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

Risk Stratified Treatment for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase I/II Non-randomized Study of Trametinib and Azacitidine With or Without Chemotherapy (IND #164058)

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.

Study Overview

• Status: Recruiting
• Conditions: Neurofibromatosis 1; JMML; Leukemia, Juvenile Myelomonocytic; JCML; CBL Syndrome
• Intervention / Treatment: Drug: Trametinib; Drug: Azacitidine; Drug: Fludarabine; Drug: Cytarabine

Detailed Description

Primary Objectives:

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

Dosing:

Patients with newly diagnosed lower-risk JMML will be treated with daily azacitidine for 5 days in combination with daily trametinib for 28 days per course for up to 12 courses. Patients with newly diagnosed high-risk JMML will be treated with daily azacitidine, fludarabine, and cytarabine for 5 days in combination with daily trametinib for 28 days per course for up to 2 courses.

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ellynore Florendo; Phone Number: 323-361-3022; Email: eflorendo@chla.usc.edu
• Study Contact Backup: Name: Suganya Rajendran; Phone Number: 323-361-8835; Email: srajendran@chla.usc.edu

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Recruiting
      • Phoenix Children's Hospital
      • Contact: Dana Salzberg, MD
  • California
    • Los Angeles, California, United States, 900027
      • Recruiting
      • Children's Hospital Los Angeles
      • Contact: Jaime Stokke, MD
    • San Francisco, California, United States, 94158
      • Recruiting
      • University of California San Francisco
      • Contact: Elliot Stieglitz, MD
  • Colorado
    • Denver, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital of Colorado
      • Contact: Kelly Faulk, MD
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Reuven Schore, MD
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Contact: Julio Barredo, MD
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Children's Hospital of Atlanta
      • Contact: Melinda Pauly, MD
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Lurie Children's Hospital of Chicago
      • Contact: Jenna Rossoff, MD
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University/Riley Hospital for Children
      • Contact: Sandeep Batra, MD
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Recruiting
      • Sidney Kimmel Cancer Center at Johns Hopkins
      • Contact: Stacy Cooper, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • C.S. Mott Children's Hospital
      • Contact: Jennifer Agrusa, MD
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Recruiting
      • Children's Mercy Hospital
      • Contact: Keith August, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Kavitha Ramaswamy, MD
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Lauren Pommert, MD
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health & Science University
      • Contact: Bill Chang, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Sarah Tasian, MD
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children's Research Hospital Memphis
      • Contact: Seth Karol, MD
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Recruiting
      • Primary Children's Hospital
      • Contact: Mallorie Heneghan, MD
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Mignon Loh, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

• Karnofsky > 50% for patients ≥ 16 years of age
• Lansky > 50% for patients < 16 years of age.

Prior Therapy

• No prior leukemia directed therapy is permitted with the exception of:

  1. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of trametinib.
  2. Cytoreduction with 6-mercaptopurine (6-MP) 6-MP can be initiated and continued for up to 72 hours prior to the start of trametinib.

  3. Intrathecal (IT) cytarabine, IT methotrexate or triple IT therapy (cytarabine, methotrexate and hydrocortisone) within 7 days of enrollment as part of a diagnostic evaluation.

     No prior hematopoietic stem cell transplant is permitted.

     Adequate Renal Function Defined as:

• Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below:

Maximum Serum Creatinine (mg/dL):

• 1 month to < 6 months old - Male: 0.4, Female 0.4
• 6 months to <1 year old - Male 0.5, Female 0.5
• 1 to < 2 years old - Male: 0.6, Female: 0.6
• 2 to < 6 years old - Male:0.8, Female: 0.8
• 6 to < 10 years old - Male: 1, Female: 1
• 10 to < 13 years old - Male: 1.2, Female: 1.2
• 13 to < 16 years old - Male: 1.5, Female: 1.4
• ≥ 16 years old - Male: 1.7, Female: 1.4 The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

Adequate Liver Function Defined as:

• Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age.
• The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia and will not be evaluable for hepatotoxicity. This must be reviewed and approved by the study chair or vice chair.

Adequate Cardiac Function Defined as:

• Ejection fraction of > or = to 50% by echocardiogram, OR
• Ejection fraction of > or = to 50% by radionuclide angiogram (MUGA).

Reproductive Function

• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lower-risk patients; Lower-risk patients are defined as having a mutational burden of one clonal alteration AND a low DNA methylation classification.	Drug: Trametinib; 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; Other Names: TMT212-NXA; GSK1120212B; Drug: Azacitidine; 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; Other Names: Vidaza; 5-azacytidine
Experimental: High-risk patients; 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; 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; Other Names: TMT212-NXA; GSK1120212B; Drug: Azacitidine; 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; Other Names: Vidaza; 5-azacytidine; Drug: Fludarabine; IV over 30 minutes Days 6-10 30 mg/m2/day (1mg/kg if <12 kg); Other Names: FLUDARA FOR INJECTION; Drug: Cytarabine; IV over 3 hours Days 6-10 2000 mg/m2/day (67mg/kg if <12 kg); Other Names: Ara-C; Cytosar; Cytosine arabinoside

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Collaborators and Investigators

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: April 25, 2023
• First Submitted That Met QC Criteria: May 4, 2023
• First Posted (Actual): May 9, 2023

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Heredodegenerative Disorders, Nervous System; Nerve Sheath Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Leukemia; Neurofibroma; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Neurofibromatoses; Leukemia, Myelomonocytic, Juvenile; Neurofibromatosis 1; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Drug Administration Routes; Drug Therapy; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Arabinonucleosides; Cytarabine; Azacitidine; Injections; trametinib; fludarabine; fludarabine phosphate
• Other Study ID Numbers: T2020-004

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No