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

NCT ID: NCT05849662

Last Updated: 2024-11-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 58 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-10-11
• Study Completion Date: 2029-12-31

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.

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lower-risk patients

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

Group Type: EXPERIMENTAL

Trametinib

Intervention Type: 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

Azacitidine

Intervention Type: 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

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.

Group Type: EXPERIMENTAL

Trametinib

Intervention Type: 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

Azacitidine

Intervention Type: 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

Fludarabine

Intervention Type: DRUG

IV over 30 minutes Days 6-10

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

Cytarabine

Intervention Type: DRUG

IV over 3 hours Days 6-10

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Fludarabine

IV over 30 minutes Days 6-10

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

Intervention Type: DRUG

Cytarabine

IV over 3 hours Days 6-10

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

Intervention Type: DRUG

Other Intervention Names

GSK1120212B; TMT212-NXA; 5-azacytidine; Vidaza; FLUDARA FOR INJECTION; Cytosine arabinoside; Ara-C; Cytosar

Eligibility Criteria

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.

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Therapeutic Advances in Childhood Leukemia Consortium

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Site Status: RECRUITING

University of California San Francisco

San Francisco, California, United States

Site Status: RECRUITING

Children's National Medical Center

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

Site Status: RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Ellynore Florendo

Role: CONTACT

eflorendo@chla.usc.edu

323-361-3022

Ben Brookhart

Role: CONTACT

bbrookhart@chla.usc.edu

323-361-5429

Facility Contacts

Jaime Stokke, MD

Role: primary

Elliot Stieglitz, MD

Role: primary

Reuven Schore, MD

Role: primary

Lauren Pommert, MD

Role: primary

Other Identifiers

T2020-004

Identifier Type: -

Identifier Source: org_study_id