Ziftomenib + Mezigdomide in Adolesc. and Adults w/ R/R AML

NCT07355335 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 25-804
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of mezigdomide in combination with ziftomenib in adolescent and adult participants with either KMT2A-rearranged (KMT2A-r) or NPM1-mutant relapsed or refractory acute myeloid leukemia (AML).

Conditions

KMT2A-rearranged; NPM1-mutant Refractory or Relapsed AML

Keywords

KMT2A rearrangement; NPM1c mutation; AML

Outcome Measures

Primary Outcomes (2)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  To characterize the safety and tolerability of mezigdomide in combination with ziftomenib, all reported toxicities will be summarized by toxicity type and maximum grade and will be reported as numbers and percentages. All participants who receive at least one dose of study treatments will be evaluable for toxicity.

  From the start of treatment until participant withdrawal, death, or removal from study, whichever comes first, assessed up to 2 years after initial dose of study treatment.

• Recommended phase 2 dose (RP2D) of mezigdomide in combination with ziftomenib.

  The RP2D of mezigdomide in combination with ziftomenib will be determined in the dose escalation phase via a traditional 3+3 dose escalation design.

  From start of treatment to end of 12 cycles (each cycle is 28 days).

Secondary Outcomes (2)

• Complete remission/complete remission with partial hematologic recovery (CR/CRh) and overall response rate (ORR)

  From start of treatment to end of 12 cycles (each cycle is 28 days) or until participant withdrawal, death, or removal from study, whichever comes first.

• 2-year overall and relapse-free survival rates

  From the start of treatment until participant withdrawal, death, or removal from study, whichever comes first, assessed up to 2 years after initial dose of study treatment.

Study Arms (1)

Ziftomenib and Mezigdomide

EXPERIMENTAL

Ziftomenib will be taken orally once daily of each cycle. A drug diary will be provided to participants to document information about taking ziftomenib. Mezigdomide will be taken orally once daily on days 1-21 or possibly days 1-14 of each cycle. The study doctor will confirm which days mezigdomide will be taken on. A drug diary will be provided to participants to document information about taking mezigdomide.

Drug: Ziftomenib; Drug: Mezigdomide

Interventions

Ziftomenib DRUG

Capsule taken orally once daily on days 1-28 of each 28-day cycle.

Also known as: KO-539

Ziftomenib and Mezigdomide

Mezigdomide DRUG

Capsule taken orally once daily on days 1-21 or possibly days 1-14 of each 28-day cycle.

Also known as: BMS-986348, CC-92480

Ziftomenib and Mezigdomide

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥16 years during dose escalation portion of study, patients must weigh ≥40 kg.
• Age \>12 years during dose expansion portion of study, patients must weight ≥40 kg.
• Diagnosis of AML per the WHO Classification of Hematolymphoid Tumors (5th Edition) with documented KMT2A rearrangement or NPM1 cytoplasmic-type (NPM1c) mutation. KMT2A-rearrangements must be confirmed by FISH or RNA-based fusion calling by a CLIA-certified laboratory. This study will only enroll KMT2A gene rearrangements in which there is a translocation between the N-terminal portion of KMT2A and a fusion partner, and will not include KMT2A partial tandem duplications (PTDs) or other structural alterations of KMT2A. NPM1c mutations must be confirmed by DNA sequencing in a CLIA-certified laboratory. Patients with myeloid sarcoma are eligible only if concurrent bone marrow involvement is present. Patients must have at least 5% bone marrow disease by morphology at the time of study entry.
• Patients with NPM1 mutated AML must either be FLT3 ITD wild type or have an ITD allelic ratio of \<0.05 (i.e. not eligible for a targeted FLT3 tyrosine kinase inhibitor).
• Patients must have relapsed or be refractory to at least one prior line of conventional therapy for AML or MDS-AML.
• Eastern Cooperative Oncology Group (ECOG) performance status must be 0, 1, or 2; Karnofsky ≥50 for patients ≥16 years of age; and Lansky ≥50 for patients ≥12 to 16 years of age.
• Participants must meet the following organ and marrow function as defined below:
• Leukocytes \<25,000/mcL (hydroxyurea, leukapheresis, or single dose of cytarabine 1 g IV are permitted to meet this criterion)
• AST(SGOT)/ALT(SGPT) ≤5 × institutional ULN and total bilirubin ≤ 2x institutional ULN unless related to leukemic involvement or known Gilbert's syndrome (for bilirubin).
• Cardiac LVEF of ≥40%, as measured by echocardiogram or MUGA scan
• Glomerular filtration rate (GFR)≥30 mL/min/1.73 m2
• The patient, a parent (if the patient is \<18 years old), or a legally authorized representative must be able to understand and provide informed consent.
• Patients of childbearing potential are eligible for the study but must comply with the pregnancy prevention plan for study drugs. See Appendix B for details.
• Patient's life expectancy attributed to AML must be greater than 3 months.
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Life expectancy attributed to malignancy other than AML must be greater than 24 months. Patients with concurrent malignancy who are receiving chemotherapy or whose disease is uncontrolled or progressing are not eligible.

You may not qualify if:

• AML diagnosis without KMT2A-rearrangement or NPM1-mutation. KMT2A-PTD patients and patients with KMT2A alterations other than translocations are excluded.
• Active central nervous system (CNS) involvement by AML (i.e., CNS-2 or CNS-3 disease). Previously treated CNS disease or those receiving prophylactic intrathecal chemotherapy per institutional standard is allowed.
• Myeloid sarcoma or extramedullary disease without bone marrow disease.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1 by the NCI-CTCAE version 5.0) with the exception of alopecia.
• Participants who are receiving any other investigational agents for this condition.
• Clinically active HIV disease.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to mezigdomide (i.e. lenalidomide, thalidomide)
• Patient received chemotherapy, immunotherapy, radiation therapy, or ancillary therapy that is considered to be investigational \<7 days prior to the first dose of ziftomenib and mezigdomide, or within 5 drug half-lives prior to the first dose of study drug, whichever is longer.
• Patients with psychiatric, familial, or geographic factors that may impede ability to provide informed consent, to follow study protocol, or hamper study compliance.
• Any other significant medical or psychosocial comorbidities that would preclude the patient from participating in the study or would confound interpretation of study results.
• Mean corrected QT interval corrected for heart rate by Frederica's formula (QTcF)\>480ms.
• Patients on dialysis.
• Patients with active infection that are deemed controlled will be permitted to enroll. Patients with uncontrolled infection may enroll once infection is treated and brought under control.
• Subjects who have undergone a hematopoietic stem cell transplant (HSCT) within 90 days of the first dose of treatment on study, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD), requiring an equivalent dose of ≥ 0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids. (The use of topical steroids for ongoing skin GVHD is permitted.)
• Patients who are unable to swallow pills.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Kura Oncology, Inc.: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Amir Fathi, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amir Fathi, MD

CONTACT

617-724-1124; AFATHI@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 5, 2026
• First Posted: January 21, 2026
• Study Start (Estimated): July 9, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: January 22, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation

Locations

US (2)