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    Summary
    EudraCT Number:2014-004685-25
    Sponsor's Protocol Code Number:GO29665
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-17
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-004685-25
    A.3Full title of the trial
    A PHASE I/II, MULTICENTER, OPEN-LABEL, DOSE-ESCALATION STUDY OF THE SAFETY AND PHARMACOKINETICS OF
    COBIMETINIB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH PREVIOUSLY TREATED SOLID TUMORS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Cobimetinib in Pediatric and Young Adult Patients with Previously Treated Solid Tumors
    A.4.1Sponsor's protocol code numberGO29665
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/124/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    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 supportF. Hoffmann La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenentech Inc. c/o F. Hoffmann La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.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.3.1Product nameCobimetinib (GDC-0973)
    D.3.2Product code RO5514041/F04
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    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 INNCobimetinib (GDC-0973)
    D.3.9.2Current sponsor codeRO5514041
    D.3.9.3Other descriptive nameCOBIMETINIB, GDC-0973/XL518
    D.3.9.4EV Substance CodeSUB122319
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Solid Tumors
    E.1.1.1Medical condition in easily understood language
    Solid tumors are masses of abnormal tissue growth that originate in organs or soft tissues and do not include fluid areas and cysts
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    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 safety and tolerability of cobimetinib in children and young adults, including estimation of the maximum-tolerated dose (MTD) or the maximum administered dose (MAD) and characterization of dose-limiting toxicities (DLTs)
    E.2.2Secondary objectives of the trial
    •To characterize the pharmacokinetics (PK) of cobimetinib in children and young adults
    •To evaluate the anticancer activity of cobimetinib in children and young adults with solid and brain tumors, as measured by objective response rate (ORR), progression-free survival (PFS), duration of objective response (DOR), and overall survival (OS)
    •To identify a recommended Phase II dose for cobimetinib in pediatric patients on the basis of safety, PK, and efficacy outcome measures
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent form or child's informed assent, when appropriate as determined by patient's age and individual site and country standards
    - Age >=6 years to <18 years (dose-escalation stage) and >=6 years to <30 years (expansion stage)
    - Able to comply with the study protocol, in the investigator’s judgment
    - Tumor for which prior treatment has proven to be ineffective (i.e., relapsed or refractory) or intolerable or for which no standard therapy exists.
    -Tumor with known or expected RAS/RAF/MEK/ERK pathway involvement. Diagnosis MUST be one of the following tumor types:
    -Central nervous system gliomas, including high- and low-grade gliomas, and diffuse intrinsic pontine glioma (DIPG)
    -Embryonal rhabdomyosarcoma and other non-rhabdomyosarcoma soft tissue sarcomas
    -Neuroblastoma
    -Melanoma
    -Malignant peripheral nerve sheath tumor
    -Tumors from the following groups that in the judgment of the investigator are life threatening, resulting in severe symptoms, or are in close proximity to vital structures:
    -NF1-associated tumors (including plexiform neurofibroma)
    -Schwannoma
    -Any solid tumor or brain tumor that occurs in a patient with a RASopathy (such as NF1 or Noonan syndrome)
    -Rhabdoid tumors, including atypical teratoid/rhabdoid tumor
    Any solid or brain tumor that has been molecularly profiled and shown to have RAS/RAF/MEK/ERK pathway activation, with approval of the Medical Monitor.
    - Tumor diagnosis must be histologically or cytologically confirmed either at the time of diagnosis or at the time of relapse, except in the following scenario:
    -DIPG does not require histologic confirmation if radiographic findings are sufficient to make diagnosis and institutional standard of care does not mandate biopsy for diagnosis.
    - Current disease state for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
    - Disease that is measurable as defined by International Neuroblastoma Response Criteria (INRC), Response Assessment in Neuro-Oncology (RANO) criteria or Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or evaluable by nuclear medicine techniques, immunocytochemistry techniques, tumor markers, or other reliable measures
    - Availability of tumor tissue at study enrollment is mandatory. Archival tumor tissue block or 15 freshly cut unstained, serial slides available for submission, and/or willingness to undergo a core or excisional biopsy prior to enrollment
    - Lansky Performance Status or Karnofsky Performance Status >=50%
    - Life expectancy >=3 months, in the investigator's judgment
    - Adequate hematologic and end organ function, defined by the following laboratory results obtained within 28 days prior to initiation of study drug:
    -Absolute neutrophil count (ANC) >= 0.75 × 10 exp9/L (unsupported)
    -Platelet count >=75 × 10 exp9/L (unsupported)
    -Hemoglobin >=8 gram/deciliter (g/dL) (transfusion is acceptable to meet this criterion)
    -Bilirubin <=1.5 × upper limit of normal (ULN) for age
    -Aspartate aminotransferase (AST) and alanine transaminase (ALT) <=2.5 × ULN for age
    -Serum creatinine <=1.5 × ULN for age or creatinine clearance (or radioisotope glomerular filtration rate) > 70 milliliter per minute (mL/min) /1.73 meter exp2/m
    - Fractional shortening (FS) >= 30% and left ventricular ejection fraction (LVEF) >= 50% at baseline, as determined by echocardiography within 28 days prior to initiation of study drug
    - Female patients of childbearing potential and male patients with a female partner of childbearing potential must agree with the required contraceptive methods as defined in the protocol
    - Body weight must be at least 20 kg

    E.4Principal exclusion criteria
    - Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell transplant) within 3 months prior to initiation of study drug
    - Treatment with thoracic or mediastinal radiotherapy within 6 weeks prior to initiation of study drug
    - Treatment with hormonal therapy (except hormone replacement therapy or oral contraceptives), immunotherapy, biologic therapy, or herbal cancer therapy within 4 weeks or < 5 half-lives, whichever is shorter, prior to initiation of study drug
    - Treatment with a long-acting hematopoietic growth factor within 2 weeks prior to initiation of study drug or a short-acting hematopoietic growth factor within 1 week prior to initiation of study drug
    - Treatment with investigational therapy (with the exception of cancer therapies as described above) within 4 weeks prior to initiation of study drug
    - Requirement for initiation of corticosteroids or an increase in the dose of corticosteroids within 1 week prior to initiation of study drug
    - Treatment with St. John's wort or hyperforin or drugs that are strong inhibitors or inducers of CYP within 1 week prior to initiation of study drug
    - Ingestion of grapefruit juice within 1 week prior to initiation of study drug
    - Any toxicity (excluding alopecia) from prior treatment that has not resolved to Grade <= 1 (per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0) at screening except as permitted in the exclusion criteria
    - Major surgical procedure or significant traumatic injury within 4 weeks prior to initiation of study drug, or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device or minor surgery is permitted if the site has healed prior to initiation of study drug
    - Known active infection (excluding fungal infection of the nail beds) within 28 days prior to initiation of study drug that has not completely resolved
    - History or evidence of retinal pathology on ophthalmologic examination that is considered to be a risk factor for or indicative of neurosensory retinal detachment, Central Serous Chorioretinopathy (CSCR), neovascular retinopathy, or retinopathy of prematurity
    - Known hypersensitivity to any component of the study drug
    - Inability to swallow tablets
    - Impaired gastrointestinal absorption
    - Prior allogenic bone marrow transplantation or prior solid organ transplantation
    - Any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or places the patient at unacceptable risk from treatment complications
    - Current drug or alcohol use or dependence that would interfere with adherence to study requirements, in the opinion of the investigator
    E.5 End points
    E.5.1Primary end point(s)
    1.Incidence and nature of DLTs
    2.Nature, frequency, severity, and timing of adverse events, including serious adverse events and adverse events of special interest
    3.Changes in physical findings and clinical laboratory results
    4.Change from baseline in growth patterns and development patterns
    5.Pharmacokinetics: cobimetinib plasma concentrations
    6.Objective response (complete or partial response)
    7.Progression free survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-4: Up to 5 years
    5: At dosing and at 2, 4, 6, and 24 hours after dosing on Days 1 and 21 of Cycle 1, and prior to dosing on Day 1 of Cycle 2
    6-7: Up to 5 years
    E.5.2Secondary end point(s)
    1.Duration of Response
    2.Overall survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-2: Up to 5 years
    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 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 No
    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
    first in paediatric population
    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 concerned41
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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
    Canada
    Denmark
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Spain
    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
    The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, or 5 years after the last patient is enrolled, whichever occurs first. The Sponsor reserves the right to present interim data to health authorities for compliance purposes.

    For an individual patient the completion of the study (i.e., the last visit) will occur when the patient withdraws consent, has completed follow-up, has been lost to follow-up, dies, or when the trial is stopped.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 40
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 50
    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)
    A patient will be eligible to receive study drug after the end of the study if all of the following conditions are met:
    • The patient has a life-threatening or severe medical condition and requires continued study drug treatment for his or her well-being
    • There are no appropriate alternative treatments available to the patient
    • The patient and his or her doctor comply with and satisfy any legal or regulatory requirements that apply to them
    (protocol 4.3.4 Post-Trial Access to Cobimetinib)
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Innovative Therapies for Children with Cancer (ITCC)
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-05-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-26
    P. End of Trial
    P.End of Trial StatusCompleted
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