Acute Myeloid Leukemia Clinical Trial
A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.
A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.
The primary purpose of this study is 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. The recommended dose of siremadlin in combination with venetoclax plus azacitidine will be determined to be explored further in the expansion phase and the preliminary efficacy in achieving Complete Remission (CR) will be evaluated in participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment.
The study will be conducted in two parts. The primary purpose of Part 1 (Safety Run-in) is to rule out excessive toxicity of siremadlin when administered in combination with venetoclax plus azacitidine while the primary purpose of Part 2 (Expansion) is 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) will be administered in cycles with a planned duration of 28 days and will continue until the participants experience disease progression/relapse or unacceptable toxicity.
In the Safety run-in part, 9-15 participants will be enrolled in each arms. Approximately 3-6 participants will 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 will be enrolled at dose level +1. Safety review meetings will 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 will be treated at the recommended dose in the expansion part.
- 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
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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There are 29 Locations for this study
Perth Western Australia, 6000, Australia
Hong Kong , , Hong Kong
Budapest , 1085, Hungary
Beer-Sheva , 84571, Israel
Jerusalem , 91031, Israel
Jerusalem , 91120, Israel
Bologna BO, 40138, Italy
Brescia BR, 25123, Italy
Milano MI, 20162, Italy
Alor Setar Kedah, 05460, Malaysia
Kuala Lumpur , 59100, Malaysia
Selangor , 68000, Malaysia
Hospitalet de LLobregat Catalunya, 08907, Spain
Valencia Comunidad Valenciana, 46010, Spain
Bern , 3010, Switzerland
Lausanne , 1011, Switzerland
Ankara Yenimahalle, 06200, Turkey
Izmir , 35340, Turkey
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