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

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.

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

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

IV over 30 minutes Days 6-10

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

IV over 3 hours Days 6-10

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

Ellynore Florendo

Ben Brookhart

Jaime Stokke, MD

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.

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.

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.

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)

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

Therapeutic Advances in Childhood Leukemia Consortium

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia	NCT05849662	Leukemia, Juven... JMML JCML Neurofibromatos... CBL Syndrome	Trametinib Azacitidine Fludarabine Cytarabine	1 Month - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia	NCT05849662	Leukemia, Juven... JMML JCML Neurofibromatos... CBL Syndrome	Trametinib Azacitidine Fludarabine Cytarabine	1 Month - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

Spots Global Cancer Trial Database for leukemia, juvenile myelomonocytic