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Protocol Details

A Phase 2 Study of the MEK inhibitor Trametinib (IND #119346, NSC# 763093) in Children with Relapsed or Refractory Juvenile Myelomonocytic Leukemia

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Recruitment has not started
Gender: Male & Female
Min Age: 2 Years
Max Age: 21 Years

Referral Letter Required


Population Exclusion(s)

Pregnant Women


Neurofibromatosis 1;
Protein Kinase Inhibitors;
Enzyme Inhibitors;
myeloproliferative disorder

Recruitment Keyword(s)



Leukemia, Myelomonocytic, Juvenile;
Myelodysplastic-Myeloproliferative Diseases

Investigational Drug(s)


Investigational Device(s)



Drug: trametinib

Supporting Site

National Cancer Institute


JMML is a cancer of the blood. In JMML, the bone marrow makes large numbers of abnormal white blood cells. These abnormal blood cells crowd out the healthy, normal cells that belong in the bone marrow. These abnormal white cells can flood the blood and invade vital organs, including the spleen, lung, GI tract, and skin. Studies have found changes in the genes of people with JMML. Trametinib is a drug that works to target some of these changes found in JMML cells.


To find out what effects trametinib has on people with JMML.


People ages 2-21 with JMML that has come back after or did not respond to chemotherapy.


Participants will be screened with their medical history.

Participants will take the study drug in 28-day cycles. They will take the drug by mouth.

Participants will keep a diary of when they take the study drug each day.

Participants will have tests after Cycles 1, 2, 4, and every second cycle after. Some tests may be repeated during cycles. Tests may include:

Physical exam

Blood tests

Skin exam. Photos or biopsies may be taken of participants lesions.

Eye exams

Tests to monitor heart function

Cheek swabs

Optional bone marrow sample

CT or MRI scans

Participants will have up to 12 treatment cycles. They will stop treatment if they get bad side effects or their JMML gets worse. They will have follow-up exams and tests after they finish treatment.

Researchers will reach out to participants every year for 5 years after treatment to find out about their health.

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-Age: Patients must be >= 1 month and < 22 years of age at the time of study entry.

-Diagnosis: 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.

-JMML Category 1 (all of the following):


--1000 (1x10^9/microLiters) circulating monocytes

--< 20% Blasts in the bone marrow or peripheral blood

--Absence of the t(9;22) or BCR/ABL fusion gene

*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.

-JMML Category 2 (at least one of the following if at least two Category 3 criteria are not present):

--Somatic mutation in RAS or PTPN11

--Clinical diagnosis of NF1 or NF1 gene mutation

--Homozygous mutation in CBL

--Monosomy 7

-JMML Category 3 (at least two of the following if no Category 2 criteria are met):

--Circulating myeloid precursors

--White blood cell count, >10 000 (10x10^9 microLiters)

--Increased Hemoglobin F for age

--Clonal cytogenetic abnormality

--GM-CSF hypersensitivity

-Disease Status for Juvenile Myelomonocytic Leukemia (JMML) Patients:

-Patients with refractory or relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a DNA demethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality. Frontline therapy is defined as one cycle of intravenous chemotherapy that includes of any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine. Frontline therapy will also include any 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.

-Performance Level

--Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to 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.

-Prior Therapy

Patients must have fully recovered from the acute toxic effects of all prior therapy, or radiotherapy prior to study enrollment.

--a. 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.

Note: Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy.

--b. 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 growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.

--c. 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.

--d. Monoclonal antibodies:

--i. At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines.

--ii. At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody. (See posting of half-lives for commonly used monoclonal antibodies on the DVL homepage

-e. Radiotherapy:

--i. >= 2 weeks must have elapsed since local palliative XRT (small port)

--ii. >= 6 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if TBI was received

--iii. >= 4 weeks must have elapsed if other substantial bone marrow irradiation was given.

-Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and >= 3 months must have elapsed since transplant. >= 4 weeks must have elapsed since any donor lymphocyte infusion.

-Organ Function Requirements

--Adequate Bone Marrow Function Defined As:

---Patients must not be known to be refractory to red blood cell or platelet transfusions.

--Adequate Renal Function Defined As:

--Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows:

Age<TAB><TAB><TAB><TAB><TAB>Maximum Serum Creatinine (mg/dL)


1 month to < 6 months<TAB>0.4<TAB><TAB>0.4

6 months to < 1 year<TAB><TAB>0.5<TAB><TAB>0.5

1 to < 2 years<TAB><TAB><TAB>0.6<TAB><TAB>0.6

2 to < 6 years<TAB><TAB><TAB>0.8<TAB><TAB>0.8

6 to < 10 years<TAB><TAB> 1<TAB><TAB> 1

10 to < 13 years<TAB><TAB>1.2<TAB><TAB>1.2

13 to < 16 years<TAB><TAB>1.5<TAB><TAB>1.4

>= 16 years<TAB><TAB><TAB>1.7<TAB><TAB>1.4

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

-Adequate Liver Function Defined As:

--Total bilirubin <= 1.5 x upper limit of normal (ULN) for age

--SGPT (ALT) <= 3 x ULN (135 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)

--Serum albumin >= 2 g/dL.

-Adequate Cardiac Function Defined As:

--Shortening fraction of >= 27% by echocardiogram OR Ejection fraction of >= 50% by MUGA

--Corrected QT (QTcB) interval <450 msecs

-Patients must be able to swallow tablets or liquid; use of a nasogastric or G tube is also allowed.


Important note: The exclusion criteria listed below are interpreted literally and cannot be waived. All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient s medical/research record. These source documents must be available for verification at the time of audit.

-Pregnancy or Breast-Feeding

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. 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.

-Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.

-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-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.

-Infection: 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.

-Veno-occlusive Disease: 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.

--Ocular Conditions: Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension.

-Systemic Diseases: 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.

- Allergic Reactions: Patients with a history of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib are not eligible.

-Noonan Syndrome: 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.

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Not Provided

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Principal Investigator

Referral Contact

For more information:

Srivandana Akshintala, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CRC BG RM 1-5750
(240) 858-3448

Srivandana Akshintala, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CRC BG RM 1-5750
(240) 858-3448

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office

Clinical Trials Number:


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