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    Summary
    EudraCT Number:2017-004110-25
    Sponsor's Protocol Code Number:TUD-PEMAZA-068
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-16
    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 - PEI
    A.2EudraCT number2017-004110-25
    A.3Full title of the trial
    MRD-guided treatment with pembrolizumab and azacitidine in NPM1mut AML patients with an imminent hematological relapse
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of imminent hematological relapse as defined by measurable residual disease in patients with nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML) using pembrolizumab and azacitidine
    A.3.2Name or abbreviated title of the trial where available
    PEMAZA
    A.4.1Sponsor's protocol code numberTUD-PEMAZA-068
    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 SponsorTechnische Universität Dresden
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMSD Sharp & Dohme GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
    B.5.2Functional name of contact pointcoordinating investigator
    B.5.3 Address:
    B.5.3.1Street AddressFetscherstr. 74
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number+493514587172
    B.5.5Fax number+493514584367
    B.5.6E-mailpemaza@medizin.uni-leipzig.de
    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 namepembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form 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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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
    Patients with NPM1mut AML >= 18 years in CR presenting with MRD after conventional chemotherapy
    E.1.1.1Medical condition in easily understood language
    Patients with NPM1-mutated acute myeloid leukemia (AML) >= 18 years of age in complete remission (CR) presenting with measurable minimal disease (MRD) after treatment with conventional chemotherapy
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and efficacy of PEM when administered in combination with AZA in NPM1mut patients with molecular relapse.
    This objective is based on the hypothesis that PEM in combination with AZA is safe and more effective than AZA alone to prevent hematological relapse of NPM1mut patients with molecular relapse.
    E.2.2Secondary objectives of the trial
    - Toxicity of the treatment with pembrolizumab and azacytidine
    - Proportion of event-free patients after 12 weeks of combination treatment
    - Treatment-related mortality during 24 weeks of combined therapy
    - Course of MRD-burden measured as quantitative NPM1/ABL ratio over time
    Exploratory:
    - Qualitative and quantitative changes in cellular subsets of the immune system during treatment with pembrolizumab and azacytidine
    - Impact of PD-1 and PD-L1 expression on outcome
    - Mutational pattern and burden of selected genes (panel) and their influence on response
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent
    - Age ≥18 years
    - Patients with NPM1mut AML in complete morphologic remission after conventional chemotherapy (anthracyclines ± cytarabin based)
    - Detectable measurable residual disease (MRD) indicating imminent hematological relapse (NPM1mut status >1%)
    - Patients who are not eligible for immediate allogeneic hematopoietic stem cell transplantation
    - Patients who are not eligible to undergo alternative intensive treatment
    - Intended AZA therapy for molecular relapse
    - ECOG performance status of 0 or 1
    - Adequate organ function as defined by protocol
    - No allogeneic stem cell transplantation (allo SCT) within 5 years prior to study treatment
    - Female subject of childbearing potential should have a negative urine or serum pregnancy within 3 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
    - Female subjects of childbearing potential must be willing to use an adequate method of contraception (Section 5.9.2), for the course of the study through 120 days after the last dose of study medication
    - Male subjects with procreative capacity must agree to use an adequate method of contraception (Section 5.9.2), starting with the first dose of study therapy through 120 days after the last dose of study therapy
    E.4Principal exclusion criteria
    - Current treatment with any investigational drug or within 4 weeks or less than 5 half-lives preceding the first dose of trial medication, whichever is longer
    - Known hypersensitivity to any of the drugs used or their constituents or to drugs with similar chemical structure
    - Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
    - Known history of active TB (Bacillus Tuberculosis)
    - Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
    - Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent
    Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    - Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is later
    - Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
    - Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
    - Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
    - Known history of, or any evidence of active, non-infectious pneumonitis
    - Severe hepatic impairment (AST and ALT may not exceed three times the normal) or liver cirrhosis or malignant liver tumor
    - Dialysis dependent renal dysfunction
    - Known severe congestive heart failure, incidence of clinically unstable cardiac or pulmonary disease
    - Active infection requiring systemic therapy
    - History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
    - Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
    - Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
    - Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
    - Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
    - Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)
    - Has received a live vaccine within 30 days of planned start of study therapy
    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of event-free patients after 24 weeks of combination treatment, events are defined as
    - Hematological relapse
    - Death from any cause
    - AML-treatment other then pembrolizumab and azacitidine or hypomethylating agents only
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 24 weeks of combination treatment
    E.5.2Secondary end point(s)
    - Overall survival (OS)
    - Toxicity of the treatment with pembrolizumab and azacytidine
    - Proportion of event-free patients after 12 weeks of combination treatment
    - Treatment-related mortality during 24 weeks of combined therapy
    - Course of MRD-burden measured as quantitative NPM1/ABL ratio over time
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 12 weeks
    after 24 weeks
    after 12 months
    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 No
    E.8.1.1Randomised No
    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) 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 concerned10
    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 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 years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 state28
    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)
    provided in 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 Decision2018-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-14
    P. End of Trial
    P.End of Trial StatusOngoing
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