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    Summary
    EudraCT Number:2014-001719-37
    Sponsor's Protocol Code Number:TL32711-RAN-0094-PTL
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-06-30
    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 number2014-001719-37
    A.3Full title of the trial
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Azacitidine with or without Birinapant with a Single Arm Open-Label Run-In Phase in Subjects with Higher Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Placebo-Controlled Study of Azacitidine with or without Birinapant with a Single Arm Open-Label Run-In Phase in Subjects with Higher Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
    A.4.1Sponsor's protocol code numberTL32711-RAN-0094-PTL
    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 SponsorTetraLogic Pharmaceuticals
    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 supportTetraLogic Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPIVOTAL S.L
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street AddressGobelas,19. La Florida
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28023
    B.5.3.4CountrySpain
    B.5.4Telephone number+34917081250
    B.5.5Fax number+34917081301
    B.5.6E-mailmiguel.villanueva@pivotal.es
    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 nameBirinapant
    D.3.2Product code TL32711
    D.3.4Pharmaceutical form Solution for injection
    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 INNBirinapant
    D.3.9.1CAS number 1260251-31-7
    D.3.9.2Current sponsor codeTL32711
    D.3.9.3Other descriptive nameBirinapant
    D.3.9.4EV Substance CodeSUB130963
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.IMP: 2
    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 Vidaza
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Corporation
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Powder for suspension for injection
    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 INNAzacididine
    D.3.9.1CAS number 320-67-2
    D.3.9.3Other descriptive name5-azacytidine
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Higher Risk Myelodysplastic Syndrome, Secondary Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
    E.1.1.1Medical condition in easily understood language
    Higher Risk Myelodysplastic Syndrome, Secondary Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10054350
    E.1.2Term Chronic myelomonocytic 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 18.1
    E.1.2Level PT
    E.1.2Classification code 10028533
    E.1.2Term Myelodysplastic syndrome
    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
    To compare the relative effect of azacitidine plus birinapant versus azacitidine plus placebo on response rate [RR=complete response (CR) + partial response (PR)] using the modified International Working Group (IWG) Response Criteria for MDS, in patients with higher risk MDS, secondary MDS or CMMoL.
    E.2.2Secondary objectives of the trial
    To compare the effect of azacitidine plus birinapant relative to azacitidine plus placebo, on the
    following:
    • hematologic improvement (HI)
    • relapse-free survival according to modified IWG 2006 criteria
    • time to response
    • change in transfusion requirements
    • duration of response according to modified IWG 2006 criteria
    • overall survival
    • adverse event (AE) profile according to NCI CTCAE v.4.03 criteria
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject is an adult greater than or equal to 18 years of age.
    2. The subject is able to understand and voluntarily sign a written informed consent, and is willing and able to comply with the protocol requirements.
    3. The subject has morphologically confirmed diagnosis of MDS or CMMoL according to FAB or WHO
    classification, including RAEB-t and MDS/MPN classifications
    4. International prognostic score-revised (IPSS-R) of >=3.5 (Intermediate, High or Very High).
    5. Procedures to obtain specimens for establishing baseline disease must be done within 30 days prior to enrollment/randomization.
    6. The subject was previously untreated with hypomethylating agents for MDS or CMMoL.
    7. The subject has performance status of 0, 1 or 2 by the ECOG scale.
    8. The subject has adequate liver function (bilirubin <= 1.2 x ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x the upper limit of normal (ULN) or < 5 x ULN if related to leukemia tissue infiltration).
    9. The subject has adequate renal function as evidenced by creatinine <= 2mg/dL (176.8 µmol/L).
    10. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and negative (serum or urine) pregnancy test within 96 hours prior to the first study dose.
    11. Female subjects of childbearing potential and male subjects with partners of childbearing potential should ensure use of a highly effective method of birth control as defined by the investigator, for example, those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectable, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner during the study and for a period of 3 months following the last dose of any drug administered during the study.
    French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
    E.4Principal exclusion criteria
    1. The subject has relapsed or is refractory to hypomethlating agents.
    2. The subject has acute myeloid leukemia (AML) (except those patients with RAEB-t who are not candidates for intensive AML therapy).
    3. The subject has been treated with an investigational agent within 4 weeks of randomization or 5 half lives (whichever is longer).
    4. The subject received any hematopoietic growth factors within 14 days prior to screening.
    5. The subject had prior malignancy or secondary malignancy within the prior 2 years (except in situ cervical cancer, squamous cell carcinoma or basal cell carcinoma of the skin).
    6. The subject has known diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C. Viral testing is not required.
    7. The subject has uncontrolled hypertension (i.e., blood pressure >160/100 mmHg without medication, or not controlled despite medications).
    8. The subject has impaired cardiac function, uncontrolled cardiac arrhythmias despite medications, or clinically significant cardiac disease including the following:
    a. New York Heart Association grade III or IV congestive heart failure
    b. documented myocardial infarction within the last 12 months
    9. The subject has not recovered from prior adverse events to Grade ≤1 severity (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03) (except alopecia) due to therapy
    administered prior to the initiation of study drug dosing.
    10. The subject is nursing or pregnant.
    11. The subject has known allergy or hypersensitivity to any of the formulation components of birinapant, placebo or azacitidine, including mannitol, citric acid monohydrate, sodium citrate dehydrate, and sodium
    chloride.
    12. The subject has a history of cranial nerve palsy.
    13. The subject has any concurrent disease and/or medical condition that, in the opinion of the Investigator, would prevent the subject's participation, render the subject at excessive risk (including excessive risks due to the toxicity profile of the planned combination chemotherapeutic regimen), or limit the subject's compliance with the protocol's required evaluations.
    14. The subject is being treated with anti-TNF therapies or has been treated with an anti-TNF therapy within 5
    half-lives of randomization.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is response rate.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final determination of response will be based on the evaluations by the independent reviewer(s) blinded to treatment assignment and will be used for the study’s efficacy analysis
    E.5.2Secondary end point(s)
    Efficacy:
    •Hematologic improvement (HI)
    • Relapse free survival (RFS)
    • Time to response (TTR)
    • Change in Transfusion requirements:
    • Duration of response (DR)
    • Overall survival(OS)

    Safety:
    Safety assessments include adverse events, clinical laboratory testing, vital signs measurements, physical examination findings, ECOG performance status, and concomitant medication usage
    E.5.2.1Timepoint(s) of evaluation of this end point
    HI assessed per Cheson et al 2006 hematological criteria
    RFS: from randomization to first relapse or death
    TTR: from randomization to first response
    Transfusion from 8 wk prior to randomization, monthly
    DR: from initial response to first relapse or death
    OS: from randomization to death

    AEs: throughout to 30d after last dose
    Hematology: at screening, d1 and 15 of each cyc, wk4 of every 4th cyc, follow-up
    Serum chemistry: at screening, d1 and 15 of each cyc, follow-up
    Urinalysis: at screening
    Bone Marrow: at screening, wk4 of every 4th cyc
    Serum Pregnancy: at screening
    Vital signs: at screening, prior to each drug administration and after study drug administration, follow up
    Concomitant therapy: Throughout study
    ECOG: at screening, day 1 of each cy, follow-up
    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 No
    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) 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 Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Germany
    Spain
    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 months5
    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 months5
    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: 48
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 110
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 158
    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 will be treated until unacceptable toxicity, disease progression, or another criterion for treatment discontinuation is encountered. Subjects who discontinue treatment because of adverse events will be followed until resolution to baseline or stabilization of the adverse event. Subjects will return for a final safety evaluation 30 days (+7 days) following the last dose of birinapant or placebo. All subjects will be followed every 3 months for survival.
    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 Decision2014-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-02-17
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