A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.
NCT ID: NCT05155709
Last Updated: 2025-10-10
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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TERMINATED
PHASE1
14 participants
INTERVENTIONAL
2022-05-17
2024-04-17
Brief Summary
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The primary purpose of this study was to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML patients without unacceptable levels of treatment-emergent toxicities.
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Detailed Description
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The study was planned to be conducted in two parts. The primary purpose of Part 1 (Safety Run- in) was to rule out excessive toxicity of siremadlin when administered in combination with venetoclax plus azacitidine while the primary purpose of Part 2 (Expansion) was to evaluate the preliminary efficacy of siremadlin when combined with venetoclax plus azacitidine in the respective patient population.
The study treatment (siremadlin in combination with venetoclax plus azacitidine) is administered in cycles with a planned duration of 28 days and will continue until the participants experience disease progression/relapse or unacceptable toxicity.
The initial enrollment plan and safety review was as follow:
* In the Safety run-in part, 9-15 participants were planned to be enrolled in each arm. Approximately 3-6 participants were planned to be enrolled at the starting dose level of siremadlin in combination with venetoclax plus azacitidine in both arms independently. Provided the starting dose level is determined to be safe, approximately 6-9 additional participants were planned to be enrolled at dose level +1. Safety review meetings were planned to take place involving participating investigators and the Sponsor Team to make decisions regarding siremadlin dose and determine the recommended dose for expansion.
* Approximately 26 patients were planned to be treated at the recommended dose in the expansion part.
In the safety run-(Part 1) 27 sites were open for recruitment with 28 patients screened and 14 patients enrolled.
After enrolling 14 patients (6 patients in Arm 1 and 8 patients in Arm 2), Novartis took the decision to put the enrollment in permanent halt and terminate the siremadlin program. For that reason, the enrollment in Part 2 (expansion phase) will not be open. The Novartis decision was not driven by any safety concerns.
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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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
siremadlin
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths
venetoclax
Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.
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
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).
siremadlin
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths
venetoclax
Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.
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
Interventions
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siremadlin
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths
venetoclax
Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.
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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
\- 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 (in both arms) 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
Exclusion Criteria
* 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 for AML indication are not eligible.
* 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.
18 Years
99 Years
ALL
No
Sponsors
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Novartis Pharmaceuticals
INDUSTRY
Responsible Party
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Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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Oregon Health Sciences University
Portland, Oregon, United States
Texas Oncology Sammons Cancer Center
Dallas, Texas, United States
Novartis Investigative Site
Hong Kong, , Hong Kong
Novartis Investigative Site
Budapest, , Hungary
Novartis Investigative Site
Beersheba, , Israel
Novartis Investigative Site
Jerusalem, , Israel
Novartis Investigative Site
Bologna, BO, Italy
Novartis Investigative Site
Alor Star, Kedah, Malaysia
Novartis Investigative Site
Kuala Selangor, , Malaysia
Novartis Investigative Site
Izmir, , Turkey (Türkiye)
Countries
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Related Links
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Novartis Results Database (NovCTRD)
A Plain Language Trial Summary is available on www.novctrd.com
Other Identifiers
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2021-001165-21
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
CHDM201I12201
Identifier Type: -
Identifier Source: org_study_id
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