Ziftomenib in Combination With Chemotherapy for Children With Relapsed/Refractory Acute Leukemia

NCT06376162 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: ITCC-101/APAL2020K2023-505262-28-00
• Study Type: interventional
• Target: 20
• Locations: 7 countries
• Sites: 20

Brief Summary

The primary objective of the study is to determine the recommended phase 2 dose (RP2D) of ziftomenib in combination with chemotherapy (FLA) in children with relapsed or refractory KMT2A-r, NUP98-r, or NPM1-m acute leukemia based on safety and pharmacokinetics (PK).

Conditions

Relapsed/Refractory KMT2A-r Acute Leukemia; Relapsed/Refractory NUP98-r Acute Leukemia; Relapsed/Refractory NPM1-m Acute Leukemia

Keywords

Ziftomenib; Acute leukemia; KMT2A-r; NUP98-r; NPM1-m

Outcome Measures

Primary Outcomes (2)

• Number of Participants Who Experience a Dose-limiting Toxicity (DLT)

  Day 1 to Day 49

• Area Under the Plasma Concentration-time Curve (AUC) of Ziftomenib

  Cycle 1 Day 8: Pre-dose and 3, 8 and 24 hours post-dose. Cycle 1 Day 22: 0, 3, 8 and 24 hours post-dose (Cycle 1 is 49 days). Cycle 2: Any day pre-dose (Cycle 2 is 28 days).

Secondary Outcomes (18)

• Number of Participants Who Experience an Adverse Event (AE)

  Up to 1 month following the last administration of study drug (up to approximately 13 months)

• Number of AEs by Severity

  Up to 1 month following the last administration of study drug (up to approximately 13 months)

• Maximum Observed Plasma Concentration (Cmax) of Ziftomenib

  Cycle 1 Day 8: Pre-dose and 3, 8 and 24 hours post-dose. Cycle 1 Day 22: 0, 3, 8 and 24 hours post-dose (Cycle 1 is 49 days). Cycle 2: Any day pre-dose (Cycle 2 is 28 days).

• Minimum Observed Plasma Concentration (Cmin) of Ziftomenib

  Cycle 1 Day 8: Pre-dose and 3, 8 and 24 hours post-dose. Cycle 1 Day 22: 0, 3, 8 and 24 hours post-dose (Cycle 1 is 49 days). Cycle 2: Any day pre-dose (Cycle 2 is 28 days).

• Time to Cmax (Tmax)

  Cycle 1 Day 8: Pre-dose and 3, 8 and 24 hours post-dose. Cycle 1 Day 22: 0, 3, 8 and 24 hours post-dose (Cycle 1 is 49 days). Cycle 2: Any day pre-dose (Cycle 2 is 28 days).

Study Arms (1)

Ziftomenib

EXPERIMENTAL

During Cycle 1 (49 days), participants will receive escalating doses of ziftomenib once daily (QD) on Days 8 to 49. Participants will also receive FLA chemotherapy consisting of fludarabine at a dose of 30 mg/m\^2 (1 mg/kg/dose in infants \<1 year of age or ≤10 kg) and cytarabine at a dose of 2000 mg/m\^2 (67 mg/kg/dose in infants \<1 year of age or ≤10 kg) QD on Day 1 to Day 5. Participants with \<5% blasts will continue ziftomenib monotherapy until Day 49. Participants with a response and \>5% blasts will continue to Cycle 2. During Cycle 2 (28 days), participants will receive escalating doses of ziftomenib QD on Day 1 to Day 28 in combination with FLA chemotherapy on Day 1 to Day 5. Participants who respond to treatment, but experience a delay prior to hematopoietic stem cell transplantation (HSCT), may receive up to 10 additional cycles (28 days) of ziftomenib monotherapy. Participants may also receive intrathecal therapy prophylaxis, if needed, during all cycles.

Drug: Ziftomenib; Drug: Cytarabine; Drug: Fludarabine

Interventions

Ziftomenib DRUG

Oral capsule

Ziftomenib

Cytarabine DRUG

Intravenous (IV) infusion

Ziftomenib

Fludarabine DRUG

IV infusion

Ziftomenib

Eligibility Criteria

• Age: 0 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: 0-21 years (and at least 5 kg body weight), with a minimum of 80% of participants under 18 years of age.
• Diagnosis: KMT2A-r, NPM1-m, or NUP98-r acute leukemia in first or greater relapse or refractory to standard (re-) induction treatment (including HSCT). Please note that genetic alteration must be confirmed by the central laboratory, or the participant will discontinue protocol therapy.
• Eligible participants also must fulfill one of the following conditions:
• Bone marrow relapse is defined as:
• A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing, or other molecular method.
• a single bone marrow sample with at least two tests showing ≥ 1% leukemic blasts, examples of tests (confirmed by central lab) include: Flow cytometry showing leukemia ≥ 1% by multiparameter flow cytometry (MFC) confirmed by central lab.
• Karyotypic abnormality as confirmed by central cytogenetic review.
• FISH abnormality identical to one present at diagnosis (must be above level of sensitivity of specific FISH probe; central cytogenetic review required).
• Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of validated leukemogenic lesion (e.g., fusion, mutation) in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory that matches initial diagnosis and is quantifiable as ≥1% confirmed by central lab.
• Participants with combined extramedullary and bone marrow relapse (defined as above) are eligible.
• Participants with isolated extramedullary disease (EMD) are not eligible. EMD relapse is defined as biopsy-proven extramedullary disease without bone marrow disease after documented complete response (CR) following initial therapy. Participants with isolated central nervous system (CNS) relapse are not eligible. Participants with a combined medullary/extramedullary relapse, including CNS disease, are eligible.
• Participants with asymptomatic CNS3 disease are eligible if they do not have isolated CNS3 extramedullary relapse.
• For participants unable to undergo bone marrow assessment, a peripheral blood absolute blast count ≥ 1,000 cell/microliter is sufficient to diagnose relapsed or refractory disease and facilitate confirmation of required genetic alterations for protocol therapy.
• Refractory disease/induction failure:
• Acute myeloid leukemia (AML): The bone marrow contains ≥ 1% leukemic blasts by MFC at the end of 2 cycles of induction therapy.

You may not qualify if:

• Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study.
• Participants with Down syndrome.
• Participants with EMD are not eligible. EMD relapse is defined as biopsy proven extramedullary disease without bone marrow disease after documented CR following initial therapy.
• Participants with isolated CNS relapse are not eligible, as well as symptomatic CNS3 disease.
• Participants with acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML).
• Participants with malabsorption syndrome or any other condition that precludes enteral administration of a menin inhibitor.
• Concomitant therapy: Gastric pH has great influence on absorption of ziftomenib; therefore, the use of proton pump inhibitors is prohibited, if necessary H2 Blockers may provide an alternative treatment option.
• Participants who are currently receiving another investigational drug.
• Participants with any known congenital bone marrow failure syndrome.
• Participants with known prior allergy to any of the medications used in protocol therapy.
• Participants with documented active, uncontrolled infection at the time of study entry.
• Active/uncontrolled known human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) and hepatitis C virus (HCV). Note: HIV testing does not need to be conducted at screening unless it is required per local guidelines or institutional standard.
• Post menarche female participants with positive pregnancy test, and a lactating female participant.
• Participant has a pre-existing disorder predisposing the participant to a serious or life-threatening infection (e.g., cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenia not related to the leukemia or its treatment).
• Participants must not be receiving other investigational medications (defined as medicinal products not yet approved for any indications, including alternative/herbal therapies) within 30 days of first dose of study drug or while on study.

Sponsors & Collaborators

• PedAL BCU, LLC: lead
• Kura Oncology: collaborator

Study Sites (20)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

RECRUITING

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

RECRUITING

Children's Healthcare of Atlanta

Atlanta, Georgia, 30329, United States

RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Memorial Sloan Kettering Cancer Center - New York

New York, New York, 10065, United States

RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3026, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105-3678, United States

RECRUITING

Texas Children's Hospital

Houston, Texas, 77030, United States

RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98105, United States

RECRUITING

Sankt Anna-Kinderspital

Vienna, Vienna, 1090, Austria

RECRUITING

SickKids - The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

RECRUITING

CHU de Nantes - Hôpital Femme-Enfant-Adolescent

Nantes, Loire-Atlantique, 44093, France

RECRUITING

CHU de Reims - Hôpital Robert Debré

Paris, Île-de-France Region, 75019, France

RECRUITING

Ospedale Pediatrico Bambino Gesù

Roma, Rome, 00165, Italy

RECRUITING

Fondazione IRCCS San Gerardo dei Tintori (Ospedale San Gerardo)

Monza, 20900, Italy

RECRUITING

Prinses Maxima Centrum Kinderoncologie

Utrecht, 3584 CS, Netherlands

RECRUITING

Hospital Universitari Vall d'Hebrón

Barcelona, 08035, Spain

RECRUITING

Hospital Infantil Universitario Niño Jesús

Madrid, 28009, Spain

RECRUITING

MeSH Terms

Conditions

Recurrence

Interventions

Cytarabine; fludarabine

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Central Study Contacts

Dr. Branko Cuglievan

CONTACT

(713) 563-1499; bcuglievan@mdanderson.org

Dr. Sarah Tasian, MD

CONTACT

(215) 590-2299; tasians@chop.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2024
• First Posted: April 19, 2024
• Study Start: March 18, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027
• Last Updated: October 20, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2); AU (1); NL (1); CA (1); US (11); FR (2); IT (2)