A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.

Acute Myeloid Leukemia Clinical Trial

Official 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05155709
• Other study ID #: CHDM201I12201
• Secondary ID: 2021-001165-21
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: May 17, 2022
• Est. completion date: May 28, 2024

Study information

• Verified date: April 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 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.

Description:

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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 14
• Est. completion date: May 28, 2024
• Est. primary completion date: May 28, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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 (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:

• 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 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.

Other protocol-defined inclusion/exclusion criteria may apply at the end

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Hong Kong	Novartis Investigative Site	Hong Kong
Hungary	Novartis Investigative Site	Budapest
Israel	Novartis Investigative Site	Beer-Sheva
Israel	Novartis Investigative Site	Jerusalem
Italy	Novartis Investigative Site	Bologna	BO
Malaysia	Novartis Investigative Site	Alor Setar	Kedah
Malaysia	Novartis Investigative Site	Selangor
Turkey	Novartis Investigative Site	Izmir
United States	Texas Oncology Sammons Cancer Center Sammons Cancer Center (SC)	Dallas	Texas
United States	Oregon Health Sciences University .	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Hong Kong,  Hungary,  Israel,  Italy,  Malaysia,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2)	The objective for the safety run-in is to determine the recommended dose of siremadlin in combination with venetoclax plus azacitidine to be explored further in the expansion part separately in Arm 1 and Arm 2.	From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
Primary	Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only)	The objective is to evaluate preliminary efficacy of siremadlin at the determined recommended dose for expansion (RDE) when administered in combination with venetoclax and azacitidine.; This endpoint will not be analyzed since the recommended dose was not determined due to early termination.	At least 7 cycles (196 days)
Secondary	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))	Assessment of CR in order to evaluate preliminary efficacy of siremadlin (in combination of venetoclax plus azacitidine) at the determined recommended dose for Arm 2 participants.; This endpoint will not be analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Secondary	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 separately)	Assessment of duration of CR in participants who achieved a CR.; This endpoint will not be analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Secondary	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)	Assessment of CR/CRh rate and CR/CRi rate.	up to 3 years
Secondary	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 separately)	Assessment of duration of CR/CRh and duration of CR/CRi.; This endpoint will not be analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Secondary	The time from start of treatment to death due to any cause (Arm 1 and Arm 2 separately)	Assessment of Overall Survival (OS).; This endpoint will not be analyzed since the recommended dose was not determined due to early termination.	up to 3 years
Secondary	Percentage of participants died due to any cause from start of treatment until 30- and 60-day (Arm 1 and Arm 2)	To assess rate of early mortality at 30 day and 60 days from start of study treatment	30 days & 60 days from start of study treatment
Secondary	Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)	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.	up to 3 years
Secondary	PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)	To characterize the PK of siremadlin, venetoclax and azacitidine administered in combination in each arm. Cmax is the maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume -1)	up to 3 years
Secondary	PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)	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).	up to 3 years
Secondary	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)	To assess the effect of siremadlin in combination with venetoclax plus azacitidine in MRD	up to 3 years