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    Summary
    EudraCT Number:2011-002893-21
    Sponsor's Protocol Code Number:GO27912
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-02-29
    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 ConcernedUK - MHRA
    A.2EudraCT number2011-002893-21
    A.3Full title of the trial
    A PHASE II, DOUBLE-BLIND, PLACEBO CONTROLLED, RANDOMIZED STUDY EVALUATING THE SAFETY AND EFFICACY OF CARBOPLATIN/PACLITAXEL AND CARBOPLATIN/PACLITAXEL/BEVACIZUMAB WITH AND WITHOUT GDC-0941 IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OR RECURRENT NON-SMALL CELL LUNG CANCER
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the novel cancer drug GDC-0941 (or placebo) in combination with : a) the approved anticancer drugs carboplatin and paclitaxel; and b) the approved anticancer drugs carboplatin, paclitaxel and bevacizumab in previously untreated patients with advanced non-small cell lung cancer
    A.4.1Sponsor's protocol code numberGO27912
    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 SponsorGenentech, Inc.
    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 supportGenentech
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenentech
    B.5.2Functional name of contact pointGenentech Trial Information Support
    B.5.3 Address:
    B.5.3.1Street Address1 DNA Way
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1888662 6728
    B.5.5Fax number+1866200 8133
    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 nameGDC-0941/RO5314482
    D.3.2Product code GDC-0941
    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.3.9.1CAS number 957054-33-0
    D.3.9.2Current sponsor codeGDC-0941/RO5314482
    D.3.9.3Other descriptive nameGDC-0941.180
    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 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 nameGDC-0941/RO5314482
    D.3.2Product code GDC-0941
    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.3.9.1CAS number 957054-33-0
    D.3.9.2Current sponsor codeGDC-0941/RO5314482
    D.3.9.3Other descriptive nameGDC-0941.180
    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.IMP: 3
    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 Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderGenentech, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameAvastin (Bevacizumab)
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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: 4
    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 Paclitaxel-GRY
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namePaclitaxel
    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.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.IMP: 5
    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 Carboplatin-GRY
    D.2.1.1.2Name of the Marketing Authorisation holderGRY Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameCarboplatin
    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 INNCARBOPLATIN
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 6
    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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharmaceuticals Polska Sp. z o.o.
    D.2.1.2Country which granted the Marketing AuthorisationPoland
    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 namePaclitaxel
    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.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.IMP: 7
    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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderHospira Productos Farmaceuticos Y Hospitalarios S.L.SL
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 namePaclitaxel
    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.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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
    PREVIOUSLY UNTREATED ADVANCED OR RECURRENT NON-SMALL CELL LUNG CANCER
    E.1.1.1Medical condition in easily understood language
    Patients with previously untreated, advanced or recurrent non-small cell 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 16.1
    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
    Part I
    •To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel (Arm A) versus carboplatin+paclitaxel (Arm B) in all patients with squamous NSCLC
    •To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel (Arm A) versus carboplatin+paclitaxel (Arm B) in patients with squamous NSCLC with PIK3CA amplification
    •To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel+bevacizumab (Arm C) versus carboplatin+paclitaxel+bevacizumab (Arm D) in all patients with non-squamous NSCLC
    •To evaluate the efficacy (as measured by PFS) of GDC-0941 340mg+carboplatin+paclitaxel+bevacizumab (Arm C) versus carboplatin+paclitaxel+bevacizumab (Arm D) in patients with non-squamous NSCLC with PTEN-loss/low status
    Part II
    •To evaluate the efficacy (as measured by PFS) of GDC-0941 260mg+ carboplatin+paclitaxel+bevacizumab (Arm E) versus carboplatin+paclitaxel+bevacizumab (Arm F) in all patients with non-squamous NSCLC
    E.2.2Secondary objectives of the trial
    Due to the character limit for this field, please refer to protocol section 2.2 for secondary objectives
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For ALL Arms, patients must meet the following criteria to undergo screening procedures:
    • Signed Informed Consent Form
    • All patients must consent to the collection of an archival formalin-fixed paraffin embedded (FFPE) block or freshly cut unstained tumor slides from archival tumor tissue (10–15 preferred, minimum of 5 slides required) or a newly collected tumor sample for PIK3CA amplification testing and/or PTEN IHC, as well as for other protocol-mandated exploratory assessments.
    Availability of archival tissue for biomarker testing must be confirmed by the site prior to any study-specific screening procedures.
    Suitability of archival non-FFPE tissue must be evaluated by the central or local study pathologist and discussed with the Genentech Medical Monitor.
    Patients with no available archival tissue (or if the sample is difficult to obtain) may undergo a new tumor biopsy to meet eligibility criteria, as long as the patient consents to this and the biopsy can be obtained with minimal risk and discomfort to the patient as determined by the local investigator.
    Adequate tumor tissue content of the patient’s archival tumor sample must be confirmed by the site’s pathologist or a third-party vendor prior to randomization of the patient (please see Section 4.5.1.e for details).
    For Arms A and B, patients must meet the following criteria to be eligible:
    • Histologically documented advanced (Stage IV) or recurrent squamous NSCLC
    Diagnoses of squamous NSCLC that are based on cytology alone are not acceptable.
    Mixed tumors should be categorized according to the predominant cell type.
    For Arms C, D, E & F, patients must meet the following criteria to be eligible:
    • Histologically documented advanced (Stage IV) or recurrent non-squamous NSCLC
    Diagnoses of non-squamous NSCLC that are based on cytology alone are not acceptable.
    Mixed tumors should be categorized according to the predominant cell type.
    For ALL Arms, patients must meet the following criteria to be eligible:
    • Age ≥ 18 years
    • ECO performance status of 0 or 1 (see Appendix E)
    • Disease that is measurable per RECIST v1.1 (see Appendix C)
    • Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
    Absolute neutrophil count (ANC) ≥ 1500 cells/μL
    Without granulocyte colony stimulating factor support within 2 weeks prior to randomization
    Platelet count ≥ 100,000/μL
    Without transfusion within 2 weeks prior to randomization
    Hemoglobin ≥ 9.0 g/dL (90 g/L)
    Patients may be transfused to meet this criterion.
    Albumin ≥ 3.0 g/dL (30 μmol/L)
    Total bilirubin ≤ 1.5 x ULN
    AST and ALT ≤ 3.0 x ULN
    Serum creatinine ≤ 1.5 x ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation:
    (140-age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg/dL)
    INR ≤ 1.5 and aPTT ≤ 1.5 x ULN, except for patients receiving allowed anti-coagulation therapy
    For patients without known type II diabetes, the following is required
    Fasting blood glucose < 135 mg/dL (7.49 mmol/L) and HbA1c < 7.0%
    For patients with type II diabetes receiving oral anti-hyperglycemic therapy the following is required:
    Fasting blood glucose < 160 mg/dL (8.88 mmol/L) and HbA1c < 8.5
    Stable regimen of oral anti-hyperglycemic therapy without the use of insulin for at least 3 weeks prior to randomization
    Fasting blood glucose levels < 160 mg/dL (8.88 mmol/L) and no hypoglycemia during home monitoring for at least 1 week prior to randomization
    • For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use two effective forms of contraception (e.g., surgical sterilization, a reliable barrier method supplemented with a spermicide, birth control pills, or contraceptive hormone implants)
    For females in Arms A and B, continued use for the duration of the study treatment or 6 months after discontinuation of paclitaxel, whichever is longer, is required.
    For females in Arms C, D, E, and F, continued use until 6 months after study treatment discontinuation or paclitaxel discontinuation, whichever is longer, is required.
    For males in Arms A, B, C, and D, E and F continued use until 90 days after study treatment discontinuation or 6 months after discontinuation of paclitaxel, whichever is longer, is required.
    E.4Principal exclusion criteria
    Exlusion criteria for all arms:
    •NSCLC with documented EGFR mutation associated with response to EGFR inhibitors or documented fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as EML4-ALK)
    •Prior therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy, or investigational therapy) before Day1 of Cycle1 for the treatment of advanced (Stage IV) or recurrent NSCLC
    Patients who received prior adjuvant chemotherapy or radiotherapy for NSCLC are not excluded if the time interval from completion of adjuvant therapy until disease progression is >12 months
    Patients who received prior palliative radiotherapy for metastatic or lobar lesions (not including target lesions) are not excluded (if >2 weeks prior to Day1 of Cycle1)
    Patients who receive hormone-replacement therapy or oral contraceptives are not excluded
    Patients who received herbal therapy >2 weeks prior to Day1 of Cycle1 are not excluded.
    •Evidence of tumor invading major blood vessels on imaging
    The investigator or the local radiologist must exclude evidence of tumor that is fully contiguous with, surrounding, or extending into the lumen of a major blood vessel (eg pulmonary artery or superior vena cava)
    •Known CNS disease except for treated brain metastases
    Treated brain metastases are defined as having no evidence of progression or hemorrhage >2 weeks after treatment & no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period
    Stable doses of non-enzyme inducing anti-convulsants are allowed
    Treatment for brain metastases may include whole brain radiotherapy, radiosurgery (Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician and if >2 weeks have passed since radiation treatment
    Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day1 of Cycle1 will be excluded
    •Leptomeningeal disease
    •Malignancies other than NSCLC successfully treated within 3 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, & carcinoma in situ of any anatomic location treated with curative intent
    •Type I diabetes
    •Type II diabetes requiring chronic therapy with insulin
    •Requirement for supplemental oxygen therapy to perform activities of daily living
    •Unstable angina
    •Serious cardiac arrhythmia requiring medication during the study
    •New York Heart Association Class II or greater congestive heart failure
    •History of malabsorption syndrome or other condition that would interfere with enteral absorption
    •Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1, or anticipation of need for major surgical procedure during the course of the study
    Placement of vascular access device will not be considered major surgery
    •Clinically significant history of liver disease, including cirrhosis, active viral hepatitis and current alcohol abuse
    •Known HIV infection
    •Active infection requiring IV antibiotics
    •Active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation such as Crohn's disease or ulcerative colitis
    - Patients currently receiving immunosuppressants (e.g., sulfasalazines) are considered to have active disease and are therefore ineligible.
    •Active autoimmune disease that is not controlled by nonsteroidal anti inflammatory drugs
    •Need for current chronic corticosteroid therapy (≥10 mg of prednisone per day or an equivalent dose of other anti inflammatory corticosteroids)
    Stable use (within 3 months prior to Day 1 of Cycle 1) of inhaled corticosteroids is allowed
    •Pregnancy, lactation, or breastfeeding
    •Uncontrolled hypercalcemia, defined as values above the ULN, despite optimal management including bisphosphonate therapy
    Chronic use of bisphosphonate therapy for other reasons (eg bone metastasis, osteoporosis, etc) is allowed
    •Uncontrolled hypomagnesemia or hypokalemia, defined as values below the LLN despite optimal electrolyte supplementation or management
    •Grade ≥2 peripheral neuropathy
    •Known severe hypersensitivity to taxanes or platinums or any of their excipients (including mannitol and macroglycol ricinoleate)
    •Inability or unwillingness to swallow pills
    •Inability to comply with study and follow up procedures
    •Current severe, uncontrolled systemic disease (eg clinically significant cardiovascular, pulmonary, or metabolic disease)

    Refer protocol (section 4.1.3.2) for remaining Exclusion Criteria and (section 4.1.3.2) for Bevacizumab-Specific Exclusion Criteria for Arms C,D,E&F
    E.5 End points
    E.5.1Primary end point(s)
    For ALL Arms and all predefined study populations (see Section 3.5), the
    primary efficacy outcome measure is:
    • PFS, defined as the time from randomization to NSCLC disease progression as assessed by the investigator per RECIST v1.1 (Appendix C) or death from any cause on study (≤ 30 days after the last dose of study treatment) whichever occurs first
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please see E.5.1
    E.5.2Secondary end point(s)
    For ALL Arms and all predefined study populations (see Section 3.5), the secondary efficacy outcome measures are:
    • Objective tumor response as assessed by the investigator using RECIST v1.1 (Appendix C); objective responses must be confirmed ≥ 28 days after initial response
    • Duration of objective response, defined as the time from first observation of an objective tumor response until first observation of disease progression as assessed by the investigator using RECIST v1.1 (Appendix C)
    • OS, defined as the time from randomization until death from any cause
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see E.5.2
    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 No
    E.6.10Pharmacogenetic No
    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 Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    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 trial6
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA42
    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
    Brazil
    Canada
    Chile
    France
    Germany
    Hungary
    Israel
    Italy
    Netherlands
    Russian Federation
    Spain
    Ukraine
    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
    When last patient reaches overal survival (OS) or is lost to follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    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 months11
    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: 288
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 208
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 496
    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)
    Following study completion or discontinuation, patients who continue to benefit from study treatment may be given the opportunity to continue treatment as part of an extension study. In circumstances when the study drug used during the study continues to be available, Genentech will work closely with the site to assess each patient's eligibility on a case-by-case basis. Depending on the reasons for study discontinuation, however, the study drug may not be offered after study discontinuation.
    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 Decision2012-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-05-18
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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