Relapsed/refractory acute myeloid leukemia MedDRA version: 16.1 Level: PT Classification code 10000880 Term: Acute myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: COSMEGEN
Product Name: ACTINOMYCIN D
Pharmaceutical Form: Powder for injection
Sponsors
Dipartimento di Medicina, Università di Perugia
Eligibility
Sex/Gender
All
Inclusion criteria
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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 10 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ;Secondary Objective: 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 ;Primary 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. ;Timepoint(s) of evaluation of this end point: after one or two induction cycles | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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 (PMN1000/?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 ;Timepoint(s) of evaluation of this end point: after patient withdrawal or at the end of follow-up | — |
Countries
Italy
Contacts
Public ContactSezione di Ematologia e Immunologia
Dipartimento di Medicina
Outcome results
None listed