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    Summary
    EudraCT Number:2019-002782-35
    Sponsor's Protocol Code Number:A18-15331
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-07-12
    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 ConcernedFrance - ANSM
    A.2EudraCT number2019-002782-35
    A.3Full title of the trial
    A Phase III Multicenter, Randomized, Open Label Study of APR-246 in Combination with Azacitidine Versus Azacitidine Alone for the Treatment of TP53 Mutant Myelodysplastic Syndromes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of systemic Azacitidine chemotherapy in combination with or without APR-246 in patients with a type of Myelodysplastic
    Syndrome
    A.4.1Sponsor's protocol code numberA18-15331
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03745716
    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 SponsorAprea Therapeutics AB
    B.1.3.4CountrySweden
    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 supportAprea Therapeutics AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTheradex (Europe) Ltd
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street Address2nd Floor, The Pinnacle, Station Way
    B.5.3.2Town/ cityCrawley
    B.5.3.3Post codeRH10 1JH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441293510319
    B.5.5Fax number+441293510322
    B.5.6E-mailregulatory@theradex.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.3.2Product code APR-246
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAPR-246
    D.3.9.2Current sponsor codeAPR-246
    D.3.9.4EV Substance CodeSUB31235
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    Myelodysplastic Syndromes
    E.1.1.1Medical condition in easily understood language
    Blood 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 HLT
    E.1.2Classification code 10028536
    E.1.2Term Myelodysplastic syndromes
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the complete response rate, defined as the proportion of patients who achieve complete remission (CR), and duration of CR with APR-246 + azacitidine treatment vs. azacitidine only
    E.2.2Secondary objectives of the trial
    To measure the following with APR-246 + azacitidine treatment vs. azacitidine alone:
    1. Overall response rate (ORR)
    2. Duration of response (DOR)
    3. Rate and time to acute myeloid leukemia (AML) transformation
    4. Overall survival (OS)
    5. Relapse-free survival (RFS)
    6. Transition rate to hematopoietic stem cell transplant (HSCT)
    7. Safety profile
    8. Rate of red blood cell (RBC) and/or platelet transfusion independence (TI) for 56 days (8 weeks)
    9. Pharmacokinetics of APR-246 and azacitidine
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements
    2. Documented diagnosis of MDS, according to WHO classification (<20% blasts), that meets IPSS-R classification of intermediate, high, or very high-risk disease
    3. Patient has adequate organ function as defined by the following laboratory values:
    a) Creatinine clearance > 30 mL/min (by Cockcroft-Gault method; see Appendix IV)
    b) Total serum bilirubin < 1.5 × ULN unless due to Gilbert’s Syndrome, underlying disease of MDS, hemolysis or considered an effect of regular blood transfusions
    c) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN, unless due to underlying disease of MDS
    4. Age ≥18 years at the time of signing the informed consent form (ICF)
    5. Having at least one TP53 mutation which is not benign or likely benign
    6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
    7. Females of childbearing potential: negative pre-treatment urine or serum pregnancy test
    8. Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter
    E.4Principal exclusion criteria
    1. Patient has a known history of HIV or active hepatitis B or active hepatitis C infection (testing not mandatory).
    2. Patient has any of the following cardiac abnormalities (as determined by treating MD):
    a) Myocardial infarction within six months prior to registration,
    b) New York Heart Association Class III or IV heart failure (see Appendix III) or known left ventricular ejection fraction (LVEF) < 40%, as assessed by echocardiogram or MUGA scan;
    c) A history of familial long QT syndrome,
    d) Symptomatic atrial or ventricular arrhythmias not controlled by medications
    e) QTc ≥ 470 msec calculated from a mean of 3 ECG readings using Fridericia’s correction (QTcF = QT/RR0.33). Note: Patients with QTcF ≥ 470 msec and with bundle branch block and/or pacemaker rhythm may be enrolled after approval by Medical Monitor.
    3. Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Patients with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis.
    4. Prior exposure to azacitidine, decitabine or investigational hypomethylating agent or induction chemotherapy for MDS or AML. Note: intensive chemotherapy for any other prior cancer is not exclusionary.
    5. Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS within 14 days of the first day of study drug treatment.
    6. Concurrent use of erythroid stimulating agents, G-CSF, or GM-CSF within 14 days of the first day of study drug treatment.
    7. History of allogeneic stem cell transplantation
    8. Pregnancy: Pregnant women are excluded from this study because APR-246 has not been studied in pregnant patients.Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with APR-246, breastfeeding should be discontinued if the mother is treated with APR-246.
    9.Active uncontrolled infection.
    E.5 End points
    E.5.1Primary end point(s)
    CR per the modified IWG (Cheson et al, 2006)1 and time between achieving CR and relapse of disease.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please refer to the study protocol.
    E.5.2Secondary end point(s)
    1. ORR is the proportion of patients achieving hematological improvement (HI), partial remission (PR), CR, marrow CR by the IWG 2006 criteria
    2. Response duration
    3. AML transformation according to World Health Organization (WHO) criteria
    4. OS
    5. RFS
    6. Proportion of patients who transition to HSCT
    7. Safety endpoints can relate to adverse events, serious adverse events, dose adjustments or dose holds, lab parameter values, vital signs, ECGs
    8. Patients who achieve RBC and/or platelet TI during the 56-day (8 week) period after randomization
    9. Pharmacokinetic endpoints: Cmax (maximum concentration), AUC (area under the curve), Vd and clearance (CL) of APR-246 and azacitidine
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to the study 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 No
    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) No
    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 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) Yes
    E.8.2.2Placebo No
    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 concerned4
    E.8.5The trial involves multiple Member States No
    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
    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 the study is defined as the date of the last visit of the last patient participating in the trial.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 38
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 116
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 154
    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)
    After discontinuation from study treatment, every effort will be made to conduct a post-treatment follow-up visit within 28 days after the last dose of the study drug. All patients
    should be followed until death. Patients who discontinue any study treatment will be contacted by the study staff for survival status, and/or response assessments, transition to
    AML, until death as described in Section 7.6 of the protocol
    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 Decision2019-08-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-01-14
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