Summary

Eligibility
for people ages 1 month to 21 years (full criteria)
Location
at San Francisco, California and other locations
Dates
study started
completion around

Description

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.

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)

Details

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.

Keywords

Leukemia, Juvenile Myelomonocytic, JMML, JCML, Neurofibromatosis 1, CBL Syndrome, Leukemia, Neurofibromatoses, Leukemia, Myelomonocytic, Juvenile, Cytarabine, Fludarabine, Azacitidine, Trametinib

Eligibility

You can join if…

Open to people ages 1 month to 21 years

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.

You CAN'T join 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.

Locations

  • UCSF accepting new patients
    San Francisco California 94158 United States
  • Children's Hospital Los Angeles accepting new patients
    Los Angeles California 900027 United States
  • Cincinnati Children's Hospital Medical Center accepting new patients
    Cincinnati Ohio 45229 United States
  • Children's National Medical Center accepting new patients
    Washington District of Columbia 20010 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
ID
NCT05849662
Phase
Phase 1/2 research study
Study Type
Interventional
Participants
Expecting 58 study participants
Last Updated