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    Summary
    EudraCT Number:2014-002230-32
    Sponsor's Protocol Code Number:WO29479
    National Competent Authority:Latvia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-07-27
    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 ConcernedLatvia - SAM
    A.2EudraCT number2014-002230-32
    A.3Full title of the trial
    A MULTISTAGE, PHASE II STUDY EVALUATING THE SAFETY AND EFFICACY OF COBIMETINIB PLUS PACLITAXEL, COBIMETINIB PLUS ATEZOLIZUMAB PLUS PACLITAXEL, OR COBIMETINIB PLUS ATEZOLIZUMAB PLUS NAB-PACLITAXEL AS FIRST-LINE TREATMENT FOR PATIENTS WITH METASTATIC TRIPLE-NEGATIVE BREAST CANCER
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multi-Part, Clinical Study Testing The Safety And Effectiveness of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel As Initial Treatment For Patients With Triple-Negative (HER2 Negative, Estrogen Receptor Negative, and Progesterone Receptor Negative) Breast Cancer That Has Spread.
    A.4.1Sponsor's protocol code numberWO29479
    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 SponsorF. Hoffman-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 organisationF.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.5.4Telephone number+4161 688 1111
    B.5.5Fax number+4161 691 9319
    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 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 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.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 Yes
    D.2.1.1.1Trade name Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderPUREN Pharma GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Ro0247506
    D.3.4Pharmaceutical form Concentrate 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.3.8INN - Proposed INNPACLITAXEL
    D.3.9.2Current sponsor codeRo024-7506
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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 Yes
    D.3.11.13.1Other medicinal product type- taxane, obtained semisynthetically from a taxane precursor derived from the needles and twigs of the European yew, Taxus baccata.
    D.IMP: 3
    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 Abraxane
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAbraxane
    D.3.4Pharmaceutical form Powder 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.3.8INN - Proposed INNpaclitaxel
    D.3.9.3Other descriptive namePACLITAXEL ALBUMIN-BOUND
    D.3.9.4EV Substance CodeSUB127678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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 Yes
    D.3.11.13.1Other medicinal product typetaxane, obtained semisynthetically from a taxane precursor derived from the needles and twigs of the European yew, Taxus baccata.
    D.IMP: 4
    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 Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAtezolizumab
    D.3.2Product code RO5541267/F03
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44-3
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameMPDL3280A, Tecentriq
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with metastatic or locally advanced, triple-negative adenocarcinoma of the breast that have not received prior systemic therapy for metastatic breast cancer
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic (cancer that has spread) or locally advanced (cancer that has regrown at or near the original site) triple-negative breast cancer (TNBC) that have not received treatment
    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 PT
    E.1.2Classification code 10075566
    E.1.2Term Triple negative 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
    Cohort I:
    •To estimate the clinical benefit of cobimetinib (CTB) plus paclitaxel (PAC) relative to placebo plus PAC, as measured by investigator-assessed progression free survival (PFS) in patients with locally advanced or metastatic TNBC
    Cohort II:
    •To estimate the clinical benefit of CTB plus atezolizumab (ATZ) plus PAC, as measured by overall response rate (ORR)
    Cohort III:
    •To estimate the clinical benefit of CTB plus ATZ plus nab-paclitaxel nab-PAC, as measured by ORR
    E.2.2Secondary objectives of the trial
    Cohort I:
    •To determine the ORR
    Cohort I, II, and III:
    •To evaluate the safety and tolerability of CTB administered in combination with PAC; CTB and ATZ administered with PAC; and CTB and ATZ administered with nab-PAC in patients with locally advanced or metastatic TNBC
    •To determine ORR unconfirmed(ORR_uc), and duration of response (DOR) of CTB plus PAC and placebo plus PAC; CTB plus ATZ plus PAC; and CTB plus ATZ plus nab-PAC
    •To evaluate overall survival (OS) benefit of CTB plus PAC and placebo plus PAC
    •To evaluate the OS and PFS of CTB plus ATZ plus PAC; and CTB plus ATZ plus nab-PAC
    •To characterize the pharmacokinetics (PK) of CTB and PAC; CTB, ATZ, and PAC; and CTB, ATZ, and nab-PAC when administered in combination (safety run-in)
    •To characterize the PK of CTB and to investigate the relationship between CTB exposure and efficacy and safety outcomes using population approaches (expansion stage)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent form
    - Women and men, age >= 18 years
    - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or1
    - Histologically confirmed estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast, with measurable metastatic or locally advanced disease
    - Locally advanced disease must not be amenable to resection with curative intent
    - Measurable disease, according to response evaluation criteria in solid tumours (RECIST), v1.1
    - Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment:
    –Absolute neutrophil count (ANC) >= 1.5 × 10 exp9/L
    –Platelet count >= 100 × 10 exp9/L
    –Hemoglobin >= 9 gram (g)/decilitre (dL)
    –Albumin >= 2.5 g/dL
    –Bilirubin <= 1.5 × the upper limit of normal (ULN)
    –Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase <= 3 × ULN, with the following exceptions:
    -Patients with documented liver metastases: AST and/or ALT <= 5 × ULN
    -Patients with documented liver or bone metastases: alkaline phosphatase <= 5 × ULN
    –Serum creatinine <= 1.5 × ULN or creatinine clearance (CrCl) >= 40 mL/min on the basis of measured CrCl from a 24-hour urine collection or Cockroft-Gault glomerular filtration rate estimation: (140-age) x (weight in kg) x (0.85 if female) 72 x (serum creatinine in milligram/dL)
    - Ability and capacity to comply with the study and follow-up procedure
    - For female patients (and female partners of male patients) who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of paclitaxel/nab-paclitaxel,at least 5 months after the last dose of
    atezolizumab, and 3 months after the last dose of cobimetinib.
    - The determination of TNBC status should, whenever possible, utilize tissue from a metastatic or recurrent lesion and where more than one biopsy source is available; priority should be given to the most recent sample.
    - Patients who have not had HER2, ER, or PR testing, and thus, the HER2, ER, and PR status of the breast adenocarcinoma is unknown, are not eligible
    - Men must agree not to donate sperm or have intercourse with a female partner
    without using appropriate barrier contraception during the treatment period and for 6 months after the last dose of paclitaxel/nab-paclitaxel and 3 months after the last dose of Cobimetinib. Male patients should seek advice on conservation of
    sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) or lower fertility with paclitaxel.
    E.4Principal exclusion criteria
    - Known HER2 positive, ER positive, or PR positive breast cancer by local laboratory assessment (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Medical Monitor to establish eligibility of patient)
    - HER2 positivity is defined as one of the following: immunohistochemistry (IHC) 3 positive or in situ hybridization (ISH) positive
    - ER and PR positivity is defined positive for ER or PR if a finding of >=1% of tumor cell nuclei are immunoreactive
    - Patients who have not had HER2, ER, or PR testing, and thus, the HER2, ER, and PR status of the breast adenocarcinoma is unknown, are not eligible
    - Any prior chemotherapy, hormonal, or targeted therapy, for inoperable locally advanced or mTNBC
    - Prior chemotherapy (including taxanes) and/or radiation in the neoadjuvant or adjuvant setting is allowable if treatment occurred >= 6 months prior to initiation of study treatment (Cycle [C] 1 Day [D]1)
    - Any systemic anti-cancer therapy within 3 weeks[W] prior to C1, D1
    - Any radiation treatment to metastatic site within 28 days of C1, D1
    - Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to C1, D1, or anticipation of need for major surgical procedure during the course of the study
    - Prior therapy with bevacizumab, sorafenib, sunitinib, or other putative vascular endothelial growth factor pathway−targeted therapy within 2 years of start of study treatment
    - Prior exposure to experimental treatment targeting rapidly accelerated fibrosarcoma (Raf), MEK (MAPK [Mitogen-activated protein kinases]/Erk kinase), or the MAPK pathway
    - Previous therapy with Akt, phosphoinositide 3-kinase (PI3K), and/or mechanistic target of rapamycin (mTOR) inhibitors
    - Prior therapy with trastuzumab
    - Grade >= 2 peripheral neuropathy
    - Brain metastases (symptomatic or non-symptomatic) that have not been treated previously, are progressive, or require any type of therapy (e.g. radiation, surgery or steroids) to control symptoms from brain metastases within 30 days prior to first study treatment dose
    - History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
    - Patients will be excluded if they currently have the following risk factors for RVO:
    -Uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg
    -Serum cholesterol >= Grade 2
    -Hypertriglyceridemia >= Grade 2
    -Hyperglycemia (fasting) >= Grade 2
    -Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower
    - Use of strong cytochromes P450 (CYP)3A4/5 inhibitors such as but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, and voriconazole
    - Strong CYP3A4/5 inducers such as but not limited to rifampin, carbamazepine, rifapentine, phenytoin, and phenobarbital
    - The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
    -St. John's wort or hyperforin (potent CYP3A4 enzyme inducer)
    -Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
    - Pregnancy (positive serum pregnancy test) or lactation
    - Uncontrolled serious medical or psychiatric illness
    - Active infection requiring intravenous (IV) antibiotics on Cycle 1 Day 1
    - Prior allogeneic stem cell or solid organ transplantation
    - History of autoimmune diseases or autoimmune-related hypothyroidism
    - History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis
    - Positive test for human immunodeficiency virus
    - Active hepatitis [hep] B or hep C (except for positive antibody test)
    - Active tuberculosis
    - Prior treatment with CD 137 agonists or immune checkpoint blockade therapies
    - Treatment with systemic immunostimulatory agents within 4W or five half-lives of the drug (whichever is shorter) prior to randomization
    - Treatment with systemic corticosteroids or immunosuppressive medications within 2W prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
    - Patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil) nab-PAC and any of the excipients, chimeric or humanized antibodies, fusion proteins, chinese hamster ovary cells or any component of the ATZ formulation
    Atezolizumab-Specific Exclusion Criteria (Cohorts II and III Only)
    History of clinically significant cardiac dysfunction (section 4.1.2)
    E.5 End points
    E.5.1Primary end point(s)
    Cohort I:
    1. The primary efficacy endpoint is PFS, defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by investigator as per RECIST v1.1, or death on study from any cause, whichever occurs first
    Cohort II & Cohort III:
    2. ORR, defined as the proportion of a partial response or complete response occurring after randomization and confirmed >= 28 days later as determined by the investigator using RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. The PFS analysis will be performed after approximately 60 investigator assessed PFS events (estimated to be approximately 21 months after the first patient is enrolled)
    2. Every 8 weeks +/- 1 week (after every 2 treatment cycles) from the date of first study drug administration (Cycle 1 Day 1) until disease progression or the patient dies
    E.5.2Secondary end point(s)
    Cohort I, Cohort II, and Cohort III:
    1. Overall survival, defined as the time from randomization to death from any cause, regardless of whether the death occurs during the study or following treatment discontinuation. For patients who have not died, OS will be censored at the date of last contact. OS will be analyzed similarly to the primary endpoint.
    2. Nature, frequency, and severity of adverse events as graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
    3. Changes in vital signs and clinical laboratory results
    4. ORR_uc, defined as the rate of a partial response or complete response occurring after randomization as determined by the investigator using RECIST v1.1, confirmation not required
    5. DOR, defined as the time from the first occurrence of a documented objective response to the time of relapse, as determined by the investigator using RECIST v1.1 or death from any cause during the study, whichever occurs first
    6. Maximum plasma concentrations (Cmax)
    7. Minimum plasma concentration (Cmin)
    8. Total exposure (AUC [area under curve] 0-τ [tau])
    Cohort I:
    9. ORR, defined as the rate of a partial response or complete response occurring after randomization and confirmed >= 28 days later as determined by the investigator using RECIST v1.1
    Cohort II and Cohort III:
    10. PFS, defined as the time from randomization to the first occurrence of disease progression or relapse as determined by the investigator using RECIST v1.1
    E.5.2.1Timepoint(s) of evaluation of this end point
    1&10. Every 12 wks until death, withdrawal of consent, or loss to follow-up
    2. From randomization & study drug administration at every assessment & for 28 days (+/- 7 days) after LD of drug until resolution.
    3. Screening visit, Day 1, 8 and 15 of every treatment cycle & at treatment discontinuation visit
    4-5, 9. Every 8 wks (+/- 1 wk) (after every 2 treatment cycles) from date of first study drug administration (Cycle 1 Day 1) until disease progression or patient dies
    6-8. Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 2 Day 15 for Cohort I; & Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 2, 4, 8 & every 8 cycles thereafter, treatment discontinuation visit & 120 (+/-30) days after LD of ATZ for Cohort II & III.
    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) 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 Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    study start with an open label safety run in stage prior to a random. placebo controlled expansion.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    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
    Australia
    Belgium
    Czech Republic
    France
    Italy
    Korea, Republic of
    Spain
    Taiwan
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    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.1.2.1Number of subjects for this age range: 137
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 101
    F.4.2.2In the whole clinical trial 162
    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)
    Once patients have ended participation in the trial they will be free to pursue other available treatments or may participate in other clinical trials as advised by their treating physician. Patients in the control/placebo arm of the expansion stage will not be allowed access to cobimetinib.
    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 Decision2015-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-08-14
    P. End of Trial
    P.End of Trial StatusOngoing
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