A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia

NCT05849662 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: T2020-004
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 19

Brief Summary

This clinical trial will test the safety and efficacy of combining trametinib and azacitidine in patients with juvenile myelomonocytic leukemia (JMML). Newly diagnosed lower-risk JMML patients will receive trametinib and azacitidine. High-risk JMML patients will receive trametinib, azacitidine, fludarabine, and cytarabine.

Conditions

Leukemia, Juvenile Myelomonocytic; JMML; JCML; Neurofibromatosis 1; CBL Syndrome

Outcome Measures

Primary Outcomes (2)

• To determine the safety of combining trametinib with azacitidine for patients with newly diagnosed lower-risk JMML.

  The incidence of dose limiting toxicities (DLTs) after the 1st course of therapy will be measured at different dose levels.

  At the end of the evaluation period of Cycle 1 (defined as 28 day cycle of therapy plus 30 days following the last dose of study therapy)

• To determine the safety of combining trametinib with azacitidine (Aza), fludarabine (FLA) and cytarabine for patients with newly diagnosed high-risk JMML.

  The incidence of dose limiting toxicities (DLTs) after the 1st course of therapy will be measured at different dose levels.

  At the end of the evaluation period of Cycle 1 (defined as 28 day cycle of therapy plus 30 days following the last dose of study therapy)

Study Arms (2)

Lower-risk patients

EXPERIMENTAL

Lower-risk patients are defined as having a mutational burden of one clonal alteration AND a low DNA methylation classification.

Drug: Trametinib; Drug: Azacitidine

High-risk patients

EXPERIMENTAL

High-risk patients are defined as having as having a mutational burden of more than one clonal alteration AND/OR an intermediate or high DNA methylation classification.

Drug: Trametinib; Drug: Azacitidine; Drug: Fludarabine; Drug: Cytarabine

Interventions

Trametinib DRUG

PO or NG QD Days 1-28 For patients age \< 6 years: 0.032 mg/kg/day at max dose = 2mg/day For patients age ≥ 6 years: 0.025 mg/kg/day at max dose = 2 mg/day

Also known as: GSK1120212B, TMT212-NXA

High-risk patients; Lower-risk patients

Azacitidine DRUG

IV over 30 minutes Days 1-5 Age \< 1 year or weight \<10kg: 2.5 mg/kg/day Age ≥ 1 year and weight ≥ 10kg: 75 mg/m2/day

Also known as: 5-azacytidine, Vidaza

High-risk patients; Lower-risk patients

Fludarabine DRUG

IV over 30 minutes Days 6-10 30 mg/m2/day (1mg/kg if \<12 kg)

Also known as: FLUDARA FOR INJECTION

High-risk patients

Cytarabine DRUG

IV over 3 hours Days 6-10 2000 mg/m2/day (67mg/kg if \<12 kg)

Also known as: Cytosine arabinoside, Ara-C, Cytosar

High-risk patients

Eligibility Criteria

• Age: 1 Month - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age
• Patients must be ≥ 1 month and ≤21 years of age at enrollment.
• Diagnosis • Patients must meet the 2022 International Consensus Classification criteria for JMML. The diagnosis is made based on the following criteria:.
• Clinical and hematologic features (the first 2 features are present in most cases; the last 2 are required):
• Peripheral blood monocyte count ≥ 1 × 109/L\*
• Splenomegaly†
• Blast percentage in PB and BM \< 20%
• Absence of BCR::ABL1
• This monocyte threshold is not reached in approximately 7% of cases. †Splenomegaly is absent in 3% of cases at presentation.
• II. Genetic studies (1 finding required):
• Somatic mutation in PTPN11‡ or KRAS‡ or NRAS‡ or RRAS or RRAS2‡
• Clinical diagnosis of neurofibromatosis type 1 or germline NF1 mutation and loss of heterozygosity of NF1 or somatic biallelic loss of NF1
• Germline CBL mutation and loss of heterozygosity of CBL, or somatic mutation(s) in CBL§
• Germline mutations (indicating Noonan syndrome) need to be excluded. §Occasional cases with heterozygous splice site mutations.
• Performance Level

You may not qualify if:

• Patients cannot have a known allergy to any of the drugs used in the study.
• Patients cannot have a systemic fungal, bacterial, viral, or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.
• Patients cannot have a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
• Patients cannot have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.
• Patients cannot have a clinical or molecular diagnosis of Noonan syndrome. Note: patients with either neurofibromatosis type 1 or Casitas B-lineage lymphoma (CBL) syndrome (also known as Noonan-like syndrome), are eligible to enroll. Patients with Down syndrome are excluded from the study.
• Patient cannot have had prior use of hematopoietic growth factors, biologics (anti-neoplastic agent), or XRT.
• Patients cannot be taking any medications for treatment of left ventricular systolic dysfunction.
• Patients cannot have a history of or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
• Patients cannot have had prior use of any MEK inhibitor.

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead

Study Sites (19)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

RECRUITING

Children's Hospital Los Angeles

Los Angeles, California, 900027, United States

RECRUITING

University of California San Francisco

San Francisco, California, 94158, United States

RECRUITING

Children's Hospital of Colorado

Denver, Colorado, 80045, United States

RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

RECRUITING

University of Miami

Miami, Florida, 33136, United States

RECRUITING

Children's Hospital of Atlanta

Atlanta, Georgia, 30322, United States

RECRUITING

Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Indiana University/Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

RECRUITING

Sidney Kimmel Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

RECRUITING

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

RECRUITING

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Oregon Health & Science University

Portland, Oregon, 97239, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

St. Jude Children's Research Hospital Memphis

Memphis, Tennessee, 38105, United States

RECRUITING

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98105, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Juvenile; Neurofibromatosis 1

Interventions

trametinib; Azacitidine; fludarabine; fludarabine phosphate; Injections; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Drug Administration Routes; Drug Therapy; Therapeutics; Arabinonucleosides

Central Study Contacts

Ellynore Florendo

CONTACT

323-361-3022; eflorendo@chla.usc.edu

Suganya Rajendran

CONTACT

323-361-8835; srajendran@chla.usc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be concurrently enrolled into both the lower-risk and high-risk arm starting at Dose Level 1. The rolling 6 design will be used during Phase 1 of the study to confirm the recommended Phase 2 dose, separately for the lower-risk and high-risk arm, with one possible de-escalation.

Study Record Dates

• First Submitted: April 25, 2023
• First Posted: May 9, 2023
• Study Start: October 11, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029
• Last Updated: April 15, 2026

Record last verified: 2025-06

Locations

US (19)