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    Summary
    EudraCT Number:2011-002167-23
    Sponsor's Protocol Code Number:IPC_2011-001
    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:2011-11-04
    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 number2011-002167-23
    A.3Full title of the trial
    A phase Ib/II open-label study evaluating safety and efficacy of oral BKM120 in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer.
    Etude de phase Ib/II évaluant la sécurité et l’efficacité du BKM120 en combinaison avec le lapatinib dans les cancers du sein récidivants, localement avancés ou métastatiques, HER2+ résistants au trastuzumab avec activation de la voie PI3K
    A.3.2Name or abbreviated title of the trial where available
    PIKHER2
    A.4.1Sponsor's protocol code numberIPC_2011-001
    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 SponsorInstitut Paoli-Calmettes
    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 supportProgramme Hospitalier de Recherche Clinique (PHRC)
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportLaboratoires Novartis
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut Paoli-Calmettes
    B.5.2Functional name of contact pointDr Dominique GENRE
    B.5.3 Address:
    B.5.3.1Street Address232, Bd Sainte Marguerite - BP 156
    B.5.3.2Town/ cityMarseille Cedex 9
    B.5.3.3Post code13273
    B.5.3.4CountryFrance
    B.5.4Telephone number04 91 22 37 78
    B.5.5Fax number04 91 22 36 01
    B.5.6E-mailGENRED@marseille.fnclcc.fr
    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 Yes
    D.2.1.1.1Trade name TYVERB
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Coated tablet
    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.3.8INN - Proposed INNLAPATINIB
    D.3.9.1CAS number 231277-92-2
    D.3.9.4EV Substance CodeSUB25379
    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) 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.3.2Product code BKM 120
    D.3.4Pharmaceutical form Capsule
    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
    locally advanced, recurrent and metastatic 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 14.1
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase Ib part: To determine the maximum-tolerated dose (MTD) of BKM120 when administered orally in combination with daily lapatinib to adult patients trastumuzab-resistant HER2+ locally advanced, recurrent and metastatic breast cancer.

    Phase II part: To determine the efficacy of daily BKM120 in combination with daily lapatinib as measured by objective response rate (ORR), defined by complete response (CR) or partial response (PR) of target and non target lesions according to RECIST V1.1., in patients with activation of PI3K/AKT pathway detected according to one at least of the following criterias, measured on primary or metastatic tissue: PTEN negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or Overexpression of phospho-AKT by IHC.
    E.2.2Secondary objectives of the trial
    - To evaluate safety and tolerability of the combination
    - To evaluate clinical benefit (CB defined as complete response (CR) + partial response (PR) + Stable disease (SD) > 6 months)
    - To assess progression-free survival (PFS)
    - To determine pharmacokinetics profile of oral BKM120 in combination with orally lapatinib and to monitor exposure to lapatinib
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Biological and pharmacodynamic study to identify biomarkers predictive of therapeutic efficacy including:

    - PBMC phospho flow Phospho-ERK1/ERK2, Phospho-AKT, phospho-S6 Ribosomal, phospho-Stat5
    - Tissue pre and post-treatment KI-67, Apoptosis,
    - Tissue: to check for ERBB2 status, to evaluate in pre- and post-treatment biopsies the cancer stem cells contents using ALDH antibody
    E.3Principal inclusion criteria
    1. Female or male patients ≥ 18 years
    2. WHO performance status ≤ 1
    3. Locally advanced, recurrent or metastatic, histologically confirmed HER2 positive (IHC 3+ or FISH positive) breast cancer after failure of trastuzumab treatment. Failure of trastuzumab treatment is defined as documented tumor progression as per RECIST 1.1 criteria:
    - while on trastuzumab or within 4 weeks since the last infusion of trastuzumab for metastatic disease
    - within 12 months of the last infusion for patients who received trastuzumab as adjuvant or neoadjuvant treatment
    4. For the phase II part, progression on trastuzumab must have occurred within 16 weeks before entering this trial.
    5. The patients should not have received more than 3 lines of anti-HER2 therapy. No more than 3 previous lines of chemotherapy in the metastatic disease setting are allowed in the phase II part and no more than 4 chemotherapy regimens for the dose escalation part.
    6. For the phase II part, activation of PI3K/AKT pathway detected according to one at least of the following criteria :
    - PTEN negative by IHC
    - Somatic mutations (exons 9 and 20) of PIK3CA and/or
    - Overexpression of phospho-AKT by IHC
    7. The patient is capable of understanding and complying with the protocol and has signed the informed consent document
    8. Patients must have the following laboratory values:
    - Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L
    - Hemoglobin (Hb) ≥ 9 g/dL (transfusion is allowed to be given to patients so they may reach this inclusion requirement prior to trial entry)
    - Platelets (Plt) ≥ 100 x 10^9/L
    - Potassium within normal limits
    - Total calcium (corrected for serum albumin) within normal limits (patients actively using biphosphonate for malignant hypercalcemia control are not allowed to enter the trial)
    - Magnesium ≥ the lower limit of normal
    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN or ≤ 3.0 x ULN if liver metastases are present
    - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome)
    - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min
    - Serum amylase ≤ ULN
    - Serum lipase ≤ ULN
    - Fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L
    - Negative serum pregnancy test within ≤ one week before first dose for child-bearing potential women and for women < 12 months after the onset of menopause
    9. Measurable disease:
    - Phase Ib: The patient has at least one measurable lesion or non-measurable disease as defined per RECIST 1.1.
    - Phase II: The patient has at least one measurable lesion as defined per RECIST 1.1.
    10. Patients may have received treatment for brain metastases, but must be neurologically stable
    11. Baseline LVEF > 50% (MUGA or ECHO)
    12. Affiliation to social security
    E.4Principal exclusion criteria
    1. Previous treatment with lapatinib, neratinib or a PI3K inhibitor
    2. Patients with untreated brain metastases. However, patients with asymptomatic metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (incl. radiation and/or surgery), is clinically stable with respect to the tumor at the time of study entry and if their signs and symptoms are well controlled with chronic therapy with low dose of corticosteroids
    3. Patients with acute or chronic liver, renal disease or pancreatitis
    4. Patients with any peripheral neuropathy ≥ CTCAE grade 2
    5. Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist, or meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of ‘1, 2, or 3’ to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9)
    - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
    - ≥ CTCAE grade 3 anxiety
    6. Patients with diarrhea ≥ CTCAE grade 2
    7. Patient has active cardiac disease including any of the following:
    - Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
    - QTc > 480 msec on screening ECG (using the QTcF formula)
    - Angina pectoris that requires the use of anti-anginal medication
    - Ventricular arrhythmias except for benign premature ventricular contractions
    - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
    - Conduction abnormality requiring a pacemaker
    - Valvular disease with documented compromise in cardiac function
    - Symptomatic pericarditis
    8. Patient has a history of cardiac dysfunction including any of the following;
    - Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
    - History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    - Documented cardiomyopathy
    - Other clinically significant heart disease such uncontrolled hypertension (please refer to WHO-ISH guidelines)
    9. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %)
    10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection, chronic pancreatitis, active chronic hepatitis) that could cause unacceptable safety risks or compromise compliance with the protocol
    11. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with unresolved diarrhea will be excluded as previously indicated.

    FOR CRITERIA 12 TO 23 SEE PROTOCOL.
    E.5 End points
    E.5.1Primary end point(s)
    When objective response is reached
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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
    Biological study
    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
    1b
    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 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 concerned11
    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 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
    A data monitoring comitee is expected.

    It is not independent because:
    - There is a rule of dose escalation and trial stop very clearly defined and disturbing for patient
    - A small number of patients at each level are included in Phase I.

    A trial stop recommended by an independent committee that is not within the rules for stopping the study seems to us unlikely.
    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
    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 Yes
    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 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 state59
    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 Decision2011-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-12
    P. End of Trial
    P.End of Trial StatusCompleted
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