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Leukemia, Juvenile MyelomonocyticPhase 1/2NCT05849662

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

A Phase 1/2 study testing Trametinib, Azacitidine and Fludarabine in people with Leukemia, Juvenile Myelomonocytic and JMML, run by Therapeutic Advances in Childhood Leukemia Consortium at 21 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 1 month to 21 years
Conditions the study is for
Leukemia, Juvenile Myelomonocytic, JMML, JCML
What is being tested?
Trametinib, Azacitidine and Fludarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
58 participants
Where
21 sitesUnited States
Study dates
11 Oct 2024to Dec 2029
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 month to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

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

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

21 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Ellynore Florendo contact

323-361-3022

eflorendo@chla.usc.edu

Suganya Rajendran contact

323-361-8835

srajendran@chla.usc.edu

21 sites in 1 country

United States21 sites, 21 recruiting

  • C.S. Mott Children's Hospital

    Ann Arbor, Michigan, 48109

    Jennifer Agrusa, MD

    Recruiting

  • Children's Hospital of Atlanta

    Atlanta, Georgia, 30322

    Melinda Pauly, MD

    Recruiting

  • Sidney Kimmel Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21231

    Stacy Cooper, MD

    Recruiting

  • Levine Children's Hospital at Carolinas

    Charlotte, North Carolina, 28203

    Joel Kalpan, MD

    Recruiting

  • Lurie Children's Hospital of Chicago

    Chicago, Illinois, 60611

    Jenna Rossoff, MD

    Recruiting

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

    Lauren Pommert, MD

    Recruiting

  • Children's Medical Center

    Dallas, Texas, 75235

    Tamra Slone, MD

    Recruiting

  • Children's Hospital of Colorado

    Denver, Colorado, 80045

    Kelly Faulk, MD

    Recruiting

  • Indiana University/Riley Hospital for Children

    Indianapolis, Indiana, 46202

    Sandeep Batra, MD

    Recruiting

  • Children's Mercy Hospital

    Kansas City, Missouri, 64108

    Keith August, MD

    Recruiting

  • Children's Hospital Los Angeles

    Los Angeles, California, 900027

    Jaime Stokke, MD

    Recruiting

  • St. Jude Children's Research Hospital Memphis

    Memphis, Tennessee, 38105

    Seth Karol, MD

    Recruiting

  • University of Miami

    Miami, Florida, 33136

    Julio Barredo, MD

    Recruiting

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

    Kavitha Ramaswamy, MD

    Recruiting

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

    Sarah Tasian, MD

    Recruiting

  • Phoenix Children's Hospital

    Phoenix, Arizona, 85016

    Dana Salzberg, MD

    Recruiting

  • Oregon Health & Science University

    Portland, Oregon, 97239

    Bill Chang, MD

    Recruiting

  • Primary Children's Hospital

    Salt Lake City, Utah, 84113

    Mallorie Heneghan, MD

    Recruiting

  • University of California San Francisco

    San Francisco, California, 94158

    Elliot Stieglitz, MD

    Recruiting

  • Seattle Children's Hospital

    Seattle, Washington, 98105

    Mignon Loh, MD

    Recruiting

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

    Reuven Schore, MD

    Recruiting

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Trametinib, Azacitidine, Fludarabine, Cytarabine
Medical subject headings
Leukemia, Myelomonocytic, Juvenile, Neurofibromatosis 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TrametinibDrug

    Also called GSK1120212B, TMT212-NXA

    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

  • AzacitidineDrug

    Also called 5-azacytidine, Vidaza

    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

  • FludarabineDrug

    Also called FLUDARA FOR INJECTION

    IV over 30 minutes Days 6-10

    30 mg/m2/day (1mg/kg if <12 kg)

  • CytarabineDrug

    Also called Cytosine arabinoside, Ara-C, Cytosar

    IV over 3 hours Days 6-10

    2000 mg/m2/day (67mg/kg if <12 kg)

Study groups in NCT05849662
Study groupRoleWhat they receive
Lower-risk patientsExperimentalLower-risk patients are defined as having a mutational burden of one clonal alteration AND a low DNA methylation classification.
Receives: Drug: Trametinib; Drug: Azacitidine
High-risk patientsExperimentalHigh-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.
Receives: Drug: Trametinib; Drug: Azacitidine; Drug: Fludarabine; Drug: Cytarabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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)

  2. 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.

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 May 2023
  2. Study start11 Oct 2024
  3. Primary completionDec 2028 (estimated)
  4. Study completionDec 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
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.
Masking
None (open label)
Enrolment
58 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05849662
Sponsor's protocol ID
T2020-004
Status last verified
Aug 2026
First submitted
25 Apr 2023
Last updated
4 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Trametinib, Azacitidine and Fludarabine in people with Leukemia, Juvenile Myelomonocytic and JMML, run by Therapeutic Advances in Childhood Leukemia Consortium at 21 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 44 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 4 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 21 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Ellynore Florendo (323-361-3022, eflorendo@chla.usc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

To determine the safety of combining trametinib with azacitidine for patients with newly diagnosed lower-risk JMML. (time frame: 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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05849662.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2026; AzTrials last refreshed its copy on 26 Oct 2026.

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