RECRUITING

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

Conditions

Leukemia, Juvenile Myelomonocytic JMML JCML Neurofibromatosis 1 CBL Syndrome

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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)

Quick Facts

Study Start:2024-10-11

Study Completion:2029-12

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05849662

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:1 Month to 21 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT

Inclusion Criteria	Exclusion Criteria
* 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. * 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. * Karnofsky \> 50% for patients ≥ 16 years of age * Lansky \> 50% for patients \< 16 years of age. * 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. * 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: * 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. * 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. * Ejection fraction of \> or = to 50% by echocardiogram, OR * Ejection fraction of \> or = to 50% by radionuclide angiogram (MUGA). * 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.	* 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.

Inclusion Criteria

Exclusion Criteria

* 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.
* 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.
* Karnofsky \> 50% for patients ≥ 16 years of age
* Lansky \> 50% for patients \< 16 years of age.
* 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.
* 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:
* 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.
* 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.
* Ejection fraction of \> or = to 50% by echocardiogram, OR
* Ejection fraction of \> or = to 50% by radionuclide angiogram (MUGA).
* 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.

* 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.

Contacts and Locations

Study Contact

Ellynore Florendo

CONTACT

323-361-3022

eflorendo@chla.usc.edu

Ben Brookhart

CONTACT

323-361-5429

bbrookhart@chla.usc.edu

Study Locations (Sites)

Children's Hospital Los Angeles

Los Angeles, California, 900027

United States

University of California San Francisco

San Francisco, California, 94158

United States

Children's National Medical Center

Washington, District of Columbia, 20010

United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229

United States

Collaborators and Investigators

Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2024-10-11

Study Completion Date2029-12

Study Record Updates

Study Start Date2024-10-11

Study Completion Date2029-12

Terms related to this study

Additional Relevant MeSH Terms

Leukemia, Juvenile Myelomonocytic
JMML
JCML
Neurofibromatosis 1
CBL Syndrome