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    Summary
    EudraCT Number:2011-001959-37
    Sponsor's Protocol Code Number:E7449-E044-101
    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:2011-08-05
    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 number2011-001959-37
    A.3Full title of the trial
    An open label, multicenter, Phase 1/2 Study of Poly(ADP-Ribose) Polymerase (PARP) Inhibitor E7449 as Single Agent in Subjects with Advanced Solid Tumours or with B-cell Malignancies and in Combination with Temozolomide(TMZ) or with Carboplatin and Paclitaxel in Subjects with Advanced Solid Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial with a daily dose of E7449, a Poly(ADP-Ribose) Polymerase (PARP) Inhibitor, in patients with Advanced Solid Tumors or with Hematological Tumors and in Combination with Chemotherapy (Temozolomide[TMZ] or with Carboplatin and Paclitaxel) in patients with Advanced Solid Tumors
    A.4.1Sponsor's protocol code numberE7449-E044-101
    A.5.4Other Identifiers
    Name:PACTNumber:E7449
    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 SponsorEisai Limited
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Limited
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEuropean Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+442086001400
    B.5.5Fax number+442086001401
    B.5.6E-maileumedinfo@eisai.net
    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 nameE7449
    D.3.2Product code PACT
    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 INNPACT (no current proposed INN/ INN)
    D.3.9.2Current sponsor codeE7449
    D.3.9.3Other descriptive namePACT
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number50 to 400
    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
    Advanced solid tumors (including ovarian cancer, triple negative breast cancer, and advanced melanoma) and B-cell lymphomas
    E.1.1.1Medical condition in easily understood language
    Cancer that has progressed including ovarian, breast and skin 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 LLT
    E.1.2Classification code 10033130
    E.1.2Term Ovarian cancer NOS
    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 LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast 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 14.1
    E.1.2Level PT
    E.1.2Classification code 10003899
    E.1.2Term B-cell lymphoma
    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 LLT
    E.1.2Classification code 10045992
    E.1.2Term Unspecified leukemia
    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 LLT
    E.1.2Classification code 10027481
    E.1.2Term Metastatic melanoma
    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
    Primary objective:
    - Determine maximum tolerated dose (MTD) as single agent, once daily (QD) continuously in 28-day cycles
    - Determine MTD of E7449, QD for 7 consecutive days in combination with TMZ, QD for 5 consecutive days in 28-day cycles
    - Determine the MTD of E7449, QD continuously in 21-day cycles in combination with carboplatin and paclitaxel administered via intravenous (i.V.) infusion on Day 1 of each cycle
    - Assess the objective response rate of E7449 as single agent in subjects with platinum-sensitive recurrent high grade serous ovarian cancer (Cohort 1) and in subjects with relapsed and/or refractory ataxia telangiectasia mutated (ATM)-deficient B-cell lymphoma (Cohort 2)
    - Assess the ORR of E7449 in combination with TMZ in subjects with advanced melanoma (Cohort 3)
    - To assess the ORR of E7449 in combination with carboplatin and paclitaxel in subjects with metastatic triple-negative breast cancer (mTNBC) (Cohort 4)
    E.2.2Secondary objectives of the trial
    To assess the following parameters of E7449 when administered as a single agent and in combination with TMZ or in combination with carboplatin and paclitaxel:
    - safety and tolerability
    - PK profiles
    - PD activity including inhibition of PARP and effect on DNA damage
    - PK and PD relationship
    - Preliminary antitumor activity
    - Assess PFS, disease control rate, and clinical benefit rate
    - Identify and investigate biomarkers and their correlation with biological activity
    Additionally, to:
    - Determine the effect of a high fat meal on the bioavailability of E7449 administered as single agent orally, QD relative to fasting conditions
    - Explore E7449 administered as a BID dose and evaluate the PK and tolerability of BID dosing.
    - Evaluate the role of DNA sequence variability on absoprtion, metabolism, excretion and susceptibility to AEs.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1- Subjects with measurable or non-measurable disease following the Response Evaluation Critieria in Solid Tumours for Phase 1 part of the study.
    2 - Histologically and/ or cytologically confirmed advanced or metastatic solid tumor or B-cell lymphomas which have progressed after treatment with approved therapies or for which there are no standard therapies available.
    3 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
    4 - Life expectancy of >= 3 months after starting E7449
    5 - Subjects with known brain metastases will be eligible under the following conditions:
    a) have undergone complete surgical excision and are more than 1 month post surgery with no radiographic evidence of brain disease recurrence or
    b) have undergone stereotactic radio surgery (gamma knife procedure) or radiotherapy and are more than 1 month post procedure and with no radiographic evidence of brain disease progression and are asymptomatic and discontinued corticosteroid treatment at least 30 days prior to C1D1.
    6- Adequate renal function defined as Serum Creatinine <1.5xULN, or use SI units or calculated creatinine clearance >= 50mL/min per the Cockcroft-Gault formula
    7- Adequate bone marrow function (as defined in protocol)
    8 - Adequate liver function (as defined in protocol)
    9 - Left ventricular ejection fraction (LVEF) >50% on echocardiography or multiple-gated acquision (MUGA) scanning
    10 - Males or females >= 18 years at the time of informed consent
    11 - Females must not be lactating or pregnant. All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically. Females of child bearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception
    12- Male subjects must have had a succesful vasetomy (confirmed azoospermia) or they and their female partner must meet the criteria above. Those with partners using hormonal contraception must also be using an additional approved method of contraception, as described previously.
    13 - Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
    E.4Principal exclusion criteria
    1 - Prior exposure to E7449
    2 - Leptomeningeal metastases or brain metastases (except as for Inclusion Criteria #5)
    3 - Prior treatment with a PARP inhibitor (Phase 2 only)
    4 - Subjects taking medications with are either strong CYP inhibitors or inducers
    5 - Subjects with a history of malignancies other than advanced ovarian cancer (Cohort 1 only), ATM-deficient B-cell lymphomas (Cohort 2 only), advanced melanoma (Cohort 3 only) or mTNBC (Cohort 4 only), will be excluded from Phase 2 unless the subject has been disease free from that additional malignancy for 5 years or the cancer was a squamous cell carcinoma of the skin, carcinoma in situ of the cervix, adequately treated Stage I or Stage II cancer from which the subject is currently in complete remission.
    6 - Subjects who have received any anticancer treatment within 4 weeks or any investigational agent within 30 days prior to the first dose of study drug or who have not recovered from any acute toxicity greater than Grade 0 or 1 related to previous anticancer treatment
    7 - Major surgery within 4 weeks prior to the first dose of study drug
    8 - Inability to take oral medication, or malabsoption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of E7449
    9 - Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction or storke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment
    10 - Prolongation of QTc interval to >480 msec when electrolytes balance is normal
    11 - Active infection requiring systemic therapy
    12 - Known hypersensitivity to any component of E7449
    13 - Other relevant disease or adverse clinical conditions such as:
    history of significant neurological(no neuropathy> Grade 2) or psychiatric disorders, significant non-neoplastic liver disease, significant non-neoplastic renal disease, immunocompromised patients, including patients known to be infected with HIV, uncontrolled endocrine diseases i.e. requiring relevant changes in medication with the last month or hospital admission within the last three months, tumor bleeding
    14 - Any other major illness that, in the investigator's judgement, will substantially increase the risk associated with the subject's participation in this study
    15 - Females who are pregnant or breast feeding
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1:
    Preliminary efficacy (e.g. best overall response[BOR]) will be assessed in subjects in the Safety Analysis Set
    Phase 2:
    Primary efficacy variable:
    - Objective Response Rate (ORR) as defined by RECIST 1.1 criteria for subjects with platinum sensitve recurrent high grade serous ovarian cancer (Cohort 1), Melanoma (Cohort 3), and nTNBC (Cohort 4); and ORR as defined by International Working Group (IWG) response criteria for subjects with B-cell lymphomas (Cohort 2). ORR is defined as the proportion of subjects who have a BOR of complete response (CR) or partial response (PR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After end of trial database lock
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints for each cohort are:
    - DCR defined as CR + PR + stable disease(SD). For subjects who do not have target lesions (e.g., some subjects in dose escalation may have non-target disease only), the response category Non-CR/Non-PD (NN) will be used instead of SD
    - CBR defined as the proportion of subjects who have BOR of CR or PR, or durable SD (duration of SD>=23 weeks)
    - Durable SD rate defined as the proportion of subjects whose BOR is SD and the duration of SD>= 23 weeks
    - Progression-free Survival (PFS) defined as the time from the date of first dosing to the date of first documentation or disease progression or death (whichever occurs first)
    E.5.2.1Timepoint(s) of evaluation of this end point
    After end of trial database lock
    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 Yes
    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) 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 No
    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.8.3 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years3
    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 years3
    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: 48
    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 state102
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 198
    F.4.2.2In the whole clinical trial 198
    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)
    Subjects who are being followed for survival at the time of data cut-off for the primary analysis (i.e. at the end of the treatment phase) will continue to be followed for survival during the Follow-Up period of the Extension Phase. The Extension Phase will consist of treatment cycles and a follow up period.
    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 Decision2011-09-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-07-14
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