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    Summary
    EudraCT Number:2014-004283-37
    Sponsor's Protocol Code Number:9785-CL-3021
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2015-09-09
    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 number2014-004283-37
    A.3Full title of the trial
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
    to Assess the Efficacy and Safety of Enzalutamide in Subjects
    with Advanced Hepatocellular Carcinoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety and effectiveness of enzalutamide in patients with advanced hepatocellular carcinoma
    A.4.1Sponsor's protocol code number9785-CL-3021
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02528643
    A.5.4Other Identifiers
    Name:INDNumber:127011
    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 pointService Desk - Global Clinical Dev.
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715455050
    B.5.5Fax number+31715455501
    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 Yes
    D.2.1.1.1Trade name Xtandi
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    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 Capsule, soft
    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 INNENZALUTAMIDE
    D.3.9.1CAS number 915087-33-1
    D.3.9.2Current sponsor codeMDV3100
    D.3.9.4EV Substance CodeSUB77412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 placeboCapsule, soft
    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
    Male and female subjects with HCC of any etiology who have progressed on or were intolerant to sorafenib or other anti-VEGF therapy in the advanced setting
    E.1.1.1Medical condition in easily understood language
    Male and female subjects with Advanced Hepatocellular Carcinoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    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
    To evaluate the efficacy of enzalutamide in subjects with advanced hepatocellular carcinoma (HCC) as measured by overall survival (OS).
    E.2.2Secondary objectives of the trial
    To evaluate:
    - the safety of enzalutamide in subjects with advanced HCC.
    - the pharmacokinetics (PK) of enzalutamide and the active metabolite N-desmethyl enzalutamide in subjects with advanced HCC.
    - the Time to Progression (TTP) and Progression Free Survival (PFS) of enzalutamide as compared to placebo in subjects with advanced HCC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Waivers to the inclusion and exclusion criteria will NOT be allowed.
    1. Subject has consented and signed an Institutional Review Board (IRB)/Independent Ethics
    Committee (IEC) approved written Informed Consent and privacy language as per national
    regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites)
    prior to any study-related procedures (including withdrawal of prohibited medication, if
    applicable).
    2. Subject is ≥ 18 years of age or is considered an adult according to local regulation at the time of signing informed consent.
    3. Subject has histological diagnosis of advanced HCC of any etiology. Clinical diagnosis by the
    European Association for the Study of the Liver (EASL) criteria is acceptable. For subjects
    without cirrhosis, histological confirmation is required (archive samples are acceptable).
    4. Subject has BCLC stage B or C.
    5. Subject’s lesions are not amenable to local therapies which may be beneficial, such as
    transarterial chemoembolization (TACE), radiofrequency ablation, radiotherapy etc., and the subject is not a
    candidate for any curative treatments such as resection or liver transplant.
    6. Subject has hepatic function status of Child Pugh Class A at Screening.
    7. Subject received prior systemic treatment for HCC with sorafenib or other anti-VEGF therapy
    and had confirmed disease progression or had discontinued treatment due to a drug-related toxicity.
    Subject may have received 1 line of systemic therapy before or after sorafenib/anti-VEGF
    treatment.
    8. Subject has adequately recovered from toxicities due to prior HCC therapy to ≤ grade 1.
    9. Subject has an ECOG performance status ≤ 1 at Screening and on Day 1.
    10. Subject has available formalin-fixed, paraffin-embedded tumor specimen with adequate viable tumor cells in a tissue block unstained serial slides accompanied by an associated pathology report prior to enrollment. Archival or fresh biopsy tissue is acceptable.
    11. Subject has an estimated life expectancy of at least 3 months on Day 1, in the opinion of the
    investigator
    12. Female subject is either:
    ● Not of childbearing potential:
    -postmenopausal (defined as no spontaneous menses for at least 12 consecutive months prior to Screening with follicle-stimulating hormone [FSH] > 40 IU/L for women < 55 years of age at Screening), or
    -documented to be surgically sterile or status posthysterectomy (at least 1 month prior to
    Screening).
    ● Or, if of childbearing potential:
    - must have a negative urine pregnancy test at Screening and on Day 1 before the first dose of study drug is administered, and
    - must use 2 acceptable methods of birth control* if sexually active from Screening through 3 months after the last dose of study drug.
    13. Sexually Active Male subject and his female partner who is of childbearing potential must use 2 acceptable
    methods of birth control from Screening through 3 months after the last dose of study drug.
    *Two acceptable methods of birth control are as follows:
    ● Condom (barrier method of contraception);
    AND
    ● One of the following is required:
    - Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female subject or female partner of a male subject;
    - Additional barrier method: contraceptive sponge or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female subject or female partner of a male subject.
    - For male subject or male partner of female subject, vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) performed at least 6 months before Screening.
    -Tubal ligation in the female partner of a male subject performed at least 6 months before Screening.
    - Established and ongoing use of oral, injected, or implanted hormonal contraceptive by female partner of a male subject.
    14. Female subject must not be breastfeeding at Screening or during the study period and for 3
    months after final study drug administration.
    15. Subject must agree not to donate sperm or ova from first dose of study drug through 3 months
    after the last dose of study drug.
    16. Throughout the study, male subject must use a condom if having sex with a pregnant woman.
    17. Subject must be able to swallow study drug and comply with study requirements.
    18. Subject agrees not to participate in another interventional study while on treatment.
    E.4Principal exclusion criteria
    1. Subject has a severe concurrent disease, infection or comorbidity that, in the judgment of the
    investigator, would make the subject inappropriate for enrollment.
    2. Subject has fibrolamellar variant of HCC.
    3. Subject has status of Child-Pugh Class B or C at Screening.
    4. Subject has a history of organ allograft including liver transplant.
    5. Subject has uncontrolled symptomatic ascites.
    6. Subject has known or suspected brain metastasis or active leptomeningeal disease.
    7. Subject has a history of a non-HCC malignancy with the following exceptions:
    -The subject with a previous history of a noninvasive carcinoma is eligible if in the opinion of
    the investigator he/she has had successful curative treatment any time prior to Screening and
    requires no further therapy for the malignancy.
    -For all other malignancies, the subject is eligible if he/she has undergone potentially curative
    therapy and has been considered disease free for at least 3 years prior to Screening.
    8. Subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as:
    -Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3)
    -Platelet count < 50 x109/L (< 50,000 cells/mm3)
    -Hemoglobin < 8.5 g/dL (< 5.3 mmol/L)
    -International normalized ratio > 1.7
    -Albumin < 2.8 g/dL (< 28 g/L)
    -Total bilirubin (TBL) > 2 x ULN
    -AST or ALT > 5 x ULN
    -Creatinine > 1.5 x ULN
    Note: Transfusions/infusions to meet eligibility criteria are not allowed but if in the opinion of the Principle Investigator, it is beneficial, the patient may be re-screened after receiving one of these procedures.
    9. Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior
    cortical stroke, significant brain trauma, encephalopathy within 3 months of Day 1).
    10. Subject has a history of bleeding esophageal varices within 3 months before the Day 1 visit.
    11. Subject has a history of loss of consciousness or transient ischemic attack within 12 months
    before the Day 1 visit.
    12. Subject has clinically significant cardiovascular disease including:
    -Myocardial infarction within 6 months before the Day 1 visit.
    -Uncontrolled angina within 6 months before the Day 1 visit.
    -Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of
    congestive heart failure NYHA Class III or IV in the past, unless a Screening echocardiogram
    or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a
    left ventricular ejection fraction that is ≥ 45%.
    - History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsade de Pointes).
    -History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
    - Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive measurements at the Screening visit.
    -Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of
    < 50 beats per minute on the Screening electrocardiogram (ECG) recording.
    -Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the Screening visit.
    13. Subject has a gastrointestinal disorder affecting absorption.
    14. Subject had previous local therapy (e.g., surgery, radiation therapy, hepatic arterial therapy,
    chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation)
    within 14 days prior to Day 1, has not recovered from toxicities from prior local therapy or may
    require major surgical procedure during the course of the study.
    15. Subject has received chemotherapy, immunotherapy or any other systemic anticancer therapy
    (including sorafenib) or any other investigational drug within 14 days prior to the Day 1 visit.
    16. Subject has received an agent that either blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, enzalutamide, ARN-509 or other investigational AR signaling inhibitors). The Exception of spironolactone is allowed after Medical Monitor consultation.
    17. Subject has used any of the following within 28 days before the Day 1visit:
    -5-α reductase inhibitors
    - Systemic androgens and estrogens (vaginal estrogen creams are allowed)
    -Herbal therapies, with an antitumor effect.
    18. Subject has a known history of positive test for Human Immunodeficiency Virus.
    19. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of
    the enzalutamide capsule components, including caprylocaproyl polyoxylglycerides (Labrasol),
    butylated hydroxyanisole and butylated hydroxytoluene.
    20. Subject has addictive/substance abuse problems.
    21. Subject has any other condition or reason that, in the opinion of the investigator, interferes with
    the ability of the subject to participate in the trial, places the subject at undue risk or complicates
    the interpretation of safety data.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is overall survival (OS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    OS is defined as the time from the date of randomization until date of death from any cause
    E.5.2Secondary end point(s)
    Safety Endpoints:
    The safety of enzalutamide will be assessed on an ongoing basis by evaluation of AEs/serious adverse
    events, clinical safety laboratory tests, vital signs, and other safety measures.
    Pharmacokinetic Endpoints:
    Predose plasma concentrations of enzalutamide and N-desmethyl enzalutamide will be analyzed.
    Efficacy Endpoints:
    ● Time to Progression (TTP),
    ● Progression Free Survival (PFS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy Endpoints:
    ● PFS, defined as the time from the date of randomization until the date of documented
    radiographic disease progression according to Response Evaluation Criteria in Solid Tumors
    (RECIST) 1.1 or death from any cause on study, whichever occurs first as assessed by the
    investigator.
    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 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 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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Canada
    France
    Hong Kong
    Italy
    Korea, Republic of
    Puerto Rico
    Spain
    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
    LVLS
    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 months4
    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 months4
    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: 72
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 43
    F.4.2.2In the whole clinical trial 144
    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)
    Plans for treatment or care after for the subject is per the treating physician's discretion and what is best for the subject.
    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 Decision2015-10-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-23
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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