. Endometrial carcinoma will not be selected for any molecular status.
    Phase II: Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by modified RECIST version 1.1, who progressed despite standard therapy or be intolerant of standard therapy, or for whom no standard therapy exists,
    fitting in one of the following groups:
    Group 1: patients with PIK3CA mutated or amplified ER + breast cancer
    Group 2: patients with endometrial carcinoma (not selected for any molecular status)
    Group 3: patients with solid tumors (with the exception of PIK3CA mutant/amplified ER+ breast cancer and endometrial carcinoma) harboring PIK3CA mutation or amplification/any PTEN status
    Group 4: patients with solid tumors (with the exception of endometrial carcinoma) harboring PTEN loss of function/ PIK3CA wild type
    Group 5: patients with non-small cell lung cancer harboring cMET activation and/or EGFR mutation
    4. Up to 3 chemotherapies in advanced/metastatic setting allowed for Phase II patients.
    5. ECOG Performance Status ≤ 2.
    6. Availability of a representative formalin fixed paraffin embedded tumor tissue sample. If archival tumor specimen is not available, a newly obtained tumor specimen needs to be submitted instead.
    E.4Principal exclusion criteria
    1. Brain metastasis unless treated and neurologically stable
    2. Patient having out of range laboratory values defined as:
    Hepatic and renal function:
    • Serum total Bilirubin≥1.5 x ULN (upper limit of normal) or aspartate aminotransferase (AST) and alanine aminotransferase (ALT≥ 2.5 x ULN)
    • Patients with tumor involvement of the liver must have AST and/or ALT >5 x ULN
    • For patients with Gilbert's syndrome total bilirubin >2.5 x ULN
    • Serum creatinine >1.5 x ULN and/or measured or calculated creatinine clearance < 75% LLN (lower limit of normal)
    Bone marrow function:
    • Platelets < 100 x 10^9/L
    • Hemoglobin (Hgb) < 9 g/dL
    • Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L
    Cardiac function:
    • Clinically significant and/or uncontrolled heart disease such as congestive heart failure (CHF) requiring treatment (NYH grade ≥ 2), hypertension or arrhythmia
    • left ventricule ejection fraction (LVEF) < 45% as determined by MUGA scan or ECHO
    • QTcF >480 msec on screening ECG or congenital long QT syndrome
    • Acute myocardial infarction (AMI) or unstable angina pectoris ≤ 3 months prior to study entry
    3. Peripheral neuropathy CTCAE Grade ≥ 2.
    4. History of pancreatitis of any grade.
    5. Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with Fasting Plasma Glucose (FPG) ≥ 140 mg/dL / 7.8 mmol/L
    6. Patients receiving treatment with medications that are known to be
    1) strong inhibitors or inducers of CYP3A4/5; 2) CYP2C9 substrate with narrow therapeutic index; 3) QT prolonging agents; 4) proton pomp inhibitors unless these medications can be discontinued at least a week prior to start of treatment.
    E.5 End points
    E.5.1Primary end point(s)
    1- Incidence of DLT
    2- Objective response rate (ORR) per RECIST v1.1 by investigator assessment
    E.5.1.1Timepoint(s) of evaluation of this end point
    1- First 28 days of dosing
    2- Baseline and every 8 weeks
    E.5.2Secondary end point(s)
    1- Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs
    Tolerability: Dose interruptions and reductions
    2- Plasma concentration of CLR457 and PK parameters including but not limited to Cmax, Cmin, AUCinf, AUCtlast, AUCtau and T1/2
    3- Best overall response (BOR), duration of response (DOR), progression free survival (PFS) per RECIST v1.1 by investigator assessment
    4- Changes from baseline in glucose metabolism markers (fasting
    glucose and insulin)
    Pre- and post- treatment immunohistochemistry of PI3K pathway molecules (e.g. p-S6, p-AKT) in newly obtained tumor samples
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- Continuously throughout the study until 30 days after safety follow up
    2- During phase I:
    Baseline; Cycle 1 Day 1, 2, 8, 15, 16 and 22; Cycle 2 Day 1, 2, from Cycle 3 to cycle 6 on Day 1
    During Phase II:
    Baseline; Cycle 1 Day 1, 2, 8, 15, 16 and 22
    3- Baseline and every 8 weeks
    4- Blood for glucose metabolism markers collected on C1D1, C1D2, C1D15, C1D16, C2D1 and C2D2.
    Paired newly obtained tumor samples collected at baseline and at C2D1.
    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 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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    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.8.2.4Number of treatment arms in the trial5
    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 EEA10
    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
    Australia
    Austria
    Canada
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Singapore
    Spain
    United States
    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
    The end of study will be upon completion of the follow-up for the disease progression period or 30 day safety follow up period (whichever is later) for all patients treated in all arms or when the study is terminated early.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months30
    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: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 53
    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 93
    F.4.2.2In the whole clinical trial 163
    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 Decision2014-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-11-12
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