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    Summary
    EudraCT Number:2015-003385-84
    Sponsor's Protocol Code Number:GO40782(RXDX-101-02)
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-02-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2015-003385-84
    A.3Full title of the trial
    AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 BASKET STUDY OF ENTRECTINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS THAT HARBOR NTRK1/2/3, ROS1, OR ALK GENE REARRANGEMENTS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Tumor Alterations Responsive to Targeting Receptor Kinases-2
    A.3.2Name or abbreviated title of the trial where available
    STARTRK-2
    A.4.1Sponsor's protocol code numberGO40782(RXDX-101-02)
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-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 nameEntrectinib
    D.3.2Product code RO7102122
    D.3.4Pharmaceutical form Capsule, hard
    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 INNENTRECTINIB
    D.3.9.1CAS number 1108743-60-7
    D.3.9.2Current sponsor codeRO7102122
    D.3.9.4EV Substance CodeSUB177830
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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
    Locally Advanced or Metastatic Solid Tumors that Harbor NTRK1/2/3, ROS1,
    or ALK Gene Rearrangements
    E.1.1.1Medical condition in easily understood language
    Cancer that arises from organs and solid tissues which has spread to
    other organs
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the objective response rate of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement
    E.2.2Secondary objectives of the trial
    •To determine the duration of response, time to response, and clinical benefit rate of entrectinib, in each patient population basket of solid tumors
    •To determine the intracranial tumor response of entrectinib and CNS
    progression-free survival (CNS-PFS) in patients presenting with
    measurable CNS disease at baseline, as assessed by BICR using RECIST v1.1 or RANO for primary CNS tumors, as applicable
    •To estimate the progression-free survival and overall survival of patients with solid tumors treated with entrectinib
    •To evaluate the safety and tolerability of entrectinib when administered at the RP2D
    •To assess the population pharmacokinetics (PK) of Entrectinib and to explore correlations between PK, response, and/or safety findings
    •To evaluate the effect of entrectinib on ventricular repolarization
    •To assess treatment-related symptoms and general health status using validated instruments of patient reported outc
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically- or cytologically-confirmed diagnosis of locally advanced
    or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein
    with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant second oncodriver (e.g., EGFR, KRAS), as determined by Foundation Medicine, Inc. or by any nucleic acid-based diagnostic testing method (please refer to Section 5.1) performed at a local CLIA-certified or equivalently-accredited diagnostic lab.. Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest may be eligible provided they meet all other in-/excl. criteria.
    2. For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. or to the alternative, approved central lab. for that region.
    3. Measurable disease as assessed locally using RECIST v1.1.
    Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the "non-evaluable for the primary endpoint" basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints.
    4. Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previouslytreated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment. If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide. Moderate inducers of CYP450, such as dexamethasone or other glucocorticoids, may be used at the discretion of the Investig. Patients requiring steroids must be at stable or decreasing doses for at least 2 weeks prior to the start of entrectinib treatm.
    5. Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK (non-NSCLC patients only) inhibitors in patients who have tumors that harbor those respective gene rearrangements). Note: There is no basket for ALK-rearranged NSCLC who are naïve to ALK inhibitors; however, ALK- or ROS1-rearranged NSCLC patients previously treated with crizotinib only (and no other ALK or ROS1 inhibitor) are eligible, if they present with CNS-only progression (measurable or non-measurable disease) and extracranial stable disease.
    Note: The ALK basket is closed to enrollm.
    6. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, resp., at the time of the start of Entrectinib treatm. Note: For targeted therapies, there must be no signs of disease flare or accelerated disease progression after
    treatm discontinuation.
    7. At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of Entrectinib treatm.
    8. Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have compl.
    whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment
    9. Age ≥ 18 years
    10. Eastern Cooperative Oncology Group (ECOG) performance status = 2
    and minimum life expectancy of at least 4 weeks.
    11. Adequate liver function as defined by the following criteria:. Serum
    aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) = 3.0 × upper limit of normal (ULN); = 5.0 × ULN if liver metastases are present. Total serum bilirubin = 2.0 × ULN; patients with a known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible
    12. Females of childb potential must have a negative serum pregnancy test during Screening and must not be breastfeeding or intending to become pregnant during the study. Female pat. will be considered to be of childbearing potential unless they have undergone permanent contraception or are postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reasons (e.g., chemical menopause due to anticancer treatm.).
    13. Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules.
    14. Willingness to comply with scheduled visits, treatm. plan, lab. tests, and other study procedures.
    15. Signed and dated informed consent doc. indicating that the patient (or legally acceptable repr.) has been informed of all pertinent aspects of the trial prior to the start of Entrectinib treatm.
    E.4Principal exclusion criteria
    1. Current participation in another therapeutic clinical trial.
    2. Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements.
    Note: In cases where the patient was intolerant to prior Trk, ROS1, or ALK inhibitors, please discuss with the Sponsor.
    In addition, prior treatment with crizotinib is permitted ONLY in ALK- or
    ROS1-rearranged NSCLC patients presenting with CNS-only progression.
    Other ALK or ROS1 inhibitors are prohibited in that scenario.
    3. History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy. Note: Patients presenting with dual primary cancers may enroll in the "non-evaluable for the primary endpoint" basket if at least one of the
    cancers harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement as per
    Inclusion Criterion 1.
    4. Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.
    5. Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.
    6. History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction 50% observed during screening for the study
    7. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24 hours apart).
    8. History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).
    9. Peripheral sensory neuropathy Grade ≥ 2.
    10. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including human immunodeficiency virus positive).
    11. Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.
    12. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. Note: Radiation-induced
    lung disorders are not included in this exclusion criterion.
    13. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug 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 or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (ORR), defined as the proportion of
    patients with complete response (CR) or partial response (PR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment).
    E.5.2Secondary end point(s)
    1.Duration of Response (DOR),
    2.Time to Response (TTR),
    3.Clinical Benefit Rate (CBR),
    4.Intracranial tumor response in patients with measurable brain
    metastases, as determined by BICR using RANO or RANO-BM as
    applicable
    5.CNS Progression-Free Survival (CNS-PFS) in patients with measurable
    CNS disease,
    6.Progression-Free Survival (PFS),
    7.Overall Survival (OS),
    8.Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities
    9.Population PK
    10.Ventricular repolarization
    11.Quality-of-life and health status
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment).
    Clinical Benefit Rate - 6 months after the first dose of entrectinib

    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 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 Yes
    E.8.1.7.1Other trial design description
    Basket study of entrectinib for the treatment of patients with solid tumors
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA72
    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
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Singapore
    Spain
    Switzerland
    Taiwan
    United Kingdom
    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 trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met, if the study is not terminated beforehand per recommendation of DMC
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months7
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 300
    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)
    Currently, the sponsor does not have any plans to provide entrectinib or any other study treatments or interventions to subject after the end of the study or if subject have discontinued or been withdrawn from the study.
    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 Decision2016-04-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-26
    P. End of Trial
    P.End of Trial StatusOngoing
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