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    Summary
    EudraCT Number:2011-002893-21
    Sponsor's Protocol Code Number:GO27912
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-04-11
    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 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
    STUDIO DI FASE II, IN DOPPIO CIECO, CONTROLLATO VERSO PLACEBO, RANDOMIZZATO DI VALUTAZIONE DELLA SICUREZZA E DELL'EFFICACIA DI CARBOPLATINO/PACLITAXEL E CARBOPLATINO/ PACLITAXEL/BEVACIZUMAB CON E SENZA GDC-0941 IN PAZIENTI AFFETTI DA CARCINOMA AL POLMONE NON A PICCOLE CELLULE AVANZATO O RECIDIVANTE NON PRECEDENTEMENTE TRATTATO
    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
    Studio su un nuovo farmaco antitumorale GDC-0941 (o placebo) in combinazione con: a) i farmaci antitumorali approvati carboplatino e paclitaxel; e b) i farmaci antitumorali approvati carboplatino, paclitaxel e bevacizumab, in pazienti affetti da carcinoma al polmone non a piccole cellule avanzato non precedentemente trattato
    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+1 888 662 6728
    B.5.5Fax number+1 866 200 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.3.4Pharmaceutical 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.3.4Pharmaceutical 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.3.4Pharmaceutical 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.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.
    Cancro del polmone non a piccole cellule avanzato o recidivante non precedentemente trattato.
    E.1.1.1Medical condition in easily understood language
    Patients with previously untreated, advanced or recurrent non-small cell lung cancer.
    Pazienti affetti da tumore del polmone non a piccole cellule, avanzato o recidivante, non precedentemente trattato.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level 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
    For Arms A and B (squamous NSCLC), the primary objectives are: • To evaluate the efficacy (as measured by PFS) of GDC-0941+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+carboplatin+paclitaxel (Arm A) versus carboplatin+paclitaxel (Arm B) in patients with squamous NSCLC with PIK3CA amplification For Arms C and D (non-squamous NSCLC), the primary objectives are: • To evaluate the efficacy (as measured by PFS) of GDC-0941+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-094+carboplatin+paclitaxel+bevacizumab (Arm C) versus carboplatin+paclitaxel+bevacizumab (Arm D) in patients with non squamous NSCLC with PTEN-low status
    Per i Bracci A e B (NSCLC squamoso): -Valutare l’efficacia (misurata in base alla PFS) di GDC-0941+carboplatino [c]+paclitaxel [p] (Braccio A) rispetto a c+p (Braccio B) in tutti i pazienti affetti da NSCLC squamoso; -Valutare l’efficacia (misurata in base alla PFS) di GDC-0941+c+p (Braccio A) rispetto a c+p (Braccio B) nei pazienti affetti da NSCLC squamoso con amplificazione di PIK3CA. Per i Bracci C e D (NSCLC non squamoso): -Valutare l’efficacia (misurata in base alla PFS) di GDC-0941+c+p+bevacizumab [b] (Braccio C) rispetto a c+p+b (Braccio D) in tutti i pazienti affetti da NSCLC non squamoso; -Valutare l’efficacia (misurata in base alla PFS) di GDC-0941+c+p+b (Braccio C) rispetto a c+p+b (Braccio D) nei pazienti affetti da NSCLC di tipo non squamoso con bassi livelli di PTEN
    E.2.2Secondary objectives of the trial
    For Arms A&B (squamous NSCLC):•To assess the clinical activity (as measured by ORR, duration of response and OS) of GDC-0941+carboplatin+paclitaxel (Arm A) versus carboplatin+paclitaxel (Arm B) in all patients with squamous NSCLC and in patients with squamous NSCLC with PIK3CA amplification. • To evaluate the safety and tolerability of GDC-0941 when combined with carboplatin+paclitaxel in all patients with squamous NSCLC. For Arms C&D (non-squamous NSCLC): • To assess the clinical activity (as measured by ORR, duration of response and OS), of GDC-0941+carboplatin+paclitaxel+bevacizumab (Arm C) vs carboplatin+paclitaxel+bevacizumab (Arm D) in all patients with non-squamous NSCLC and in patients with non-squamous NSCLC with PTEN-low status •To evaluate the safety and tolerability of GDC-0941 when combined with carboplatin+paclitaxel+bevacizumab in all patients with nonsquamous NSCLC.
    Bracci A e B (NSCLC squamoso): -Valutare l’attività clinica (misurata in base a ORR, durata della risposta e OS) di GDC-0941+c+p (Braccio A) rispetto a c+p (Braccio B) in tutti i pazienti affetti da NSCLC squamoso e nei pazienti affetti da NSCLC squamoso con amplificazione di PIK3CA; -Valutare la sicurezza e la tollerabilità di GDC-0941 somministrato in combinazione con c+p in tutti i pazienti affetti da NSCLC squamoso. Bracci C e D (NSCLC non squamoso): -Valutare l’attività clinica (misurata in base a ORR, durata della risposta e OS) di GDC-094+c+p+b (Braccio C) rispetto a c+p+b (Braccio D) in tutti i pazienti affetti da NSCLC non squamoso e nei pazienti affetti da NSCLC non squamoso con bassi livelli di PTEN; -Valutare la sicurezza e la tollerabilità di GDC-0941 somministrato in combinazione con c+p+b in tutti i pazienti affetti da NSCLC non squamoso. Fare rif al Protocollo di studio
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PHARMACOGENOMIC:
    Vers:Emend.1
    Date:2012/02/06
    Title: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
    Objectives:• To explore the prevalence of oncogenic alterations of EGFR, KRAS, LKB1, MET and other potential biomarkers in archival tumor (or new biopsy, if archival tissue is not available), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and/or tumor DNA in urine • To explore the value of oncogenic alterations of EGFR, KRAS, LKB1, MET, and other potential biomarkers in archival tumor (or new biopsy, if archival tissue is not available), CTCs, ctDNA and/or tumor DNA in urine as predictors of response to GDC-0941 + carboplatin + paclitaxel with or without bevacizumab compared with standard of care without GDC-0941 • To explore predictors of response to GDC-0941 + carboplatin + paclitaxel with or without bevacizumab compared with standard of care without GDC-0941 based on exploratory analyses using molecular data obtained from tumor tissue by exon resequencing, mRNA and/or miRNA expression profiling and/or DNA copy number profiling • To explore the relationship between pharmacogenetic differences in drug-metabolizing enzymes and transporters and other patient-specific covariates with pharmacokinetics and pharmacodynamics of GDC-0941 when administered in combination with carboplatin + paclitaxel with or without bevacizumab

    FARMACOGENOMICA:
    Vers:Emend.1
    Data:2012/02/06
    Titolo:Studio di fase II, in doppio cieco, controllato verso placebo, randomizzato di valutazione della sicurezza e dell'efficacia di carboplatino/paclitaxel e carboplatino/ paclitaxel/bevacizumab con e senza GDC-0941 in pazienti affetti da carcinoma al polmone non a piccole cellule avanzato o recidivante non precedentemente trattato
    Obiettivi:A causa dei limiti di spazio, per un elenco degli obiettivi fare riferimento al protocollo di studio: obiettivi esplorativi No. 1, 2, 4, 6.

    E.3Principal inclusion criteria
    For ALL Arms: •Signed ICF •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, min. 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 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 crit., 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 PI. 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. For Arms A & B: •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: •Histologically documented advanced (Stage IV) or recurrent nonsquamous 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: •Age ≥18 years •ECO performance status of 0 or 1 •Disease that is measurable per RECIST v1.1 •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 ≥9.0g/dL (90g/L) Patients may be transfused to meet this criterion. Albumin ≥3.0g/dL (30μmol/L) Total bilirubin ≤1.5xULN AST and ALT ≤3.0xULN Serum creatinine ≤1.5xULN, or creatinine clearance ≥50mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140-age)x(weight in kg)x(0.85 if female)/72x(serum creatinine in mg/dL) INR ≤1.5 and aPTT ≤1.5xULN, except for patients receiving allowed anti-coagulation therapy For patients without known type II diabetes, the following is required Fasting blood glucose <135mg/dL (7.49mmol/L) and HbA1c <7.0% For patients with type II diabetes receiving oral anti-hyperglycemic therapy the following is required: Fasting blood glucose <160mg/dL (8.88mmol/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 <160mg/dL (8.88mmol/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, birth control pills, or contraceptive hormone implants) For females in Arms A & 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, continued use until 6 months after study treatment disc. is required. For males in Arms A,B,C & D, continued use until 90 days after study treatment or 6 months after disc. of paclitaxel, whichever is longer, is required.
    Per TUTTI i Bracci: •Modulo di consenso informato firmato, •Tutti i pazienti devono acconsentire alla raccolta di una porzione archiviata fissata con formalina e inclusa in paraffina (FFPE)o di vetrini di tessuto tumorale non colorati ottenuti di recente da tessuto tumorale archiviato (preferibilmente 10-15; sono necessari almeno 5 vetrini) o di un campione tumorale prelevato di fresco per l’analisi della amplificazione di PIK3CA e/o analisi IHC di PTEN, oltre che per altre valutazioni esplorative previste dal protocollo. La disponibilità di tessuto archiviato per l’analisi dei biomarcatori deve essere confermata dal centro prima di qualsiasi procedura di screening specifica dello studio. L’adeguatezza del tessuto archiviato non FFPE deve essere valutata dal patologo del centro dello studio e discussa con il Medical Monitor di Genentech. I pazienti per i quali non è disponibile del tessuto archiviato (o per i quali è difficile ottenere un campione) potrebbero essere sottoposti a una nuova biopsia del tumore per soddisfare i criteri di idoneità, a condizione che acconsentano a questa procedura e che la biopsia possa essere realizzata con il minimo rischio e disagio per il paziente secondo quanto stabilito dallo sperimentatore del centro. L’adeguatezza del contenuto del tessuto tumorale, del campione tumorale archiviato del paziente deve essere confermata dal patologo del centro o da un patologo esterno prima della randomizzazione del paziente. Per i Bracci A e B: •NSCLC avanzato (Stadio IV) o recidivante di tipo squamoso documentato istologicamente. Le diagnosi di NSCLC di tipo squamoso basate solamente sulla citologia non sono accettabili. I tumori misti devono essere classificati in base al tipo cellulare predominante. Per i Bracci C e D: •NSCLC avanzato (Stadio IV) o recidivante di tipo non squamoso documentato istologicamente. Le diagnosi di NSCLC di tipo non squamoso basate solamente sulla citologia non sono accettabili. I tumori misti devono essere classificati in base al tipo cellulare predominante. Per TUTTI i Bracci: •Età ≥18 anni, •Stato di performance ECOG pari a 0 o 1, •Malattia misurabile in base a i RECIST v1.1, •Adeguata funzionalità ematologica e degli organi principali, definita dai risultati dei seguenti esami di laboratorio ottenuti 14 gg prima del primo trattamento in studio: Conta assoluta dei neutrofili (ANC) ≥ 1500 cellule/μL. Senza il supporto del fattore di stimolazione delle colonie di granulociti nelle 2 sett. precedenti la randomizzazione. Conta piastrinica ≥ 100.000/μL. Senza trasfusione nelle 2 sett. precedenti la randomizzazione. Emoglobina ≥ 9,0 g/dL (90 g/L). I pazienti possono essere sottoposti a trasfusione per soddisfare questo criterio. Albumina ≥ 3,0 g/dL (30 μmol/L). Bilirubina totale ≤ 1,5 x ULN. AST e ALT ≤ 3,0 x ULN. Creatinina sierica ≤ 1,5 x ULN o clearance della creatinina ≥ 50 mL/min sulla base della stima della velocità di filtrazione glomerulare secondo la formula di Cockcroft-Gault: (140-età)x(peso in kg)x(0,85 per i soggetti di sesso femminile)/72x(creatinina sierica in mg/dL). INR ≤ 1,5 e aPTT ≤ 1,5 x ULN, eccetto che per i pazienti che ricevono una terapia anticoagulante consentita. Per i pazienti con un non noto diabete di tipo II, sono necessari i seguenti valori: Glucosio nel sangue a digiuno &lt; 135 mg/dL (7,49 mmol/L) e HbA1c &lt; 7,0%. Per i pazienti affetti da diabete di tipo II che ricevono una terapia anti-iperglicemica orale, sono necessari i seguenti valori: Glucosio nel sangue a digiuno &lt; 160 mg/dL (8,88 mmol/L) e HbA1c &lt; 8,5. Un regime stabile di terapia orale anti-iperglicemica senza l’utilizzo di insulina per almeno 3 sett. prima della randomizzazione. Livelli di glucosio nel sangue a digiuno &lt; 160 mg/dL (8,88 mmol/L) e assenza di ipoglicemia durante il monitoraggio eseguito a casa per almeno 1 sett. prima della randomizzazione. Per elenco completo rif. Ptc.
    E.4Principal exclusion criteria
    Patients for ALL Arms: •NSCLC with documented EGFR mutation 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 Day 1 of Cycle 1 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 Day 1 of Cycle 1). Patients who receive hormone-replacement therapy or oral contraceptives are not excluded. Patients who received herbal therapy >2 weeks prior to Day 1 of Cycle 1 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 (e.g., 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 and 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 Day 1 of Cycle 1 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, ductal carcinoma in situ treated surgically 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 • NYHA 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 •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. Refer to the protocol for a complete list of exclusion criteria.
    Per TUTTI i Bracci: •NSCLC con documentata mutazione di EGFR o documentata fusione nel gene che coinvolge il gene del linfoma anaplastico chinasi (ALK) (ad es. EML4-ALK), •Precedente terapia (compresa chemioterapia, terapia con anticorpi, inibitori della tiroxina chinasi, radioterapia, immunoterapia, terapia ormonale o terapia sperimentale) prima del Giorno 1 del Ciclo 1 per il trattamento dell'NSCLC avanzato (Stadio IV) o recidivante. I pazienti che hanno ricevuto una precedente chemioterapia o radioterapia adiuvante per l’NSCLC non sono esclusi se l’intervallo di tempo tra il completamento della terapia adiuvante e la progressione di malattia è &gt; 12 mesi. I pazienti che hanno ricevuto una precedente radioterapia palliativa per lesioni metastatiche o lobari (escluse le lesioni target) non sono esclusi (se &gt; 2 sett. prima del Giorno 1 del Ciclo 1). I pazienti che ricevono terapie ormonali sostitutive o contraccettivi orali non sono esclusi. I pazienti che hanno ricevuto terapie con rimedi erboristici &gt; 2 sett. prima del Giorno 1 del Ciclo 1 non sono esclusi. •Evidenze della diffusione del tumore nei grandi vasi sanguigni negli esami di imaging. Lo sperimentatore o il radiologo del centro devono escludere l’evidenza che il tumore sia totalmente contiguo o circostante oppure invada il lume di un grande vaso sanguigno (quali l'arteria polmonare o la vena cava superiore). •Patologia nota a carico del SNC con l’eccezione delle metastasi cerebrali trattate Le metastasi cerebrali trattate sono definite come metastasi che non presentano evidenze di progressione o emorragia &gt; 2 sett. dopo il trattamento e che attualmente non richiedono desametasone, come accertato attraverso gli esami clinici ed di imaging del cervello (RM o TC) durante il periodo di screening. Sono consentite dose stabili di anticonvulsivanti a non-induzione enzimatica. Il trattamento delle metastasi cerebrali può includere radioterapia cerebrale totale, radiochirurgia (Gamma Knife, LINAC o equivalente) o una combinazione di queste in base a quanto ritenuto opportuno dal medico curante e se sono trascorse &gt; 2 sett. dal trattamento con le radiationi. I pazienti con metastasi a carico del SNC trattate con resezione neurochirurgica o biopsia cerebrale nei 3 mesi precedenti al Giorno 1 del Ciclo 1 saranno esclusi. •Malattia leptomeningea. •Altri tumori maligni diversi dall’NSCLC trattati con esito positivo nei 3 anni precedenti la randomizzazione, con l’eccezione del carcinoma in situ della cervice adeguatamente trattato, carcinoma della pelle a cellule basali o squamose, cancro della prostata localizzato trattato chirurgicamente a scopo curativo, carcinoma duttale in situ trattato chirurgicamente a scopo curativo. •Diabete di tipo I. •Diabete di tipo II che richiede una terapia cronica con insulina. •Necessità di una terapia con ossigeno supplementare per portare a termine le normali attività quotidiane. •Angina instabile. •Aritmia cardiaca grave che necessita di trattamento durante lo studio. •Insufficienza cardiaca congestizia di classe II o superiore secondo la NYHA. •Anamnesi di sindrome da malassorbimento o altra patologia che interferisce con l’assorbimento enterale. •Intervento chirurgico maggiore, biopsia aperta o lesione traumatica significativa nei 28 gg precedenti il Giorno 1 del Ciclo 1 o previsione di un intervento chirurgico maggiore durante lo studio. Il posizionamento di un dispositivo di accesso vascolare non è considerato un intervento chirurgico maggiore. •Anamnesi clinicamente significativa di patologie epatiche, compresi cirrosi, epatite virale attiva e corrente abuso di alcol. •Infezione da HIV nota. •Infezione attiva che richiede antibiotici per via endovenosa. Per elenco completo rif. protocollo.
    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 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
    Per TUTTI i Bracci e tutte le popolazioni predefinite dello studio (vedere Sezione 3.5), l’ outcome primario di efficacia è: •PFS, definita come il tempo intercorso tra la randomizzazione e la progressione di malattia valutata dallo sperimentatore tramite i RECIST v1.1 (Appendice C) o il decesso per una causa qualsiasi durante lo studio (≤ 30 giorni dopo l’ultima dose del trattamento in studio), a seconda dell’evento che si verifica prima.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Disease progression or death from any cause on the study
    Progressione di malattia o morte per una causa qualsiasi durante lo studio
    E.5.2Secondary end point(s)
    For ALL Arms and all predefined study populations (see Section 3.3.5), 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
    Per TUTTI i Bracci e tutte le popolazioni predefinite dello studio (vedere Sezione 3.5), gli outcome secondario di efficacia sono: •Risposta obiettiva del tumore valutata dallo sperimentatore tramite i RECIST v1.1 (Appendice C); le risposte obiettive devono essere confermate ≥ 28 giorni dopo la risposta iniziale. •Durata della risposta obiettiva, definita come il tempo intercorso tra la prima osservazione di una risposta obiettiva del tumore e la prima osservazione di progressione di malattia valutata dallo sperimentatore tramite i RECIST v1.1 (Appendice C). •OS, definita come il tempo intercorso tra la randomizzazione e il decesso per una qualsiasi causa.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Objective tumor response - Confirmed ≥ 28 days after the initial response • Duration of objective response - Disease progression • OS - Death from any cause
    •Risposta obiettiva del tumore - confermata ≥ 28 giorni dopo la risposta iniziale. •Durata della risposta obiettiva - progressione di malattia •OS - decesso per una qualsiasi causa.
    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 trial4
    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 EEA45
    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
    Israel
    Russian Federation
    Ukraine
    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.
    Quando l'ultimo paziente raggiunge lo stato di overal survival (OS) o viene perso al follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months37
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months43
    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.1.1Number of subjects for this age range: 0
    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: 226
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 76
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-04-11. Yes
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 175
    F.4.2.2In the whole clinical trial 302
    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 discont., 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 discont., however, the study drug may not be offered after study discont.
    Alla conclusione o discontinuazione dello studio, i pazienti che continuano a beneficiare del trattamento in studio potrebbero avere la possibilità di continuare il trattamento in uno studio di estensione. Se il farmaco in studio dovesse continuare ad essere disponibile, Genentech valuterà con il singolo centro, l'elegibilità di ogni singolo paziente. A seconda delle ragioni di un'eventuale discontinuazione del farmaco in studio, esso potrebbe non essere reso disponibile.
    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 Decision2012-06-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-03-30
    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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