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    Summary
    EudraCT Number:2008-001971-30
    Sponsor's Protocol Code Number:AP23573-08-207
    National Competent Authority:Czech Republic - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-09-09
    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 ConcernedCzech Republic - SUKL
    A.2EudraCT number2008-001971-30
    A.3Full title of the trial
    A Phase II Trial of Oral Deforolimus (AP23573; MK-8669), an mTOR Inhibitor, in Combination with Trastuzumab for Patients with HER2-positive Trastuzumab-Refractory Metastatic Breast Cancer
    A.4.1Sponsor's protocol code numberAP23573-08-207
    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 SponsorMerck & Co, Inc.
    B.1.3.4CountryUnited States
    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 nameridaforolimus
    D.3.2Product code AP23573 or MK-8669
    D.3.4Pharmaceutical form Gastro-resistant tablet
    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 INNridaforolimus
    D.3.9.1CAS number 572924-54-0
    D.3.9.2Current sponsor codeAP23573
    D.3.9.3Other descriptive nameMK-8669, defrolimus
    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) 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
    HER2-positive metastatic breast cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess the objective response rate by RECIST guidelines of oral deforolimus in combination with trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) with progression after treatment with at most 2 prior trastuzumab-based regimens.
    E.2.2Secondary objectives of the trial
    •Characterize safety and tolerability of oral deforolimus administered in combo with std dose trastuzumab
    •Evaluate the clinical-benefit response rate (CR or PR, SD ≥ six 4-wk cycles)
    •Evaluate addtn'l efficacy endpts, (e.g. duration of response, time to tumor progression, pfs, pfs rate, os).
    •Perform a series of exploratory molecular analyses such as:
    •Exploratory analysis of molecular parameters in archival tumor samples for predictive/indicative ability of mTOR inhibition impacting trastuzumab resistance (e.g. markers of tumoral PI3K/mTOR-pathway activity and related pathways). Possible analysis of the mutational/expression/activation status of specific genes (e.g. PI3CA; PTEN, p95HER2 and IGF-1R) or gene expression profiling for status of entire signaling pathways
    •Exploratory analysis of pre-/post-treatment changes in circulating tumor cells and their expression of certain HER2 and PI3K/mTOR pathway-related changes pending evolving technology
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Female patients, age ≥ 18 yrs
    •Histologically confirmed HER-2 positive (IHC 3+ or FISH+) metastatic breast cancer (MBC)
    •Trastuzumab-resistance, defined as disease progression on trastuzumab treatment, with at most 2 prior trastuzumab-based regimens permitted
    •Either combination or single-agent trastuzumab treatment acceptable
    •Maintenance after combination therapy considered part of that overall regimen (i.e., will be counted as one regimen)
    •Single-agent trastuzumab therapy (without disease progression) followed by combination trastuzumab therapy acceptable at the time of disease progression.
    •Adjuvant trastuzumab-containing therapy permitted and will count as one regimen
    •Measurable disease according to modified RECIST guidelines (histological/cytological confirmation of the neoplastic nature of a solitary lesion is not required in this trial)
    •ECOG performance status ≤ 1
    •Life expectancy > 3 months
    •No prior treatment with temsirolimus, everolimus, rapamycin, or any other mTOR inhibitor
    •At least 4 weeks much have elapsed between prior investigational therapy, chemotherapy or radiotherapy, and the first dose of deforolimus (≥2 weeks for signal transduction inhibitors with a half-life known to be < 24 hours, and ≥ 6 weeks for nitrosourea or mitomycin)
    •Left ventricular ejection fraction of ≥ 50%
    •Adequate cardiovascular function (e.g., ≤ class 2 New York Heart Association congestive heart failure, no myocardial infarction in the previous six months)
    •Adequate haematological, hepatic and renal function as defined below:
    •haemoglobin ≥ 9 g/dL, absolute neutrophil counts [ANC] ≥ 1.5 x 109 /L
    •platelets ≥ 100 x 109 /L
    •bilirubin ≤ ULN
    •alkaline phosphatase ≤ 2.5 x ULN
    •AST, ALT ≤ 2.5 x ULN; albumin ≥ 2.5mg/dL; creatinine ≤ 1.5 x ULN
    •Serum cholesterol ≤350 mg/dL and triglycerides ≤ 400 mg/dL
    •Patients with childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of study drug and must use an approved contraceptive method as appropriate from time of study screening until 30 days after the last dose of study drug. Non-hormonal methods must be used in this trial. Approved contraceptive methods include, for example, intra-uterine device, diaphragm with spermicide, cervical cap with spermicide or female condom with spermicide. (Spermicides alone are not an acceptable method of contraception.)
    •Availability and patient consent to obtain archival tumor tissue
    •Signed informed consent document stating that the patient understands the investigational nature of the proposed treatment
    E.4Principal exclusion criteria
    •Inadequate recovery from any prior surgical procedure or having undergone any major surgery within 2 weeks before trial entry (with the exception of minor procedures, e.g., central venous access port placement)
    •Grade 1 or Grade 2 hypersensitivity reaction to prior trastuzumab therapy if these reactions prevented further trastuzumab administration
    •Grade 3 or Grade 4 hypersensitivity reaction to prior trastuzumab
    •Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest
    •Known allergy to macrolide antibiotics
    •Pregnant or breast-feeding
    •Known history of HIV sero-positivity
    •Diagnosis of brain metastasis or leptomeningeal carcinomatosis within 3 months, and/or active brain metastases or leptomeningeal carcinomatosis, including those requiring glucocoricoid treatment
    •Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinoma of the skin
    •Active infection requiring prescribed intervention
    •Newly diagnosed (within 3 months before enrolment) or poorly controlled Type 1 or 2 diabetes
    •Newly diagnosed (within 3 months or before enrolment) or poorly controlled Type 1 or 2 diabetes
    •Other concurrent illness which, in the Investigator’s judgment, would either compromise the patient’s safety or interfere with the evaluation of the safety of the study drug
    •Concurrent treatment with medications that strongly induce or inhibit cytochrome P450 (CYP3A). Patients should be off these medications ≥ 2 weeks prior to the first dose of deforolimus. Concomitant medications that are metabolied by CYP3A are allowed (e.g., atorvastatin or simvastatin)
    •Any condition in the Investigator’s judgement that renders the patient unable to fully understand and provide informed consent and/or comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate by modified RECIST guidelines
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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
    The definition of end of trial (completion) date, per the protocol, is up to 24 moths after the last patient has received the first dose of study drug or has otherwise discontinued from the study.
    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 months4
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days15
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 37
    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 Decision2008-11-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-11-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-05-10
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