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    Summary
    EudraCT Number:2013-002620-17
    Sponsor's Protocol Code Number:B7461001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-06-04
    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 number2013-002620-17
    A.3Full title of the trial
    Phase 1/2 study of PF-06463922 (an ALK/ROS1 tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer harboring specific molecular alterations.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study with investigational drug PF-06463922 in patients with a specific type of advanced lung cancer
    A.4.1Sponsor's protocol code numberB7461001
    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 SponsorPfizer 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 supportPfizer Inc, 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 E 42nd Street
    B.5.3.2Town/ cityNew York, NY
    B.5.3.3Post code10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.5Fax number+13037391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 nameLorlatinib
    D.3.2Product code PF-06463922
    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 INNLorlatinib
    D.3.9.3Other descriptive namePF-06463922 Form 3 (acetic acid solvate)
    D.3.9.4EV Substance CodeSUB126819
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 nameLorlatinib
    D.3.2Product code PF-06463922
    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 INNLorlatinib
    D.3.9.3Other descriptive namePF-06463922 Form 3 (acetic acid solvate)
    D.3.9.4EV Substance CodeSUB126819
    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: 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 nameLorlatinib
    D.3.2Product code PF-06463922
    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 INNLorlatinib
    D.3.9.3Other descriptive namePF-06463922 Form 3 (acetic acid solvate)
    D.3.9.4EV Substance CodeSUB126819
    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: 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 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 nameLorlatinib
    D.3.2Product code PF-06463922
    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 INNLorlatinib
    D.3.9.3Other descriptive namePF-06463922 (anhydrous form 7)
    D.3.9.4EV Substance CodeSUB126819
    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 Xalkori 200 mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited UK
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameXalkori
    D.3.2Product code PF-02341066
    D.3.4Pharmaceutical form Capsule
    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 INNPF-02341066
    D.3.9.1CAS number 877399-52-5
    D.3.9.2Current sponsor codePF-02341066
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit IU/mg international unit(s)/milligram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Xalkori 250 mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited UK
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameXalkori
    D.3.2Product code PF-02341066
    D.3.4Pharmaceutical form Capsule
    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 INNPF-02341066
    D.3.9.1CAS number 877399-52-5
    D.3.9.2Current sponsor codePF-02341066
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit IU/mg international unit(s)/milligram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Anaplastic Lymphoma Kinase (ALK)-positive (ALK+) or ROS oncogene 1 (ROS1)-positive (ROS1+) advanced non-small cell lung cancer (NSCLC).
    E.1.1.1Medical condition in easily understood language
    a specific type of advanced 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 20.0
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066490
    E.1.2Term Progression of non-small cell lung cancer
    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 20.0
    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
    This study has separate primary objectives for the two study portions: Phase 1 and Phase 2.
    Phase 1 study portion:
    To assess safety and tolerability of PF-06463922 as a single agent at increasing dose levels in patients with advanced ALK+ or advanced ROS1+ NSCLC in order to estimate the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
    Phase 2 study portion:
    To evaluate overall (intra- and extra-cranial) and intracranial anti-tumor activity of single-agent PF-06463922 at RP2D in patients with advanced ALK+ NSCLC and advanced ROS1+ NSCLC.
    E.2.2Secondary objectives of the trial
    Please refer to study protocol to check separate secondary objectives for the two study portions Phase 1 and Phase 2.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - During the Phase 1 portion of the study, a midazolam (MDZ) drug-drug interaction (DDI) substudy will be conducted at 3 to 4 PF-06463922 dose levels to evaluate the effect of PF-06463922 on CYP3A inhibition/
    induction. Additionally, a food effect substudy will be conducted in approximately 6 patients enrolled in Phase 1.
    - During the Phase 2 portion of the study, a MDZ DDI substudy and a food effect substudy will be conducted at the Recommended Phase 2 Dose (RP2D) in advanced ALK+ NSCLC patients.
    - Additionally, to satisfy local regulatory requirements, a Japanese patient only lead in cohort (LIC) will be enrolled to examine the safety and PK of PF-06463922 at a previously tested dose in Phase 1. The LIC
    will be conducted at Japanese sites concurrently with the Phase 2 portion of the study.
    - Addition of optional crizotinib treatment after PF-06463922 in Phase 2 for ALK+ NSCLC patients who were treatment naïve prior to receiving PF-06463922.
    E.3Principal inclusion criteria
    1. Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA)-approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT-PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). A central laboratory confirmation by a Sponsor-selected, validated test will retrospectively determine final ROS1 status. All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
    2. Disease Status Requirements
    Phase 1: ALK-positive NSCLC patients must either be treatment naïve in the advanced setting or have had disease progression after atleast 1 previous ALK inhibitor therapy(ies). ROS1+positive NSCLC patients must either be treatment naïve in the advanced setting or have had disease progression after atleast 1 previous ROS1 inhibitor therapy(ies).
    Phase 2: ALK-positive NSCLC patients must either be or have had:
    - Treatment naïve (ie, no prior chemotherapy in the metastatic disease
    setting and no prior ALK inhibitor therapy allowed) [EXP-1];
    - Disease progression after crizotinib only. No prior chemotherapy is
    allowed in the metastatic disease setting. [EXP-2];
    - Disease progression after crizotinib and 1 or 2 prior regimens of
    chemotherapy in the metastatic disease setting. [EXP-3];
    - Disease progression after 1 prior ALK inhibitor therapy other than
    crizotinib. Patients may have had any number of prior chemotherapy
    regimens in any disease setting. [EXP-3];
    - Disease progression after 2 prior ALK inhibitor therapies. Patients may
    have had any number of prior chemotherapy regimens in any disease
    setting. [EXP-4];
    - Disease progression after 3 prior ALK inhibitor therapies. Patients may
    have had any number of prior chemotherapy regimens in any disease
    setting. [EXP-5];
    ROS1- positive NSCLC patients may be:
    - Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ROS inhibitor therapy). [EXP-6];
    - Any number of prior therapies (ie, chemotherapy and/or ROS inhibitor therapies). [EXP-6].
    -3. Tumor Requirements:
    Phase 1: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. The brain metastases may be newly diagnosed or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion #3 for the lapsed time period required between the end of radiotherapy and study entry). Patients who have asymptomatic radiologically suspected leptomeningeal disease (LM) or carcinomatous meningitis (CM) and negative spinal fluid (CSF) are eligible to enter Phase 1.
    Phase 2: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients controlled with stable or decreasing steroid use within the last 2 weeks prior to study entry) will be eligible. The brain metastases may be newly diagnosed or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion #3 for the lapsed time period required between the end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the LM/CM is visualized on MRI or if documented baseline cerebral spinal fluid (CSF) positive cytology is available.
    4. Age >=18 years (or ≥20 years of age if required by local regulation).
    5. ECOG Performance Status (PS):
    - Phase 1: 0 or 1;
    - Phase 2: 0, 1, or 2.
    6. Adequate Bone Marrow Function, including:
    - Absolute Neutrophil Count (ANC) >=1.5 x 1 000 000 000/L;
    - Platelets >=100 x 1 000 000 000/L;
    - Hemoglobin >=9 g/dL.
    7. Adequate Pancreatic Function, including:
    - Serum total amylase <=1.5 ULN.
    - Serum lipase <=1.5 ULN.
    8. Adequate Renal Function, including:
    - Serum creatinine <=1.5 x ULN or estimated creatinine clearance >=60 mL/min as calculated using the method standard for the institution.
    9. Adequate Liver Function, including:
    - Total serum bilirubin <=1.5 x ULN;
    - Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)
    <=2.5 x ULN; <=5.0 x ULN if there is liver metastases involvement;
    10. Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade <=1 except for AEs that in the investigator' judgment do not constitute a safety risk for the patient.
    For more inclusion criteria refer to the protocol.
    E.4Principal exclusion criteria
    1.Spinal cord compression is excluded unless the patient demonstrates good pain control attained through therapy and there is stabilization or recovery of neurological function for the 4 weeks prior to study entry
    2.Major surgery within 4 weeks of study entry.Minor surgical procedures are not excluded but sufficient time should have passed for wound healing
    3.Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry.Palliative radiation (<=10 fractions) must have been completed at least 48 hours prior to study entry.Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry.Whole brain radiation must have completed at least 4 weeks prior to study entry
    4.Systemic anti-cancer therapy completed within a minimum of 5 halflives of study entry (unless clinically meaningful tumor flare per discretion of the investigator, in which discussion with the sponsor is warranted).
    5.Prior therapy with an antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T
    lymphocyte associated antigen 4 (anti-CTLA-4) antibody.
    6.Previous high-dose chemotherapy requiring stem cell rescue
    7.Prior irradiation to >25% of the bone marrow
    8.Active and clinically significant bacterial, fungal, or viral infection including HBV, HCV, known HIV or AIDS-related illness
    9.Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction,
    unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or thirddegree AV block (unless paced) or
    any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
    10.Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (see protocol for more details).
    11.History of extensive,disseminated,bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersentivity pneumonitis, interstitial pneumonia,
    interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis. Patients with history of prior radiation pneumonitis are not excluded
    12.Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior,or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results
    and,in the judgment of the investigator,would make the patient inappropriate for entry into this study
    13.Patients who are investigational site staff members directly involved in the conduct of the trial and their family members,site staff members otherwise supervised by the Investigator,or patients who are Pfizer
    employees directly involved in the conduct of the trial
    14.Evidence of active malignancy within the last 3 years. See protocol for more details
    15. Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease or previous gastric resection or lap band.
    For more exclusion criteria refer to the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1 Primary Endpoint:
    - Cycle 1 Dose-Limiting Toxicities (DLTs).
    Phase 2 Primary Endpoint:
    - Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. In patients with asymptomatic CNS metastases, up to five (5) intracranial target lesions in addition to the five (5) extracranial target lesions will be assessed.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1 Primary Endpoint:
    - Cycle 1 Dose-Limiting Toxicities (DLTs): cycle 1.
    Phase 2 Primary Endpoint:
    - Objective tumor response: at baseline and at the stipulated intervals during treatment.
    Please refer to Schedule of Activities of the protocol.
    E.5.2Secondary end point(s)
    Secondary Endpoints [all patients unless otherwise indicated]:
    - Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), seriousness and relationship to study therapy.
    - Laboratory abnormalities as characterized by type, frequency and severity (as graded by NCI CTCAE v.4.03).
    - Left Ventricular Ejection Fraction (LVEF).
    - Vital Signs (heart rate, blood pressure).
    - Total Mini-Mental State Examination Score [Phase 1 only].
    - Mood assessment, Cognitive Function assessment, Suicidal Ideation and Behavior assessment [Phase 2 only].
    - Pharmacokinetic parameters of PF-06463922: Single Dose - Cmax, Tmax, AUClast,AUC t, CL/F, and Vz/F and t1/2, AUCinf as data permit.
    Multiple Dose (assuming steady-state is achieved) - Css,max, Tss,max, AUCss,t, t1/2, Css,min, Css,av, CL/F, Vz/F, Rac (AUCss,t/AUCsd,t) and Rss (AUCss,t/AUCsd,inf) as data permit. Phase 1 only: Urine PK parameters (Ae%, and CLR) of PF-06463922 from MDZ and food effect substudy.
    - Phase 1 only: Pharmacokinetic parameters of midazolam: Cmax, Tmax, AUClast, CL/F, and Vz/F and t1/2, AUCinf as data permit.
    - Patient reported functioning and impact on disease/treatment-related symptoms of lung cancer and global QOL.
    - QTc interval.
    - Disease Control Rate (DCR) at 12 weeks defined as the percent of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1 at 12 weeks.
    - Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 (Appendix 3) [Phase 1 only - primary endpoint in Phase 2]. In patients with asymptomatic CNS metastases, up to 5 intracranial target lesions in addition to the 5 extracranial target lesions will be assessed.
    - Time-to-event endpoints: Progression-Free Survival (PFS), Overall Survival (OS) at 1 year and 18 months, Duration of Response (DR), and Time to Tumor Response (TTR).
    - Probability of first event being a CNS progression, non CNS progression, or death.
    - Time to Progression (TTP) [Phase 2 only].
    - Response to prior systemic therapies.
    - Selected molecular profiling of tumor tissue, eg, ALK kinase domain mutations and circulating nucleic acid (CNA), eg, ALK kinase domain mutations.

    Secondary Endpoints [ALK+ NSCLC Phase 2 patients receiving singleagent crizotinib
    following first-line treatment with PF-06463922]:
    - Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), seriousness and relationship to study therapy.
    - Laboratory abnormalities as characterized by type, frequency, and severity (as graded
    by NCI CTCAE v.4.03).
    - Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1, and time-to-event endpoints including PFS, DR, TTR and OS.

    Phase 1 Exploratory Endpoints:
    - Time to Progression (TTP).

    Phase 1 and 2 Exploratory Endpoints
    - CSF concentration of PF-06463922.
    Japanese Patient Only Lead-In Cohort (LIC)
    - Cycle 1 Dose Limiting Toxicities (DLTs).

    Endpoint for Drug-Drug Interaction (DDI)/Holter Monitoring Study
    - Pharmacokinetic parameters (as data permit) for probe substrate after single oral administration with or without PF-06463922: Plasma AUC24, AUClast, AUCinf , Cmax, Tmax, CL/F, Vz/F and t1/2.
    - Pharmacokinetic parameters (as data permit) for relevant probe substrate metabolite(s) and PF-06463922 metabolite(s): Plasma and AUC24, AUClast, AUCinf , Cmax, Tmax, t1/2, MRCmax, MRAUCinf, and MRAUClast.
    - PR interval with PF-06463922 treatment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to Schedule of Activities of the protocol.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To characterize the effect of food on PF-06463922
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Singapore
    Spain
    Switzerland
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    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: 245
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 95
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 340
    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)
    Patients may continue PF-06463922 treatment after objective progression of disease is determined if the patient is continuing to experience clinical benefit, in the opinion of the investigator, and after discussion with the Sponsor.
    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 Decision2014-07-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-11
    P. End of Trial
    P.End of Trial StatusOngoing
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