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    Summary
    EudraCT Number:2006-002766-20
    Sponsor's Protocol Code Number:CAUY922A2101
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-05-16
    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 ConcernedUK - MHRA
    A.2EudraCT number2006-002766-20
    A.3Full title of the trial
    A phase I dose escalation, multi-center, open-label study of AUY922 administered IV on a once-weekly schedule in adult patients with advanced solid malignancies including phase II expansion arms in patients with either HER2 positive or ER positive locally advanced or metastatic breast cancer.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberCAUY922A2101
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberN/A
    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 nameAUY922
    D.3.2Product code 7006253
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 747412-49-3
    D.3.9.2Current sponsor codeAUY922-AGA
    D.3.9.3Other descriptive nameAUY922 mesylate
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Dose-expansion study to assess safety, tolerability & efficacy:
    -One arm (MTD expansion) will enroll advanced cancer patients (other than breast carcinoma).
    -Two arms (phase II) to assess response in following breast cancer patients:
    1. HER2+ inoperable locally advanced or metastatic breast cancer.
    2. ER+ inoperable advanced/metastatic breast cancer progressed on at least 1 and received up to 3 lines of standard seq. endocrine therapy and who received up to 2 lines of cytotoxic therapy.
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Breast cancer dose expansion arms (phase II component): two arms will be expanded to assess response in the following breast cancer pt:
    1. Pts with HER2+ inoperable locally advanced or metastatic breast cancer:
    • History of trastuzumab resistance
    • Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or apatinib in combination with other agents) and up to 2 lines of cytotoxic therapy for advanced disease.
    • Pts who develop metastases whle receiving adjuvant or neoadjuvant trastuzumab.
    2. Pts with ER+ inoperable locally advanced or metastatic breast cancer whose disease has progressed on at least 1 and received up to 3 lines of standard sequence endocrine therapy and who received up to 2 lines of cytotoxic therapy for advanced disease.
    E.2.2Secondary objectives of the trial
    • The MTD expansion arm will enrol patients with solid tumors other than breast cancer to assess safety and preliminary anti-tumor activity.
    • Assess changes in pre and post AUY922 dosing in:
    -target and downstream PD markers in PBMCs and in tumor tissue biopsies
    -relevant client proteins and in cellular response markers in biopsies of tumor tissue
    -cellular response markers in peripheral blood
    •Quantitate the nb of CTC
    • Assess:
    -changes in the HER2 extracellular domain in pre and post AUY922 dosing in peripheral blood in HER2+ and ER+(including HER2-) locally advanced or metastatic
    breast cancer pts
    -genetic variants of the UGT1A1 gene and their potential impact on the PK profiles
    -the original status of the HER2 and ER HSP90 client proteins in archival tumor tissue, the mutational status of specific genes of client proteins in tumor tissue, and their
    potential association with response
    -changes in cellular physiology
    • Evaluate the biomarkers
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. MTD dose expansion arm: Patients with histologically confirmed, advanced malignant solid tumors whose disease has progressed on standard therapy or for whom no standard therapy exists.
    Breast cancer phase II expansion arms only
    a. Female patients with ER positive HER2 positive inoperable locally advanced or
    metastatic breast cancer must have:
    • History of trastuzumab resistance, defined as either local or systemic disease
    progression on treatment with at least 8 weeks of a trastuzumab containing regimen.
    • Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or lapatinib in combination with other agents) for advanced disease.
    • Recieved up to 2 lines of cytotoxic therapy for advanced disease.
    Patients who develop metastases while receiving adjuvant or neo-adjuvant trastuzumab are eligible.
    HER2 positive patients, tumor/s must demonstrate HER2 over-expression based on either:
    • Immunohistochemistry (IHC) at the 3+ level, or
    • IHC 2+ confirmed by fluorescence in-situ hybridization (FISH). Tumors tested by FISH must be positive by the specific FISH assay for the amplification of HER2.
    b. Female patients with ER positive inoperable locally advanced or metastatic breast cancer whose disease has progressed on at least one and up to 3 lines of std squence endocrine therapy and who have received up to 2 lines of cytotoxic therapy for advanced disease.
    2. All patients must have at least one measurable lesion as defined by RECIST. Irradiated lesions are only evaluable for disease progression.
    3. All patients must have progressive disease before entering to the study.
    4.Patients who fulfill the following criteria will be eligible for PET assessments:
    Indications: tumor types expected to have a high FDG uptake, such as breast, lung, GIST, melanoma & colorectal cancer.
    • At least one lesion must be measurable (>2cm).
    • To be eligible for follow-up scans, patients should have uptake of the tracer in at least one lesion with a tumor-muscle ratio ≥2.
    • Able to lie still and flat on the PET table.
    5. Age ≥ 18 years.
    6. World Health Organization (WHO) Performance Status of ≤ 2.
    7. Life expectancy of ≥ 12 weeks.
    8. Patients must have the following laboratory values:
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
    • Hemoglobin (Hgb) ≥ 9 g/dl
    • Platelets (plt) ≥ 100 x 109/L
    • Potassium within normal limits or correctable with supplements
    • Total calcium (corrected for serum albumin) within normal limits or correctable with
    supplements
    • Magnesium within normal limits or correctable with supplements
    • Phosphorus within normal limits or correctable with supplements
    • AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if
    liver metastases are present
    • Serum bilirubin ≤ 1.5 x ULN
    • Serum albumin ≥ 2.5g/dl
    • Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 ml/min
    • Negative serum pregnancy test. The serum pregnancy test must be conducted prior to the first administration of AUY922 (≤72 hours prior to dosing) in all pre-menopausal women and women < 2 years after the onset of menopause.
    9. Able to sign informed consent and to comply with the protocol.
    E.4Principal exclusion criteria
    1. Patients with CNS metastasiswhich are symptomatic or require ttt for symptom control and/or growing. Note: patients without clinical signs or symptoms of CNS involvement are not required to have a CT/MRI of the brain.
    2. Prior treatment with any HSP90 or HDAC inhibitor compound.
    3. Patient who received systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:
    • Chemotherapy within 4 weeks
    • Wide-field radiotherapy within 4 weeks
    • Localized palliative radiotherapy: within 2weeks
    • Trastuzumab ttt within 4 weeks
    • Nitrosoureas, mitomycin and monoclonal antibodies (except trastuzumab): within 6 weeks
    • Any continuous-dosing (i.e. daily dosing, every-other-day dosing, Monday- Wednesday-Friday dosing, weekly etc) of systemic anticancer treatment for
    which the recovery period is not known, or investigational drugs (i.e. targeted agents) within a duration of ≤ 5 half lives of the agent and their active metabolites (if any)
    4. Patients who have recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to the first dose of study treatment
    5. Treatment with therapeutic doses of sodium warfarin (Coumadin). Low doses of
    Coumadin (e.g. ≤ 2mg/day for line patency) are permitted.
    6. Patients using medications that are substrates, inhibitors or inducers of CYP3A4,
    CYP2C8, CYP2C9 and CYP2C19 and cannot be switched or discontinued to an
    alternative drug prior to commencing AUY922 dosing need special consideration (please refer to Post-text supplement 2 and see Section 6.6.7 for further details).
    7. Unresolved diarrhea ≥ CTCAE grade 2.
    8. Patients who do not have either an archival tumor sample available or are unwilling to have a fresh tumor sample collected at baseline.
    9. Pregnant or lactating women.
    10. Fertile women of childbearing potential (WCBP) not using adequate contraception
    (abstinence, oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile). Male patients whose partners are WCBP, not using adequate contraception.
    11. Acute or chronic liver disease.
    12. Acute or chronic renal disease.
    13. Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled
    diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
    14. Cardiac exclusion criteria:
    • History (or family history) of long QT syndrome.
    • Mean QTc ≥ 450 msec on screening ECG.
    • History of clinically manifest ischemic heart disease including myocardial infarction,
    stable or unstable angina, coronary arteriography or cardiac stress testing/imaging
    with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to
    study start.
    • History of heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA
    or ECHO.
    • Clinically significant ECG abnormalities including one or more of the following: left
    bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior
    hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd (Mobitz II)
    or 3rd degree AV block.
    • History of atrial fibrillation, atrial flutter or ventricular arrhythmias including
    ventricular tachycardia or Torsades de Pointes.
    • Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled
    hypertension, history of labile hypertension, or history of poor compliance with an
    antihypertensive regimen).
    • Clinically significant resting bradycardia (< 50 beats per minute).
    • Patients who are currently receiving treatment with any medication which has a
    relative risk or prolonging the QTcF interval or inducing Torsades de Pointes (as
    listed in Post-text supplement 2) and cannot be switched or discontinued to an
    alternative drug prior to commencing AUY922 dosing.
    • Obligate use of a cardiac pacemaker.
    15. Known diagnosis of HIV infection (HIV testing is not mandatory).
    16. Patients with known disorders due to a deficiency in bilirubin glucuronidation (e.g
    Gilbert’s syndrome).
    17. Patients with a history of another primary malignancy that is currently clinically
    significant or currently requires active intervention.
    18. Patients unwilling or unable to comply with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Breast cancer dose expansion arm
    • Efficacy: For locally advanced or metastatic breast cancer expansion
    arms patients only; categorical endpoint with categories responders
    (CR and/or PR), non-responders with stable disease for at least 6
    months (SD ≥ 6 months), progressive disease within 6 months from
    study start or other (PD) according to a multinomial design.
    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 Yes
    E.6.13.1Other scope of the trial description
    determine the maximum tolerated dose
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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 Decision2008-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-02-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-04-20
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