Trial Title:
A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia
NCT ID:
NCT05849662
Condition:
Leukemia, Juvenile Myelomonocytic
JMML
JCML
Neurofibromatosis 1
CBL Syndrome
Conditions: Official terms:
Leukemia
Neurofibromatoses
Neurofibromatosis 1
Leukemia, Myelomonocytic, Juvenile
Cytarabine
Fludarabine
Azacitidine
Trametinib
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention 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.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trametinib
Description:
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
Arm group label:
High-risk patients
Arm group label:
Lower-risk patients
Other name:
GSK1120212B
Other name:
TMT212-NXA
Intervention type:
Drug
Intervention name:
Azacitidine
Description:
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
Arm group label:
High-risk patients
Arm group label:
Lower-risk patients
Other name:
5-azacytidine
Other name:
Vidaza
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
IV over 30 minutes Days 6-10
30 mg/m2/day (1mg/kg if <12 kg)
Arm group label:
High-risk patients
Other name:
FLUDARA FOR INJECTION
Intervention type:
Drug
Intervention name:
Cytarabine
Description:
IV over 3 hours Days 6-10
2000 mg/m2/day (67mg/kg if <12 kg)
Arm group label:
High-risk patients
Other name:
Cytosine arabinoside
Other name:
Ara-C
Other name:
Cytosar
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.
Criteria for 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.
Gender:
All
Minimum age:
1 Month
Maximum age:
21 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Children's Hospital Los Angeles
Address:
City:
Los Angeles
Zip:
900027
Country:
United States
Status:
Recruiting
Contact:
Last name:
Jaime Stokke, MD
Facility:
Name:
University of California San Francisco
Address:
City:
San Francisco
Zip:
94158
Country:
United States
Status:
Recruiting
Contact:
Last name:
Elliot Stieglitz, MD
Facility:
Name:
Children's National Medical Center
Address:
City:
Washington
Zip:
20010
Country:
United States
Status:
Recruiting
Contact:
Last name:
Reuven Schore, MD
Facility:
Name:
Cincinnati Children's Hospital Medical Center
Address:
City:
Cincinnati
Zip:
45229
Country:
United States
Status:
Recruiting
Contact:
Last name:
Lauren Pommert, MD
Start date:
October 11, 2024
Completion date:
December 2029
Lead sponsor:
Agency:
Therapeutic Advances in Childhood Leukemia Consortium
Agency class:
Other
Source:
Therapeutic Advances in Childhood Leukemia Consortium
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05849662
