A Phase 2 Study of the MEK Inhibitor Trametinib (NSC# 763093) in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

  • End date
    Mar 31, 2027
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 21 September 2022
ct scan
white blood cell count
absolute neutrophil count
ejection fraction
monoclonal antibodies
biologic agent
measurable disease
total serum bilirubin
growth factor
transplant conditioning
hematopoietic growth factors
tumor cells
chromosomal abnormality


This phase II trial studies how well trametinib works in treating patients with juvenile myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.



I. To determine the objective response rate to trametinib in children with recurrent or refractory juvenile myelomonocytic leukemia (JMML).


I. To further define and describe the toxicities of single agent trametinib in children with recurrent or refractory JMML.

II. To further characterize the pharmacokinetics of trametinib in children with recurrent or refractory JMML.

III. To prospectively evaluate mutant allele burden as a marker of disease activity in JMML.

IV. To measure the rate of complete responses in children with recurrent or refractory JMML.

V. To measure the duration of response among responders.


I. To describe the distribution of JMML diagnostic criteria in children with recurrent or refractory JMML.


Patients receive trametinib orally (PO) once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and may undergo a bone marrow aspiration or biopsy at baseline, on day 28 of cycles 1 and 2, at all subsequent odd numbered cycles, and at end of treatment.

After completion of study treatment, patients are followed up annually for up to 5 years.

Condition Juvenile Myelomonocytic Leukemia, Neurofibromatosis Type 1
Treatment laboratory biomarker analysis, computed tomography, magnetic resonance imaging, pharmacological study, Trametinib, Bone Marrow Aspiration and Biopsy
Clinical Study IdentifierNCT03190915
SponsorNational Cancer Institute (NCI)
Last Modified on21 September 2022


Yes No Not Sure

Inclusion Criteria

Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease; the diagnosis is made based on the following criteria
Patients must be >= 1 month and < 22 years of age at the time of study entry
JMML category 1 (all of the following): the diagnostic criteria must include all features in category 1 and EITHER (i) one of the features in category 2 OR (ii) two features from category 3 to make the diagnosis
> 1000 (1 x 10^9/uL) circulating monocytes
< 20% blasts in the bone marrow or peripheral blood
Absence of the t(9;22) or BCR/ABL fusion gene
JMML category 2 (at least one of the following if at least two category 3
Somatic mutation in RAS or PTPN11
criteria are not present)
Clinical diagnosis of NF1 or NF1 gene mutation
Homozygous mutation in CBL
Monosomy 7
Circulating myeloid precursors
JMML category 3 (at least two of the following if no category 2 criteria are
White blood cell count, > 10 000 (10 x 10^9/ uL)
Increased hemoglobin F for age
Clonal cytogenetic abnormality
GM-CSF hypersensitivity
Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment
Patients with refractory or relapsed JMML must have had at least one cycle of
Myelosuppressive chemotherapy: patients must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea
intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid
Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy
(DNA) demethylating agent with persistence of disease, defined by clinical
symptoms or the presence of a clonal abnormality; frontline therapy is defined
Biologic (anti-neoplastic agent): at least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
Monoclonal antibodies
agents: fludarabine, cytarabine, or any anthracycline but specifically
as one cycle of intravenous chemotherapy that includes any of the following
At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines
excludes oral 6-mercaptopurine; frontline therapy will also include any
At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody
conditioning regimen as part of a stem cell transplant; patients who transform
to AML at any point with more than 20% blasts are not eligible for this trial
>= 2 weeks must have elapsed since local palliative external radiation therapy (XRT) (small port)
>= 6 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if traumatic brain injury (TBI) was received
>= 4 weeks must have elapsed if other substantial bone marrow irradiation was given
Patients must not be known to be refractory to red blood cell or platelet transfusions
Hematopoietic growth factors: at least 14 days after the last dose of a
long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting
Age: Maximum serum creatinine (mg/dL)
growth factor; for agents that have known adverse events occurring beyond 7
month to < 6 months: 0.4 (male) 0.4 (female)
days after administration, this period must be extended beyond the time during
months to < 1 year: 0.5 (male) 0.5 (female)
which adverse events are known to occur
to < 2 years: 0.6 (male) 0.6 (female)
to < 6 years: 0.8 (male) 0.8 (female)
to < 10 years: 1 (male) 1 (female)
to < 13 years: 1.2 (male) 1.2 (female)
to < 16 years: 1.5 (male) 1.4 (female)
>= 16 years: 1.7 (male) 1.4 (female)
Stem cell transplant or rescue without TBI: no evidence of active graft versus
Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA)
(vs.) host disease and >= 3 months must have elapsed since transplant; >= 4
Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs
weeks must have elapsed since any donor lymphocyte infusion
Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (=< 135 U/L) (within 7 days prior to enrollment) (for the purpose of this study, the ULN for SGPT is 45 U/L)
Serum albumin >= 2 g/dL (within 7 days prior to enrollment)

Exclusion Criteria

Patients who are pregnant or breast-feeding are not eligible for this study as there is yet no available information regarding human fetal or teratogenic toxicities; negative pregnancy tests must be obtained in girls who are post-menarchal; patients of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; women of childbearing potential should be advised to use effective contraception for 4 months after the last dose of trametinib; trametinib may also potentially be secreted in milk and therefore breastfeeding women are excluded; female patients should not breastfeed during treatment with trametinib, and for 4 months following the last dose; male patients must use a condom during intercourse and agree not to father a child during therapy and for 4 months following discontinuation of trametinib to avoid unnecessary exposure of trametinib to the fetus
Concomitant Medications
Corticosteroids: patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
Note: hydrocortisone used as a pre-medication to prevent transfusion related reactions is not considered a concomitant corticosteroid
Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible (except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
Anti-graft versus host disease (GVHD) or agents to prevent organ rejection post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
Cardiac medications: any medications for treatment of left ventricular systolic dysfunction
Patients who have an uncontrolled infection are not eligible
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Patients with a history of hepatic sinusoid obstructive syndrome (veno-occlusive disease) within the prior 3 months are not eligible
Patients with a history of or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible
Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension
Patients with uncontrolled systemic disease(s) such as hypertension or diabetes mellitus are not eligible; blood pressure must be =< the 95th percentile for age, height, and gender
Patients with a history of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib are not eligible
Patients with a clinical diagnosis of Noonan syndrome are not eligible; Note: patients with Casitas B-lineage lymphoma (CBL) syndrome, also known as Noonan-like syndrome, are eligible to enroll
Investigational drugs: patients who are currently receiving another
investigational drug are not eligible
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