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 on Acute Myeloid Leukemia Leukemia

Summary

Eligibility
for people ages 18-99 (full criteria)
Location
at Los Angeles, California and other locations
Dates
study start
estimated completion
Principal Investigator
by Caspian Oliai

Description

Summary

A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.

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

Details

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.

Keywords

Acute Myeloid Leukemia, AML, Azacitidine, venetoclax, p53, MDM2, siremadlin, HDM201, unfit adult AML participants, newly diagnosed unfit AML, presenting with high-risk clinical features, Leukemia, Myeloid Leukemia, Leukemia, Myeloid, Acute

Eligibility

You can join if…

Open to people ages 18-99

  • 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

You CAN'T join if...

  • 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

Locations

  • University of California Los Angeles . accepting new patients
    Los Angeles California 90095 United States
  • Oregon Health and Science Univ accepting new patients
    Portland Oregon 97239 United States

Lead Scientist at UCLA

  • Caspian Oliai
    HS Assistant Clinical Professor, Medicine. Authored (or co-authored) 23 research publications

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Novartis Pharmaceuticals
ID
NCT05155709
Phase
Phase 1/2 research study
Study Type
Interventional
Participants
Expecting 56 study participants
Last Updated