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    Summary
    EudraCT Number:2010-020916-12
    Sponsor's Protocol Code Number:OSI-906-205
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-10-28
    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 number2010-020916-12
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-controlled Phase 2 Study of Maintenance OSI 906 plus Erlotinib (Tarceva®), or Erlotinib plus Placebo in Patients with Nonprogression Following Four Cycles of 1st-line Platinum-based Chemotherapy for Advanced NSCLC
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study in non small cell lung cancer investigating whether a new product added to an existing treatment has beneficial effects.
    A.4.1Sponsor's protocol code numberOSI-906-205
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01186861
    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 SponsorAstellas Pharma Global Development, 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 supportAstellas Pharma Global Development, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointAstellas Pharma Service Desk
    B.5.3 Address:
    B.5.3.1Street AddressElisabethhof 19
    B.5.3.2Town/ cityLeiderdorp
    B.5.3.3Post code2353 EW
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715455878
    B.5.5Fax number+31715455224
    B.5.6E-mailcontact@nl.astellas.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 nameOSI-906 150 mg
    D.3.2Product code OSI-906
    D.3.4Pharmaceutical form 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 INNlinsitinib
    D.3.9.1CAS number 867160-71-2
    D.3.9.2Current sponsor codeOSI-906
    D.3.9.3Other descriptive nameOSI-906 150 mg
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 nameOSI-906 100 mg
    D.3.2Product code OSI-906
    D.3.4Pharmaceutical form 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 INNlinsitinib
    D.3.9.1CAS number 867160-71-2
    D.3.9.2Current sponsor codeOSI-906
    D.3.9.3Other descriptive nameOSI-906 100 mg
    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 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 nameOSI-906 25 mg
    D.3.2Product code OSI-906
    D.3.4Pharmaceutical form 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 INNlinsitinib
    D.3.9.1CAS number 867160-71-2
    D.3.9.2Current sponsor codeOSI-906
    D.3.9.3Other descriptive nameOSI-906 25 mg
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 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 Tarceva 25 mg Film-coated Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products Limited
    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.3.4Pharmaceutical 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 INNERLOTINIB HYDROCHLORIDE
    D.3.9.1CAS number 183319-69-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 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 Tarceva 100 mg Film-coated Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products Limited
    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.3.4Pharmaceutical 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 INNERLOTINIB HYDROCHLORIDE
    D.3.9.1CAS number 183319-69-9
    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: 6
    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 Tarceva 150 mg Film-coated Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products Limited
    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.3.4Pharmaceutical 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 INNERLOTINIB HYDROCHLORIDE
    D.3.9.1CAS number 183319-69-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Non-small cell lung cancer
    E.1.1.1Medical condition in easily understood language
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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
    The primary objective of this study is to determine the progression free survival (PFS) of maintenance OSI-906 plus erlotinib (Arm A), or erlotinib and placebo (Arm B) in patients with nonprogression following four cycles of first-line platinum-based chemotherapy for advanced NSCLC in the overall population.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate:
    • EGFR mutation positive and EGFR mutation negative subsets;
    • PFS in the squamous and non-squamous subsets;
    • Disease control (DCR);
    • Response upgrade rate (RUR);
    • Best overall response rate (ORR);
    • Duration of response;
    • Overall survival (OS);
    • Safety profile of OSI-906/erlotinib combination;
    • Pharmacokinetic (PK) profile of OSI-906/erlotinib combination;
    • Tissue analysis looking at protein expression – including the relationship
    between E-cadherin and Vimentin expression and clinical outcomes (PFS and OS);
    • Exploratory biomarkers and correlations with treatment outcome.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed locally advanced or metastatic stage IIIB or IV NSCLC;
    2. Have experienced CR, PR or SD following completion of 4 cycles of
    first-line platinum-based chemotherapy and are not progressing at time of entry into study (prior completed first-line combination bevacizumab therapy is permitted however, current use of maintenance bevacizumab is not permitted);
    3. A maximum interval of 28 days between the last day of the treatment cycle and randomization;
    4. Patient has recovered from prior chemotherapy-related toxicity to ≤ grade 2;
    5. EGFR mutation status must be confirmed for participation in the study.
    EGFR analysis can be performed either by central or local laboratory. If analysis is done locally, verifiable documentation confirming the EGFR mutation status must be submitted for review and approval by APGD prior to randomization. If no local result is available, formalin-fixed, paraffin-embedded archival tissue representative of the tumor or in the absence of archival tissue, a fresh tumor tissue sample of sufficient size to perform EGFR mutation analysis must be submitted centrally. Results of the central analysis must be available prior to randomization. Additionally, subjects should provide tissue blocks centrally for biomarker analysis whenever possible. Ideal tissue requirement: block with ≥5mm2 tumor area sufficient to provide four 4-micron, and five 10-micron sections;
    6. Measurable disease (for those patients with SD or PR following 4 cycles of first-line platinum based chemotherapy) according to RECIST (version 1.1);
    7. Age ≥ 18 years;
    8. ECOG PS 0 – 1 (Appendix 13-2);
    9. Previous adjuvant or neo-adjuvant treatment is permitted;
    10. Must be able to take oral medication;
    11. Fasting glucose ≤ 150 mg/dL (8.3 mmol/L). Concurrent use of noninsulinotropic
    antihyperglycemic therapy is permitted if the dose has been stable for ≥ 4 weeks at the time of randomization;
    12. Adequate hematopoietic, hepatic, and renal function defined as
    follows:
    - Neutrophil count ≥ 1.5 x 109/L;
    - Platelet count ≥ 100 x 109/L;
    - Bilirubin ≤ 1.5 x ULN;
    - AST and ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if patient has documented liver
    metastases;
    - Serum creatinine ≤ 1.5 x ULN
    - Potassium, magnesium and calcium within normal limits (supplementation and retesting is permitted).
    13. Female patient must be either:
    - Of non child bearing potential:
    • post-menopausal (defined as at least 1 year without any menses) prior to
    • documented surgically sterile or status post hysterectomy (at least 1 month prior to
    Screening)
    - Or, if of childbearing potential:
    • must have a negative urine pregnancy test at Screening, and
    • must use two forms of birth control (one of which must be a barrier method)
    starting at Screening and throughout the study period and for 30 days after final
    study drug administration
    Acceptable forms include:
    • Established use of oral, injected or implanted hormonal methods of
    contraception
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    • Barrier methods of contraception: Condon OR Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;
    14. Female patient must not be breastfeeding at Screening or during the study period and for 30 days after final study drug administration;
    15. Female patient must not donate ova starting at Screening and throughout the study period
    and for 30 days after final study drug administration;
    16. Male patient and their female spouse/partners who are of childbearing potential must be
    using highly effective contraception consisting of two forms of birth control (one of which
    must be a barrier method) starting at Screening and continue throughout the study period
    and for 30 days after final study drug administration
    Acceptable forms include:
    • Established use of oral, injected or implanted hormonal methods of contraception
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    • Barrier methods of contraception including a condom or occlusive cap (diaphragm
    or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;
    17. Male patient must not donate sperm starting at Screening and throughout the study period
    and for at least 30 days after final study drug administration;
    18. Prior radiation therapy is permitted provided patients have recovered from acute toxic
    effects of radiotherapy prior to randomization. A minimum of 28 days must have elapsed
    between the end of radiotherapy and randomization;
    19. Prior surgery is permitted provided that the surgery was performed ≥ 21 days prior to
    randomization and adequate wound healing has occurred prior to randomization; and
    20. Patients must provide written (signed) informed consent to participate in the study and for
    use of tumor tissues.
    E.4Principal exclusion criteria
    1. Prior exposure to agents directed at the HER axis (e.g., erlotinib,gefitinib, cetuximab, and trastuzumab);
    2. Malignancies other than NSCLC within past 3 years (exceptions if curatively treated: basal or squamous cell carcinoma of skin; locally advanced prostate cancer; ductal carcinoma in situ of breast; in situ cervical carcinoma; and superficial bladder cancer);
    3. Type 1 diabetes mellitus or Type 2 diabetes mellitus currently requiring insulinotropic orinsulin therapy;
    4. Prior IGF-1R inhibitor therapy;
    5. Participated in any interventional clinical study or has been treated with any investigational
    drugs within 30 days or 5 half lives whichever is longer, prior to the initiation of Screening
    or during the course of the study;
    6. Concurrent use of maintenance bevacizumab;
    7. History of poorly controlled gastrointestinal disorders that could affect the absorption of study drug (e.g., Crohn's disease, ulcerative colitis, etc);
    8. History (within last 180 days) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes second/third degree
    heart block; clinically significant ischemic heart disease; superior vena cava (SVC)
    syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea);
    9. History of arrhythmia (multifocal premature ventricular contractions[PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that
    is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded;
    10. Mean QTcF interval ≥ 450 msec based on independent central
    reviewer analysis of screening visit ECGs;
    11. Use of drugs that have a known risk of causing Torsades de Pointes
    (TdP) ('Torsades List' on www.azcert.org/medical-pros/drug-lists/bycategory.cfm, see Appendix 13-3) are prohibited within 14 days prior to randomization;
    12. Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded;
    13. Use of potent CYP3A4 inhibitor such as ketoconazole, clarithromycin, atazanavir, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
    troleandomycin (TAO), or voriconazole;
    14. Use of proton pump inhibitors such as omeprazole. H2-receptor antagonists such as ranitidine are not excluded;
    15. History of cerebrovascular accident (CVA) within 180 days prior to randomization or that resulted in ongoing neurologic instability;
    16. Active infection, serious underlying medical condition (including any type of active seizure disorder within 12 months prior to randomization), or serious chronic
    illness that would impair the ability of the patient to receive study drug;
    17. History of any psychiatric or neurologic condition that might impair the patient's ability to understand or to comply with the requirements of the study or to provide informed consent;
    18. Pregnant or breast-feeding females;
    19. Symptomatic brain metastases that are not stable, require steroids, are potentially life-threatening, or that have required radiation and/or other related treatment (e.g., antiepileptic medication) within 21 days prior to randomization; and/or
    20. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drug.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is PFS.
    The secondary efficacy variables include: OS, DCR, best ORR, RUR, and duration of response.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy variable is PFS based on RECIST.

    Assessments are done every 6 wks pre-dose on D1 of every TP unless otherwise stated and at the post-treatment visit.

    E.5.2Secondary end point(s)
    The secondary efficacy variables include: OS, DCR, best ORR, RUR, and duration of response.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessments are conducted every 6 weeks pre-dose on D1 of every TP unless otherwise stated and at the post-treatment visit
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic 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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Brazil
    Canada
    Korea, Republic of
    Russian Federation
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study will be defined as when the stated objectives of the trial are able to be evaluated for the purpose of completing the final analysis, unless the study is otherwise terminated early.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 82
    F.4.2.2In the whole clinical trial 200
    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)
    Treatment after the subject has ended participation in the trial is the expected normal treatment of this condition.
    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 Decision2010-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-02-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-10-31
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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