Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML) MedDRA version: 21.0 Level: LLT Classification code 10028552 Term: Myeloid leukaemia, acute System Organ Class: 100000004864
Conditions
Interventions
Product Name: Non applicabile
Product Code: [NMS-03592088]
Pharmaceutical Form: Capsule, hard
CAS Number: 1409989-68-9
Current Sponsor code: NMS-03592088
Concentration unit: mg milligram(s)
Concentrat
Sponsors
NERVIANO MEDICAL SCIENCES SRL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients with confirmed diagnosis of de novo or secondary AML as defined by the 2017 ELN recommendations (Dohner H et al., Blood, Jan 2017) positive for FLT3 ITD and/or TKD point mutations in the BM or PB as determined by the local standard test performed at study entry. Patients with an allelic frequency = or > 5 % as determined by local laboratories will be considered to have FLT3-ITD positive disease. • Patients must be refractory to at least 1 cycle of induction chemotherapy or relapsed after achieving remission with a prior intensive treatment which may include HSCT. Patients must have received = or 18 years) patients. 4. ECOG performance status 60 mL/min as calculated by the BSA-unadjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 9. Patients must use highly effective contraception or abstinence. Female patients of childbearing potential must agree to the use of highly effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment. Male patients must be surgically sterile or must agree to use highly effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment. 10. Capability to swallow capsules intact (without chewing, crushing, or opening) 11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures 12. Signed and dated IEC or IRB-approved informed consent form indicating that the patient is aware of the neoplastic nature of his/her disease and has been informed of the procedures to be followed, the investigational nature of the therapy, potential benefits, side effects, discomforts, risks and alternative treatments. Are the trial subjects under 18? no Number of subjects f
Exclusion criteria
Exclusion criteria: 1. Current enrollment in another interventional clinical study 2. Diagnosis of acute pro-myelocytic leukemia or BCR-ABL-positive leukemia 3. Currently active second malignancy, except for adequately treated basal or squamous cell skin cancer and/or cone biopsied in situ carcinoma of the cervix uteri and/or superficial bladder cancer. 4. Patients with known leukemia involvement of CNS. 5. Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent non-hematologic toxicities of Grade = or > 2 related to the transplant 6. Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment 7. Patients with QTcF interval = or > 480 milliseconds or with risk factors for torsade de pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of prolonged QTc interval or family history of long QT syndrome). For patients receiving treatment with concomitant medications known to prolong the QTc interval, replacement with another treatment should be considered. If replacement or discontinuation is not clinically feasible, a careful risk/benefit evaluation should be performed prior to enrollment. 8. Pregnancy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within the screening period prior to start of study drug. 9. Breast-feeding or planning to breast feed during the study or within 3 months after study treatment. 10. Known hypersensitivity to any components of the NMS-03592088 drug product or AZA drug product. 11. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis 12. Known active, life threatening or clinically significant uncontrolled systemic infection. 13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness 14. Known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection requiring systemic treatment. 15. Known active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption. 16. Known active gastrointestinal ulcer 17. 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 and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of NMS-03592088 in combination with AZA in adult patients with FLT3-mutated acute myeloid leukemia (AML) who have relapsed/refractory disease or are not eligible for intensive induction chemotherapy, or in Chronic Myelomonocytic Leukemia (CMML) patients (Phase I). • To determine the antitumor activity of NMS-03592088 in combination with AZA in adult patients with FLT3-mutated acute myeloid leukemia (AML) who have relapsed/refractory disease or are not eligible for intensive induction chemotherapy, or in Chronic Myelomonocytic Leukemia (CMML) patients (Phase II).;Secondary Objective: • To characterize the safety profile and tolerability of NMS-03592088 in combination with AZA. • To evaluate the pharmacokinetics (PK) in plasma and, limited to Phase I, also in urine of NMS-03592088 and its metabolites (NMS-03593860 and NMS 03603422) when administered in combination with AZA. •To evaluate additional measures of antitumor efficacy of NMS-03592088 when administered in combination with AZA.;Primary end point(s): Phase I: •First-cycle dose limiting toxicities (DLTs); Phase II: •FLT3-mut AML: Composite Complete Remission Rate (CRc: CR +CRi), i.e. Complete Remission (CR)+ Complete Remission with Incomplete Hematologic Recovery (CRi), as determined by the Investigators based on the 2017 European LeukemiaNet (ELN) recommendations. •CMML: Overall Response Rate, i.e. Complete Response (CR) + Complete cytogenetic remission (CCR) + Partial remission (PR) + Marrow response (MR) + Clinical Benefit (CB) as defined by disease specific International Working Group (IWG) criteria.;Timepoint(s) of evaluation of this end point: Phase I: during the first two cycles Phase II: all the study duration | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Plasma pharmacokinetic profile and corresponding parameters of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422;; Renal clearance and fraction of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 excreted in urine (only Phase I); FLT3-mut AML: best response by remission category defined as Complete Remission (CR), Complete Remission with partial hematologic recovery (CRh), Complete Remission with Incomplete Hematologic Recovery (CRi), Morphologic Leukemia-free State (MLFS) as determined based on the 2017 ELN recommendations and as defined by Shallis RM et al.,; CR/CRh rate; Overall Response Rate (ORR: CRc + CRh + PR); Overall Survival (OS), Time to Response (TTR), Duration of Response (DoR), Event-free Survival (EFS) and Relapse-free Survival (RFS) as determined by the Investigators based on the 2017 ELN recommendations and disease-specific International Working Group criteria.; Overall safety profile of the combination of NMS-03592088 and AZA characterized by type, frequency, severity (graded using the NCI CTCAE Version 5.0), timing of the AEs and laboratory abnormalities, and relationship of the AEs to study treatment.;Timepoint(s) of evaluation of this end point: Phase I: during first two treatment cycles. Phase II: to be defined based on results from phase I.; During first cycle (only phase I); All the study duration; All the study duration; All the study duration | — |
Countries
Italy
Contacts
Public ContactGlobal Clinical Development
Nerviano Medical Sciences S.r.l.
Outcome results
None listed