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    Summary
    EudraCT Number:2014-000693-18
    Sponsor's Protocol Code Number:ActD-AML-PG01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-03-10
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-000693-18
    A.3Full title of the trial
    A PHASE II STUDY OF THE CLINICAL ACTIVITY AND SAFETY OF ACTINOMYCIN D IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA WITH NUCLEOPHOSMIN (NPM1) GENE MUTATION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A PHASE II STUDY OF THE CLINICAL ACTIVITY AND SAFETY OF ACTINOMYCIN D IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA WITH NUCLEOPHOSMIN (NPM1) GENE MUTATION
    A.4.1Sponsor's protocol code numberActD-AML-PG01
    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 SponsorDipartimento di Medicina, Università di Perugia
    B.1.3.4CountryItaly
    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 supportDipartimento di Medicina, Università di Perugia
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDipartimento di Medicina
    B.5.2Functional name of contact pointSezione di Ematologia e Immunologia
    B.5.3 Address:
    B.5.3.1Street AddressPiazzale Menghini, 1
    B.5.3.2Town/ cityPerugia
    B.5.3.3Post code06132
    B.5.3.4CountryItaly
    B.5.4Telephone number+390755783190
    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 Yes
    D.2.1.1.1Trade name COSMEGEN
    D.2.1.1.2Name of the Marketing Authorisation holderORPHAN EUROPE SRL
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameACTINOMYCIN D
    D.3.4Pharmaceutical form Powder for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) 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
    Relapsed/refractory acute myeloid leukemia
    E.1.1.1Medical condition in easily understood language
    Acute myeloid leukemia, blood neoplasm
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10000880
    E.1.2Term Acute myeloid leukaemia
    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
    To determine the anti-tumor activity of the intravenously administered single agent actinomycin D in AML patients carrying the NPM1 mutations fulfilling the eligibility criteria for enrollment in this study.
    E.2.2Secondary objectives of the trial
    To assess the safety of actinomycin D in NPM1-mutated AML patients
    To determine the time to response to actinomycin D in NPM1-mutated AML patients
    To determine the duration of response to actinomycin D in NPM1-mutated AML patients not eligible for allotransplantation
    To determine the role of actinomycin D as bridge-to transplantation salvage therapy in NPM1-mutated AML patients eligible for allotransplantation
    To determine the efficacy and safety of actinomycin D re-treatment in NPM1-mutated AML patients initially responding to the drug, but relapsing after a period of at least 6 months
    To investigate the pharmacokinetics of actinomycin D in the plasma of NPM1-mutated AML patients and to compare it to clinical response and adverse events
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female NPM1-mutated AML patients ≥ 18 years of age
    2. Proven diagnosis of NPM1-mutated AML according to the morphological and immunophenotypic criteria (aberrant cytoplasmic expression of nucleophosmin) of the World Health Organization (WHO-2008) classification of lymphoid neoplasms18, accompanied by the presence of NPM1 mutation as detected using molecular techniques62
    3. Patients with refractory/relapsed NPM1-mutated AML (as indicated above) and patients with the same disease who, at the time of first diagnosis, are not eligible for intensive chemotherapy
    4. Any prior treatment (chemotherapy and/or hemopoietic stem cell transplant) must have been completed at least 4 weeks prior to initiation of study medication
    5. ECOG PS of 0-2
    6. Patients must have recovered from all side effects of their most recent treatment for LAM
    7. Adequate renal and liver function as defined by the following laboratory values performed within 7 days prior to first dose of actinomycin D: serum creatinine ≤2.0 mg/dl; serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤3 times the upper limit of normal (ULN), alkaline phosphatase ≤2.5 times ULN and bilirubin ≤1.5 times the ULN. Higher values are acceptable if they are directly related to the disease
    8. Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year
    9. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intrauterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.]
    10. No psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry
    11. Signed informed consent must be obtained prior to performing any study-related procedures
    12. Clinical indication for treatment include: morphological and immunohistochemical documentation of disease relapse (≥ 20% bone marrow infiltration by leukemic cells showing aberrant cytoplasmic expression of NPM1); morphologically and immunohistologically documented extramedullary relapse (with the exception of meningeal leukemia involvement, see below) with or without concomitant bone marrow infiltration.
    13. Signed informed consent
    E.4Principal exclusion criteria
    1. Patients with a previous malignancy within the past 2 years. This criterion does not apply to patients with treated and controlled basal or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix. Isolated elevation in prostate specific antigen (PSA) in absence of radiographic evidence of metastatic prostate cancer is allowed
    2. Central nervous system (CNS) leukemia involvement because actinomycin D does not cross the blood-brain barrier
    3. Concurrent administration of any anti-leukemic therapy (e.g. chemotherapy, experimental drug, etc.) other than that administered in this study
    4. Known hypersensitivity to actinomycin D
    5. Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women
    6. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications
    7. Active hepatitis infection or positivity for human immunodeficiency virus
    8. Uncontrolled medical illness (e.g. infectious complications)
    9. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, which at the investigator’s discretion would make the patient inappropriate for entry into this study
    10. Unwillingness to practice effective birth control
    11. Inability to comply with other requirements of the protocol
    12. Unwillingness to participate to the study
    E.5 End points
    E.5.1Primary end point(s)
    • To determine the complete response rate (CR) of NPM1-mutated AML patients to the treatment with single drug actinomycin D at the end of the induction arm administration (i.e. after one or two cycles of treatment, according to the time schedule indicated in the study flow chart shown in Appendix 3). Complete response rate is intended as the sum of complete response (CR) and complete response with incomplete marrow recovery (CRi), defined according to the criteria indicated below.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after one or two induction cycles
    E.5.2Secondary end point(s)
    • To summarize the type, incidence, severity, and relationship to the study-drug of adverse events (AE), severe adverse events (SAE) and any laboratory abnormalities
    • To assess time to grade 4 neutropenia (PMN<500/l) and/or grade 4 thrombocytopenia (PLT<20000/l) either after first induction cycle and after each consolidation cycle
    • To assess time to neutrophil (PMN>1000/l) and platelet (PLT>50000/l) recovery either after first induction or after each consolidation cycle
    • To assess time to response, i.e. the time from start of treatment to the first documented objective response (including CR and CRi)
    • To define the duration of response (assessed from the date of achievement of CR/CRi) in patients not eligible for allotransplantation. After drug discontinuation, patients will be monitored for up to 2 (two) years, based on clinical, hematological and molecular parameters (see below, Appendix 4)
    • To establish the feasibility of allogeneic bone marrow transplantation in patients pretreated with actinomycin D who achieved CR and eligible for allotransplantation
    • To determine the overall survival (OS) at 1 (one) year, leukemia free survival (LFS) at 1 (one) year, event free survival (EFS) at 1 (one) year and the cumulative incidence of relapse at 1 (one) year
    • To investigate the plasma levels of actinomycin D in NPM1-mutated AML patients using mass spectrometry analysis
    E.5.2.1Timepoint(s) of evaluation of this end point
    after patient withdrawal or at the end of 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 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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    At the last visit of the last subject undergoing the trial
    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 months6
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state10
    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 receive the same treatment/follow-up as patients not included in the trial
    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 Decision2014-05-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-07-19
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