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

Novartis

Status and phase: Completed; Phase 1

Conditions: Acute Myeloid Leukemia

Treatments: Drug: azacitidine; Drug: venetoclax; Drug: siremadlin

Study type: Interventional

Funder types: Industry

Identifiers

NCT05155709

CHDM201I12201

2021-001165-21 (EudraCT Number)

Details and patient eligibility

About

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 participants without unacceptable levels of treatment-emergent toxicities.

Full description

The recommended dose of siremadlin in combination with venetoclax plus azacitidine was to be determined to be explored further in the expansion phase and the preliminary efficacy in achieving Complete Remission (CR) 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) was administered in cycles with a planned duration of 28 days for each cycle and would continue until the participants experienced 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 was 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) 10 sites in 7 countries enrolled 14 patients.

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) did not open. The Novartis decision was not driven by any safety concerns.

Enrollment: 14 patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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14 participants in 2 patient groups

Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care

Experimental group

Description:

Unfit adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy. Siremadlin was adminstered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m\^2.

Treatment:

Drug: siremadlin

Drug: venetoclax

Drug: azacitidine

Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features

Experimental group

Description:

Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants). Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m\^2.

Treatment:

Drug: siremadlin

Drug: venetoclax

Drug: azacitidine