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    Summary
    EudraCT Number:2014-003850-15
    Sponsor's Protocol Code Number:CINC280A2201
    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:2015-07-17
    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 number2014-003850-15
    A.3Full title of the trial
    A phase II, multicenter, three-cohort study of oral cMET inhibitor INC280 in adult patients with EGFR wild-type (wt), advanced non-small cell lung cancer (NSCLC) who have received one or two prior lines of systemic therapy for advanced/metastatic disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study of oral cMET inhibitor INC280 in adult patients with advanced non-small cell lung cancer who have received one or two prior lines of therapy
    A.3.2Name or abbreviated title of the trial where available
    Study of oral cMET inhibitor INC280 in patients with EGFR wild-type, advanced NSCLC
    A.4.1Sponsor's protocol code numberCINC280A2201
    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.1.3.4CountryUnited 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 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.3.2Product code INC280
    D.3.4Pharmaceutical form Film-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 INNcapmatinib
    D.3.9.1CAS number 1197376-85-4
    D.3.9.2Current sponsor codeINC280
    D.3.9.3Other descriptive nameINC280
    D.3.9.4EV Substance CodeSUB31645
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 non-small cell ling cancer
    E.1.1.1Medical condition in easily understood language
    Lung cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung 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
    To evaluate the antitumor activity of INC280, as measured by overall response rate (ORR) by Blinded Independent Review Committee (BIRC) assessment, by cohort
    E.2.2Secondary objectives of the trial
    To evaluate duration of response (DOR) as assessed by BIRC, by cohort
    To evaluate ORR and DOR by investigator assessment, by cohort
    To evaluate time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) by investigator and by BIRC assessment, by cohort
    To evaluate overall survival (OS), by cohort
    To evaluate INC280 safety profile as monotherapy in NSCLC patients who have received one or two prior lines of systemic therapy for advanced/metastatic disease
    To characterize the pharmacokinetics of INC280
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years
    2. Stage IIIB or IV NSCLC (any histology) at the time of study entry
    3. Histologically or cytologically confirmed diagnosis of NSCLC that is:
    a. EGFR wild-type. This should have been assessed as part of the patient standard of care by a validated test for EGFR mutations, as per the Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors from College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (Lindeman et al 2013). The EGFR wt status (for exon 19 deletions and exon 21 L858R substitution mutations) must be documented in the patient source documents before the patient can be consented for pre-screening for cMET amplification. Patients with NSCLC of pure squamous cell histology can enter pre-screening without EGFR mutation testing or result, however patients with pure squamous cell histology and are known to have EGFR mutations in exons 19 or 21 will be excluded,
    b. AND ALK-negative rearrangement. This should have been assessed as part of the patient standard of care by a validated test. The ALK rearrangement negative status must be documented in the patient source documents before the patient can be consented for pre-screening for cMET amplification; if local ALK testing is not available, patient status will be determined centrally along with the cMET status. Patients with NSCLC of pure squamous cell histology can enter pre-screening without ALK testing or result, however patients with pure squamous cell histology that are known to have ALK rearrangement will be excluded
    c. AND (as determined by central assessment at a Novartis designated laboratory) either:
    • Cohort 1: Patients with cMET GCN ≥ 6, or
    • Cohort 2: Patients with cMET GCN ≥ 4 and < 6
    • Cohort 3: Patients with cMET GCN < 4
    cMET (and ALK, if applicable) testing may be performed while patient is still receiving anti-cancer therapy. However, the patient can only be screened for the main study once the patient has discontinued the last prior systemic treatment due to either disease progression or intolerance.
    4. Patients must have received one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB or IV NSCLC). Maintenance therapy given after first line chemotherapy will be considered as part of the first line if given to patients with documented response or stable disease before starting the maintenance therapy. Neoadjuvant and adjuvant systematic therapies will count as one prior line of treatment if relapse occurred within 12 months from the end of the neo-adjuvant or adjuvant systemic therapy.
    5. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.
    6. Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study.
    7. Patients must have adequate organ function including the following laboratory values at the screening visit:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support
    • Platelets ≥ 75 x 109/L
    • Hemoglobin (Hgb) > 9 g/dL
    • Calculated creatinine clearance (using Cockcroft-Gault formula) > 45 mL/min
    • Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert’s syndrome, who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
    • Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, who are included if AST ≤ 5 x ULN
    • Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, who are only included if ALT ≤ 5 x ULN
    • Alkaline phosphatase (ALP) ≤ 5.0 x ULN
    • Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
    • Serum lipase ≤ ULN
    • Fasting plasma glucose ≤ 175 mg/dL (≤ 9.8 mmol/L)
    • Patients must have the following laboratory values within the laboratory normal limits or corrected to within normal limits with supplements during screening:
    • Potassium
    • Magnesium
    • Phosphorus
    • Total calcium (corrected for serum albumin)
    8. ECOG performance status (PS) of 0 or 1.
    9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests
    E.4Principal exclusion criteria
    1. Prior treatment with crizotinib, or any other cMET or HGF inhibitor
    2. Patients with known hypersensitivity to any of the excipients of INC280
    3. Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations.
    4. Patients with characterized ALK-positive rearrangement
    5. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms
    6. Presence or history of carcinomatous meningitis
    7. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, indolent malignancies that currently do not require treatment, and completely resected carcinoma in situ of any type
    8. Clinically significant, uncontrolled heart diseases.
    • Unstable angina within 6 months prior to screening
    • Myocardial infarction within 6 months prior to screening
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
    • Ventricular arrhythmias
    • Supraventricular and nodal arrhythmias not controlled with medication
    • Other cardiac arrhythmia not controlled with medication
    • QTcF > 480 msec
    9. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting INC280 or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting INC280 is allowed
    10. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting INC280 or who have not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and patients can be enrolled in the study ≥ 1 week after the procedure
    11. Patients receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with INC280 and for the duration of the study:
    • Strong and moderate inhibitors of CYP3A4
    • Strong inducers of CYP3A4
    • Proton pump inhibitors (PPI)
    12. Impairment of GI function or GI disease that may significantly alter the absorption of INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
    13. Unable or unwilling to swallow tablets as per dosing schedule
    14. Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS related, dose must have been stabilized (or decreasing) for at least 5 days before first dose of INC280
    15. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 1 week before first dose of INC280, and for the duration of the study. Patients on non-enzyme-inducing anticonvulsants are eligible
    16. Previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x half-life of the agent (whichever is longer) before first dose of INC280. If previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 4 weeks before first dose of INC280
    17. Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results
    18. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc
    19. Pregnant or nursing women
    20. Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 7 days after stopping treatment
    21. Sexually active males unless they use a condom during intercourse while taking drug and for 7 days after stopping treatment and should not father a child in this period.
    E.5 End points
    E.5.1Primary end point(s)
    ORR, proportion of patients with a best overall response defined as complete response or partial response (CR+PR) by BIRC assessment per RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    as defined per protocol
    E.5.2Secondary end point(s)
    1. DOR, calculated as the time from the date of the first documented CR or PR by BIRC per RECIST 1.1 to the first documented progression or death due to any cause for patients with PR or CR
    2. ORR (CR+PR) and DOR per RECIST 1.1 by investigator assessment
    3. All calculated per RECIST 1.1, both by BIRC and investigator:
    • TTR, calculated as the time from first dose of INC280 to first documented response (CR+PR) for patients with PR or CR
    • DCR, calculated as the proportion of patients with best overall response of CR, PR, or SD
    • PFS, defined as time from first dose of INC280 to progression or death due to any cause
    4. OS, defined as time from first dose of INC280 to death due to any cause
    5. Incidence of adverse events and serious adverse events, change in vital signs, laboratory results (hematology, blood chemistry, and urinalysis) and ECG
    6. Plasma concentration-time profiles of INC280 and pharmacokinetic parameters estimated by non-compartmental analysis or population PK modeling
    E.5.2.1Timepoint(s) of evaluation of this end point
    as defined per protocol
    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 No
    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) 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 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.8.3 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    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
    Argentina
    Australia
    Austria
    Brazil
    Bulgaria
    Canada
    China
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Lebanon
    Mexico
    Netherlands
    Norway
    Russian Federation
    Singapore
    Spain
    Turkey
    United Kingdom
    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
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 107
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 100
    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 82
    F.4.2.2In the whole clinical trial 207
    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)
    None
    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 Decision2015-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-05-16
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