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    Summary
    EudraCT Number:2015-003594-14
    Sponsor's Protocol Code Number:KCP-330-020
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-12-27
    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 ConcernedGermany - BfArM
    A.2EudraCT number2015-003594-14
    A.3Full title of the trial
    A Phase 2-3 Multicenter, Randomized, Double-blind Study of Selinexor (KPT-330) versus Placebo in Patients with Advanced Unresectable Dedifferentiated Liposarcoma (DDLS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2-3 Multicenter, Randomized, Double-blind Study of Selinexor (KPT-330) versus Placebo in Patients with Advanced Unresectable Dedifferentiated Liposarcoma (DDLS)
    A.3.2Name or abbreviated title of the trial where available
    SEAL: Selinexor in Advanced Liposarcoma
    A.4.1Sponsor's protocol code numberKCP-330-020
    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 SponsorKaryopharm Therapeutics, 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 supportKaryopharm Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKaryopharm Therapeutics, Inc.
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street Address85 Wells Ave
    B.5.3.2Town/ cityNewton
    B.5.3.3Post codeMA 02459
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@karyopharm.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 nameSelinexor 20mg coated tablets
    D.3.2Product code KPT-330
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSelinexor
    D.3.9.1CAS number 1393477-72-9
    D.3.9.2Current sponsor codeKPT-330
    D.3.9.3Other descriptive nameSELINEXOR
    D.3.9.4EV Substance CodeSUB177942
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 placeboFilm-coated tablet
    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
    Dedifferentiated Liposarcoma (DDLS)
    E.1.1.1Medical condition in easily understood language
    Dedifferentiated Liposarcoma (DDLS)
    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 10073135
    E.1.2Term Dedifferentiated liposarcoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 2 (now complete):
    Assess and compare PFS of patients with advanced unresectable DDLS treated with selinexor (60 mg) or placebo twice weekly. Progression will be defined by disease progression according to RECIST v. 1.1 (Eisenhauer 2009), or by death due to any cause

    Phase 3:
    Assess and compare PFS of patients with advanced unresectable DDLS treated with selinexor (60 mg) or placebo twice weekly. PFS is defined as time from date of randomization until the first date of progression per RECIST v. 1.1, or death due to any cause. Evaluation of the radiographic data for the PFS primary endpoint will be based on data from a scan review by the independent central reader.
    E.2.2Secondary objectives of the trial
    Phase 2 (now complete, refer to protocol for Phase 2 secondary objectives).

    Phase 3:
    • Assess Overall Survival (OS), measured from date of randomization until death due to any cause.
    • Compare TTP on study treatment, per RECIST v. 1.1, with TTP on the patient's last prior systemic therapy.
    • Assess Quality of Life (QoL) and patient-reported outcomes as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of-Life Questionnaire (QLQ-C30) and the EuroQoL Group Health Questionnaire (EQ-5D-5L).
    • Determine the ORR, supported by DOR. Responses will be defined by RECIST v. 1.1.
    • Assess PFS according to the Investigator based on clinical and/or radiologic criteria.
    • Assess safety of each treatment arm
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study must meet all of the following criteria:
    1. Written informed consent in accordance with national, local, and institutional guidelines obtained prior to any screening procedures
    2. Must be willing and able to comply with the protocol
    3. Patients ≥ 12 years of age (patients <18 years of age are permitted only in countries in which adolescents have been approved by the national/local regulatory/ethical authority).
    4. Patients with a body surface area (BSA) ≥ 1.2 m2 as calculated per Dubois 1916 or Mosteller 1987.
    5. Documented histologic evidence of DDLS at any time from initial diagnosis to randomization AND current evidence of DDLS requiring treatment (documented evidence of disease progression from the most recent treatment):
    • Documentation of histologic evidence of DDLS requires the following:
    o This information will be provided based on prior diagnostic testing and is required for randomization.
    o Tissue (fresh or archival) will be provided for confirmatory histology at a central laboratory but confirmatory results are not required prior to randomization.
    o If archival tissue > 12 months old, the quality of the sample for confirmatory histology must be confirmed by the site histopathologist prior to randomization.
    6. Must have measurable disease according to:
    • The bidimensional WHO Response Criteria (Miller 1981) (Phase 2 patients only)
    • RECIST v. 1.1 (Eisenhauer 2009)(Phase 3 patients only)
    7. Radiologic evidence of progressive disease (PD) within 6 months prior to randomization. If the patient received other intervening therapy after PD is documented, further PD must be documented after the completion of the intervening therapy, with the exception of patients who discontinued most recent treatment after no more than 1 dose.
    8. Must have received at least 2 but no more than 5 prior systemic therapies for the treatment of liposarcoma.
    9. Patients should have recovered from all major surgery, radiation or other interventions ≥ 21 days prior to randomization. Patients must have recovered from any clinically significant therapy-related toxicity to ≤ Grade 1 per CTCAE v. 4.03. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous line for infusion, are permitted.
    10. If patients received any previous systemic therapy, the last dose must have been ≥21 days prior to randomization (or ≥5 half-lives of that drug [whichever is shorter]), with all clinically significant therapy-related toxicities having resolved to ≤ Grade 1 CTCAE v. 4.03.
    11. ECOG performance status ≤1 (Oken 1982)
    12. Adequate laboratory functional values:
    • Adequate hematopoietic function:
    o Absolute neutrophil count (ANC) ≥1500/mm3
    o Platelets ≥100,000/mm3
    o Hemoglobin (Hb) ≥9 g/dL
    o Transfusions, hematopoietic growth factors, and hematinics are NOT permitted during screening
    • Adequate hepatic function:
    o Bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤3 x ULN)
    o Alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) <3.0 x ULN (except patients with liver involvement of their liposarcoma who must have an AST and ALT ≤5 x ULN).
    • Adequate renal function: Serum creatinine of ≤ 1.5 mg/dL or estimated creatinine clearance of ≥ 30 mL/min, calculated using the Cockcroft and Gault formula (140 – Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976).
    13. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must agree to use highly effective contraception throughout the study and for 3 months following the last dose of study treatment. Highly effective methods of contraception are listed in Section 13.3.1.

    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
    1. Patients with liposarcoma of pure WDLS, myxoid/round cell or pleomorphic tumor histologic subtypes.
    2. Significant cardiovascular impairment, defined as:
    a. Cardiac failure, New York Heart Association (NYHA) Class ≥ 3 according to the NYHA Functional Classification
    b. Unstable angina or myocardial infarction within 3 months of enrollment
    c. Serious and potentially life-threatening arrhythmia.
    3. Patients with known central nervous system metastases.
    4. Female patients who are pregnant or nursing.
    5. Prior malignancy that required treatment, or has shown evidence of recurrence (except for non melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to randomization. Cancer treated with curative intent > 5 years prior to randomization and without evidence of recurrence is allowed.
    6. Known active hepatitis B infection, as defined by seropositivity for hepatitis B surface antigen (HBs Ag); or known hepatitis C infection, as defined by seropositivity for hepatitis C antibody, with elevated liver aminotransferases (ie, above the levels specified in inclusion criterion #12) or any other evidence of active hepatitis.
    7. Known human immunodeficiency virus (HIV) infection.
    8. Any medical condition, such as an uncontrolled infection or uncontrolled diabetes mellitus (Type 2), which in the opinion of the Investigator would make study involvement unreasonably hazardous
    9. Psychiatric illness that would prevent the patient from giving informed consent or being compliant with the study procedures
    10. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment
    11. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the NCCN CPGO for antiemesis and anorexia/cachexia (palliative care).
    12. Patients who had involuntary weight loss of ≥ 10% in the 3 months prior to randomization.
    13. Participation in an investigational anticancer study ≤ 21 days prior to randomization.
    14. A circulating lymphocyte count of >50,000/µL (for sites in France only)
    E.5 End points
    E.5.1Primary end point(s)
    Phase 2:
    The primary endpoint PFS for Phase 2 is defined as time from date of randomization until the first date of PD per RECIST v. 1.1, or death due to any cause.
    A preplanned preliminary analysis of PFS after 40 PFS events was conducted with an 11 August 2017 data cut with 49 eligible patients whose treatment assignments were available. Patients were analyzed in the treatment arm to which they were randomized. The preliminary PFS analysis was conducted by both WHO and RECIST v. 1.1 Criteria and served as a guideline to inform the final design of the Phase 3 portion of the study.
    At the time of the preliminary PFS analysis, there were 48 events by WHO (22 selinexor, 26 placebo) and 28 events by RECIST v.1.1. (10 selinexor, 18 placebo). Both analyses showed trends favoring selinexor over placebo, while RECIST v. 1.1 results show a more significant effect size (hazard ration [HR] of 0.84, 95% CI [0.47, 1.49] by WHO as compared with HR of 0.60, 95% CI [0.28, 1.31] by RECIST v. 1.1). A Landmark analysis based on RECIST v. 1.1 for patients continuing on study after 45 days showed a more significant HR of 0.24 (95% CI [0.05,1.15]) in favor of selinexor.
    Of the 57 patients in Phase 2, only 56 met the eligibility criteria for the study. The formal primary Phase 2 PFS analysis will be performed on all 56 eligible patients randomized to study treatment in Phase 2 when their
    treatment assignments are unblinded. Phase 2 patients will be analyzed in the treatment arm to which they are randomized.

    Phase 3:
    The primary PFS analysis will be performed on the intent-to-treat (ITT) population for Phase 3 patients and on the per-protocol (PP) population as a supportive analysis. The stratified log-rank test will be used to test the null hypothesis that the PFS distributions are the same for both treatment groups versus the alternative hypothesis that the duration of PFS for the selinexor arm is longer than the placebo arm using a 1-sided
    test and alpha=0.025 level of significance, adjusted using the Cui, Hung, and Wang (CHW) method (Cui 1999).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 2: The primary endpoint analysis has been completed.

    Phase 3: The primary endpoint analysis will be performed approximately 12 months after enrollment of the last patient, once 209 PFS events have occurred, at which time all Phase 3 patients will be evaluable for assessment of the primary endpoint.
    E.5.2Secondary end point(s)
    • OS for non-inferiority, defined as the time from randomization until death due to any cause, for all randomized patients.
    • OS for superiority, defined as the time from randomization until death due to any cause, for all randomized patients.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of study
    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 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) Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Refer to protocol regarding different phases (Phase 2 is now complete).
    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 EEA24
    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
    Israel
    United States
    France
    Sweden
    Spain
    Germany
    Italy
    Belgium
    United Kingdom
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days22
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 164
    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 state21
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 135
    F.4.2.2In the whole clinical trial 334
    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 will remain on treatment until disease progression, another withdrawal criteria is met or until death. After stopping study treatment patients will be followed up for survival and their own doctorwill manage any further treatment.
    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 Decision2018-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-10-26
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