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    Summary
    EudraCT Number:2012-002214-38
    Sponsor's Protocol Code Number:VAROCE-1206
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-17
    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 ConcernedFrance - ANSM
    A.2EudraCT number2012-002214-38
    A.3Full title of the trial
    A PHASE II RANDOMIZED STUDY OF DOCETAXEL WITH OR WITHOUT NINTEDANIB (BIBF-1120) IN PATIENT RECEIVING A SECOND-LINE OF CHEMOTHERAPY FOR HER NEGATIVE, METASTATIC OR LOCALLY RECURRENT BREAST CANCER
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    DOCETAXEL WITH OR WITHOUT NINTEDANIB IN PATIENT RECEIVING A SECOND-LINE OF CHEMOTHERAPY FOR HER NEGATIVE METASTATIC OR LOCALLY RECURRENT BREAST CANCER
    A.3.2Name or abbreviated title of the trial where available
    VAROCE
    A.4.1Sponsor's protocol code numberVAROCE-1206
    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 SponsorCentre Oscar Lambret
    B.1.3.4CountryFrance
    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 supportBoehringer Ingelheim
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre Oscar Lambret
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address3 rue Frédéric Combemale
    B.5.3.2Town/ cityLILLE
    B.5.3.3Post code59020
    B.5.3.4CountryFrance
    B.5.4Telephone number33320295918
    B.5.5Fax number33320295896
    B.5.6E-maily-vendel@o-lambret.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Docetaxel
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharma B.V.
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameDocetaxel
    D.3.4Pharmaceutical form Concentrate and solvent 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.3.9.1CAS number 114977-28-5
    D.3.9.3Other descriptive nameANHYDROUS DOCETAXEL
    D.3.9.4EV Substance CodeSUB22289
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number27.73
    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.2.1.1.1Trade name Nintedanib
    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 nameNintedanib
    D.3.2Product code BIBF 1120
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    Second-line chemotherapy for metastatic or locally recurrent breast cancer
    E.1.1.1Medical condition in easily understood language
    Breast cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10006198
    E.1.2Term Breast cancer recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the median PFS in patients receiving Docetaxel + Nintedanib treatment (Arm A) compared to Docetaxel alone (Arm B)
    E.2.2Secondary objectives of the trial
    To describe the safety profile of Nintedanib (NCI CTC-AE v3.0)
    To estimate response rate and overall survival according to RECIST 1.1
    To study the quality of life (EORTC QLQ C30 (Additional module BR23)
    To determine VEGFR-1, -2, -3, PDGFR-a, -b and FGFR-1, -2, -3 RNA expression levels in tumors and endothelial cells
    To determine the levels of VEGF-A, C, FGF-1, -2, PDGF-AA, -AB, -BB in patient serum
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age ≥ 18 years old
    • Histologically or cytologically confirmed adenocarcinoma of the breast
    • Locally recurrent or metastatic disease
    • HER 2 negative status
    • Relapsing after a first line chemotherapy for locally recurrent or metastatic disease
    • Prior first line chemotherapy not containing Docetaxel
    • Measurable or evaluable disease according to RECIST 1.1 criteria
    • Allowed prior chemotherapy as follows :
    - Docetaxel in the neoadjuvant or adjuvant setting is allowed provided that relapse has been observed more than 12 months after the end of docetaxel treatment
    - Bevacizumab in 1st line is allowed with a wash-out of 3 months
    • ECOG performance status 0-1
    • Adequate bone marrow, hepatic and renal functions as evidence by the following:
    - Hemoglobin ≥ 10 G/100 mL
    - Neutrophils count ≥ 1500 /mm3
    - Platelets ≥ 100 000 /mm3
    - Total bilirubin ≤ ULN (ULN:Upper Limit of Normal)
    - SGOT/SGPT ≤ 1.5 x ULN (≤ 2.5 x ULN in case of hepatic metastasis)
    - Creatinin clearance ≥ 45 ml/min or creatinin ≤ 1.5 x ULN
    - Proteinuria < NCI CTC-AE grade 2
    • Coagulation parameters: International normalised ratio (INR) ≤ 2, prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 50% of deviation of institutional ULN
    • Effective contraception for patients (male and female) of reproductive potential during their entire participation in the study and during 3 months after the last administration of Nintedanib or Docetaxel
    • Negative pregnancy test (serum beta-HCG) within 1 week prior to start of study treatment in females of reproductive potential
    • Patient covered by government health insurance
    • Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and to the local legislation
    E.4Principal exclusion criteria
    • Concomitant hormone therapy for metastatic breast cancer
    • Patients with dysphagia, or inability to swallow the tablets
    • Other serious illness or medical conditions: Cardiac disease
    • Unstable diabetes
    • Uncontrolled hypercalcemia
    • Pregnancy or breast feeding woman
    • Unable for medical follow-up (geographic, social or mental reasons)
    • Prior treatment with Nintedanib or any other VEGFR inhibitor or stratify if trial aims to establish anti-angiogenic retreatment
    • Known hypersensitivity to the trial drugs , to their excipients or to contrast media
    • Contra indication to the use of the backbone treatment and to the comparator
    • Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomisation)
    • Leptomeningeal disease
    • Radiographic evidence of cavitary or necrotic tumors
    • Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels
    • History of clinically significant haemorrhagic or thromboembolic event in the past 6 months
    • Known inheritated predisposition to bleeding or thrombosis
    • Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion)
    • Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix
    • Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy
    • Active or chronic hepatitis C and/or B infection
    • Active alcohol or drug abuse
    • Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the trial
    E.5 End points
    E.5.1Primary end point(s)
    Median Progression Free Survival (PFS), defined as the time from randomization to first occurrence of disease progression or death from any cause by independent review (IRF) of tumor assessments using RECIST version 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    every 3 cycles of treatment
    E.5.2Secondary end point(s)
    • Safety according to NCI CTC-AE v3.0
    • Response rate (RR) using RECIST version 1.1. Responses must be confirmed at least 28 days after initial documentation of response
    • Overall survival (OS), defined as the time from the date of randomization to the date of death from any cause
    • Quality of life: EORTC QLQ C30 (Additional module BR23)
    • VEGFR-1, -2, -3, PDGFR-a, -b and FGFR-1, -2, -3 RNA levels determination in tumor sections by RT-qPCR analysis, including endothelial cells using a specific reference gene
    • Dosage of VEGF-A, -C, FGF-1, -2, PDGF-AA, -AB, -BB in patient’s serum
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy, QoL and biological evaluation every 3 cycles of treament

    Safety each cycle
    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 Yes
    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 Yes
    E.8.1.1Randomised Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned9
    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 Yes
    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
    Last visit of the last patient treated in this study
    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 months0
    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 months0
    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.1.3Elderly (>=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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state220
    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)
    it is not different from the 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 Decision2013-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-13
    P. End of Trial
    P.End of Trial StatusOngoing
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