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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT05155709
Registration number
NCT05155709
Ethics application status
Date submitted
20/10/2021
Date registered
14/12/2021
Date last updated
13/09/2023
Titles & IDs
Public title
A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.
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Scientific title
A Phase Ib/II Open Label Dose Confirmation, Proof of Concept Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Unfit Adult AML Participants Who Responded Sub-optimally to First-line Venetoclax Plus Azacitidine Treatment and in Participants With Newly Diagnosed Unfit AML Presenting With High-risk Clinical Features
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Secondary ID [1]
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2021-001165-21
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Secondary ID [2]
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CHDM201I12201
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - siremadlin
Treatment: Drugs - venetoclax
Treatment: Drugs - azacitidine
Experimental: Arm 1: Unfit adult participants with AML who responded sub-optimally to standard of care - Unfit adult participants with AML who responded sub-optimally to at least 2 and not more than 4 cycles ( 1 cycle=28 days) of first-line venetoclax plus azacitidine therapy
Experimental: Arm 2: Newly diagnosed unfit adult participants with high-risk AML - Unfit adult participants with newly diagnosed AML and with adverse genetic risk stratification (according to ELN 2022)(Except TP53 mutation positive participants).
Treatment: Drugs: siremadlin
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths
Treatment: Drugs: venetoclax
Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.
Treatment: Drugs: azacitidine
Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2)
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Assessment method [1]
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Assessment of Dose Limiting Toxicity (DLT); Safety/Tolerability during the first cycle of study treatment
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Timepoint [1]
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From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
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Primary outcome [2]
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Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only)
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Assessment method [2]
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Assessment of Complete remission (CR) in order to evaluate preliminary efficacy of siremadlin (in combination of venetoclax plus azacitidine) at the determined recommended dose for expansion
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Timepoint [2]
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At least 7 cycles (196 days)
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Secondary outcome [1]
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Percentage of participants treated at the recommended dose for expansion, achieving CR as per investigator assessment (Arm 2 only; for Arm 1 assessment of CR is a primary outcome measure))
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Assessment method [1]
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Assessment of CR in order to evaluate preliminary efficacy of siremadlin (in combination of venetoclax plus azacitidine) at the determined recommended dose for expansion in participants with newly diagnosed AML having high-risk disease features.
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Timepoint [1]
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up to 3 years
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Secondary outcome [2]
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Time of the date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2)
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Assessment method [2]
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Assessment of duration of CR in participants who achieved a CR.
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Timepoint [2]
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up to 3 years
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Secondary outcome [3]
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Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) and percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2)
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Assessment method [3]
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CRh is defined as CR with partial hematological recovery (i.e. neutrophil >0.5 X109/L and platelet > 50X109/L) and CRi is defined as CR with incomplete hematological recovery (i.e. neutrophil <1.0X109/L and/or platelet <100X109/L)
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Timepoint [3]
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up to 3 years
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Secondary outcome [4]
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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 (Arm 1 and Arm 2)
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Assessment method [4]
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Assessment of duration of CR/CRh and duration of CR/CRi
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Timepoint [4]
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up to 3 years
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Secondary outcome [5]
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The time from start of treatment to death due to any cause (Arm 1 and Arm 2)
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Assessment method [5]
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Assessment of Overall Survival (OS)
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Timepoint [5]
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up to 3 years
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Secondary outcome [6]
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Percentage of participants died due to any cause from start of treatment until 30- and 60-day (Arm 1 and Arm 2)
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Assessment method [6]
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To assess rate of early mortality at 30 day and 60 days from start of study treatment
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Timepoint [6]
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30 days & 60 days from start of study treatment
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Secondary outcome [7]
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Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)
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Assessment method [7]
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PK parameters AUC and concentration vs time profiles of siremadlin, venetoclax and azacitidine.
AUC0-t: The area under the concentration vs. time Curve (AUC) from time zero to specified time point.
AUClast is the AUC from time zero to the last quantifiable concentration point (last) (mass x time x volume -1).
AUCtau is the AUC to the end of the dosing interval as when possible PK samples will be collected up to 24 h postdose for siremadlin and venetoclax. Steady-state will be assumed on Day 5 (AUCtau, ss) in case of continuous dosing.
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Timepoint [7]
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up to 3 years
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Secondary outcome [8]
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PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)
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Assessment method [8]
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PK parameter Cmax and concentration vs time profiles of siremadlin, venetoclax and azacitidine. Cmax is the maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume -1)
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Timepoint [8]
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up to 3 years
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Secondary outcome [9]
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PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)
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Assessment method [9]
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PK parameter Tmax and concentration vs time profiles of siremadlin, venetoclax and azacitidine. Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after drug administration (time).
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Timepoint [9]
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up to 3 years
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Secondary outcome [10]
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Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Arm 1 and Arm 2)
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Assessment method [10]
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To assess the effect of siremadlin in combination with venetoclax plus azacitidine in MRD
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Timepoint [10]
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up to 3 years
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Eligibility
Key inclusion criteria
- Age at the date of signing the informed consent form (ICF): Arm 1 and Arm 2: = 18 years
- Participants diagnosed with AML based on WHO 2016 classification (Arber et al 2016) who
are ineligible for standard induction chemotherapy and: Arm 1 : 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.
Arm 2 : newly diagnosed AML with adverse genetic risk stratification (according to ELN
2022) (except TP53 mutation positive participants).
- Participant must be considered ineligible for standard of care intensive induction
chemotherapy 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 congestive heart failure (CHF) requiring treatment or Ejection Fraction = 50%
or chronic stable angina; DLCO = 65% or FEV1 = 65%.
- 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.
- WBC < 25x109/L
- AST and ALT = 3 × ULN
- Estimated Glomerular Filtration Rate (eGFR)= 60 mL/min/1.73 m2
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Minimum age
18
Years
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Maximum age
99
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Prior exposure to MDM2-inhibitor therapy at any time.
- Participants with TP53 mutation positive.
- Participants with del17p.
- Participants with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA
(Promyelocytic leukemia/retinoic acid receptor alpha) or with AML secondary to Down's
syndrome.
- Participants treated with FLT3 inhibitors
- Participants who require treatment with moderate or strong CYP3A4 inducers within 14
days prior to starting study treatment, or are expected to receive moderate or strong
CYP3A4 inducers during the entire study
- Participants who require treatment with substrates of CYP3A4/5 with a narrow
therapeutic index.
Other protocol-defined inclusion/exclusion criteria may apply at the end
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
17/05/2022
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
13/11/2026
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Actual
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Sample size
Target
56
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
WA
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Recruitment hospital [1]
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Novartis Investigative Site - Perth
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Recruitment postcode(s) [1]
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6000 - Perth
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Colorado
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Country [3]
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United States of America
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State/province [3]
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Massachusetts
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Country [4]
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United States of America
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State/province [4]
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New York
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Country [5]
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United States of America
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State/province [5]
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Ohio
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Country [6]
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United States of America
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State/province [6]
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Oregon
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Country [7]
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United States of America
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State/province [7]
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Pennsylvania
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Country [8]
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United States of America
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State/province [8]
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Texas
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Country [9]
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United States of America
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State/province [9]
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Virginia
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Country [10]
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United States of America
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State/province [10]
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Wisconsin
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Country [11]
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Hong Kong
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State/province [11]
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Hong Kong
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Country [12]
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Hungary
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State/province [12]
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Budapest
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Country [13]
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Israel
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State/province [13]
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Beer-Sheva
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Country [14]
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Israel
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State/province [14]
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Jerusalem
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Country [15]
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Italy
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State/province [15]
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BO
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Country [16]
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Italy
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State/province [16]
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BR
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Country [17]
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Italy
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State/province [17]
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MI
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Country [18]
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Malaysia
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State/province [18]
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Kedah
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Country [19]
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Malaysia
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State/province [19]
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Kuala Lumpur
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Country [20]
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Malaysia
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State/province [20]
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Selangor
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Country [21]
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Spain
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State/province [21]
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Catalunya
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Country [22]
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Spain
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State/province [22]
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Comunidad Valenciana
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Country [23]
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Switzerland
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State/province [23]
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Bern
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Country [24]
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Switzerland
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State/province [24]
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Lausanne
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Country [25]
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Turkey
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State/province [25]
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Yenimahalle
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Country [26]
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Turkey
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State/province [26]
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Izmir
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
A study of siremadlin in combination with venetoclax plus azacitidine in adult participants
with AML who are ineligible for chemotherapy.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT05155709
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Novartis Pharmaceuticals
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Address
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Country
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Phone
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1-888-669-6682
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT05155709
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