Acute Myeloid Leukemia MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Participants eligible for inclusion in this study must meet all of the following criteria: 1. Signed informed consent must be obtained prior to participation in the study. 2. Age at the date of signing the informed consent form (ICF): Arm 1 and Arm 2: = 18 years 3. Participants with AML based on WHO 2016 classification (Arber et al 2016) who are ineligible for chemotherapy and: Arm 1 (sub-optimal responders): have received at least 2 cycles and not more than 4 cycles of first-line venetoclax plus azacitidine treatment and have not achieved a CR, CRi, CRh or MLFS. A participant can be enrolled in the study after 2 cycles only if the participant is no better than in SD at the end of the 2nd cycle of venetoclax plus azacitidine treatment. Otherwise, the participants should be enrolled after cycle 3 of venetoclax plus azacitidine treatment. Arm 2 (newly diagnosed AML presenting with high-risk clinical features): newly diagnosed AML with adverse-risk according to 2022 ELN genetic risk stratification (except TP53 mutation positive participants). 4. Participant (in both arms) must be considered ineligible for standard of care intensive induction chemotherapy (in Arm 1, ineligibility for standard induction chemotherapy must be determined by the investigator, prior to initiation of venetoclax plus azacitidine treatment) defined by the following: = 75 years of age; OR = 18 to 74 years of age with at least one of the following co-morbidities: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; Cardiac history of CHF requiring treatment or Ejection Fraction = 50% or chronic stable angina; DLCO = 65% or FEV1 = 65%; 5. Participants with antecedent of myelodysplastic syndromes (MDS), myelofibrosis, essential thrombocythemia, polycythemia vera or therapy related AML may be included in the study, provided no prior therapy, as specified in exclusion criteria 6. Participants must have an ECOG performance status: 0 to 2 for participants = 75 years of age. OR 0 to 3 for participants = 18 to 74 years of age. 7. AST and ALT = 3 × upper limit of normal (ULN) 8. Total bilirubin = 1.5 × ULN (except in the setting of isolated Gilbert syndrome, in which case higher total bilirubin is allowed provided that conjugated bilirubin is = 3.0 x ULN) 9. Estimated Glomerular Filtration Rate (eGFR) = 60 mL/min/1.73 m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory) 10. WBC =65 years) yes F.1.3.1 Number of subjects for this age range 46
Exclusion criteria
Exclusion criteria: 1. Prior exposure to MDM-inhibitor therapy at any time 2. Participants with TP53 mutation positive 3. Participants with del17p 4. Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, with the exception of hydroxyurea, growth factors, ruxolitinib, and supportive care. In Arm 1, as defined in the inclusion criteria pre-treatment with venetoclax and azacitidine is allowed provided the participant is enrolled in the study within 28 days from their last dose of venetoclax and/or azacitidine treatment. 5. Participants with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA or with AML secondary to Down's syndrome 6. Participants treated with FLT3 inhibitors 7. Participants with known active CNS leukemia or neurologic symptoms suggestive of CNS leukemia (unless CNS leukemia has been excluded by at least one lumbar puncture showing negativity prior to starting protocol therapy) 8. Participants with concurrent or prior malignancy, except: • Participant with history of MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, aplastic anemia or other antecedent hematologic disorder • Participant with history of adequately treated malignancy for which the participant has been disease free (absence of residual disease) for at least 1 years and if no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Participants who are receiving adjuvant therapy such as hormonal therapy or long-term maintenance therapy who have had no residual disease for at least 1 year are eligible Other protocol-defined exclusion criteria may apply
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Safety Run-in, Arm 1, Arm 2: To determine the recommended dose of siremadlin in combination with venetoclax plus azacitidine to be explored further in the expansion phase (RDE), separately in Arm 1 and Arm 2. Safety Run-in and expansion, Arm 1: To evaluate preliminary efficacy of siremadlin at the determined recommended dose for expansion (RDE) when administered in combination with venetoclax plus azacitidine in achieving Complete Remission (CR) (Arm 1 only). ;Secondary Objective: 1. safety and tolerability profile of siremadlin when administered in combination with venetoclax plus azacitidine (Arms 1 and 2). 2. CR rate (Arm 2 only; for Arm 1, assessment of CR is a primary endpoint). 3. duration of CR in Arm 1 as well as in Arm 2. 4. CR/CRh and CR/CRi rates with CRh defined as CR with partial hematological recovery (neutrophils > 0.5 X109/L and platelet > 50X109/L) and CRi defined as CR with incomplete hematological recovery (neutrophils <1.0X109/L and/or platelets <100X109/L) (Arm 1 and 2). 5. duration of CR/CRh and CR/CRi (Arm 1 and 2). 6. Overall Survival (OS) (Arm 1 and 2). 7. Assessment of early mortality, defined by 30- and 60- day mortality from the start of study treatment (Arm 1 and 2). 8. PK of siremadlin, venetoclax and azacitidine administered in combination (Arms 1 and 2). 9. effect of siremadlin in combination with venetoclax plus azacitidine on measurable residual disease (MRD).;Primary end point(s): • Proportion of participants with DLT as per investigator assessment reported during the first cycle. • Proportion of participants achieving a complete remission (CR) as per investigator assessment (Cheson et al 2003, Döhner et al 2017). ;Timepoint(s) of evaluation of this end point: Analysis for primary safety endpoint (proportion of participants with DLT) will be conducted conducted for each cohort when participants have received siremadlin plus azacitidine plus venetoclax for at least one cycle. The primary efficacy analysis (proport | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1.Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs, incidence of notable ECG abnormalities. 2.Proportion of participants achieving a CR as per investigator assessment (Cheson et al 2003, Döhner et al 2017). 3.Time from the date of the first documented CR to the date of first documented relapse or death due to any cause, whichever occurs first. 4.Proportion of participants achieving a CR or CRh, Proportion of participants achieving a CR or CRi. 5.Time from the date of the first documented CR/CRh and CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first. 6.The time from start of treatment to death due to any cause. 7.Proportion of participants died due to any cause from start of treatment until 30- and 60-day. 8.Pharmacokinetic parameters (e.g., AUC, Cmax, Tmax) and concentration vs time profiles of siremadlin, venetoclax and azacitidine. 9.Proportion of CR-MRD negative overall and in participants achieving a CR, CR/CRh, and CR/CRi.;Timepoint(s) of evaluation of this end point: Timepoint of evaluation will be at evaluation of primary efficacy analysis and final analysis, respectively. | — |
Countries
Australia, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Malaysia, Russian Federation, Switzerland, Turkey, United States
Contacts
Public ContactClinical Trial Information Desk
Novartis Pharma AG
Outcome results
None listed