Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Juvenile Myelomonocytic Leukemia; Neurofibromatosis Type 1
• Intervention / Treatment: Drug: Trametinib; Procedure: Bone Marrow Aspiration and Biopsy

Detailed Description

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVE:

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

OUTLINE:

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 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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Kaiser Permanente Downey Medical Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children
    • Tampa, Florida, United States, 33607
      • Saint Joseph's Hospital/Children's Hospital-Tampa
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta - Arthur M Blank Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
    • Peoria, Illinois, United States, 61637
      • OSF Children's Hospital of Illinois
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center/Levine Cancer Institute
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Saint Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must be >= 1 month and < 22 years of age at the time of study entry

• 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): 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

    • Splenomegaly
    • > 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 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 (10 x 10^9/ uL)
    • Increased hemoglobin F for age
    • Clonal cytogenetic abnormality
    • GM-CSF hypersensitivity
• Patients with refractory or relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (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 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
• 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

  • 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
  • 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
  • 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:

    • At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines
    • At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody

  • Radiotherapy:

    • >= 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
  • Stem cell transplant or rescue without TBI: no evidence of active graft versus (vs.) host disease and >= 3 months must have elapsed since transplant; >= 4 weeks must have elapsed since any donor lymphocyte infusion
• Patients must not be known to be refractory to red blood cell or platelet transfusions

• 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):

  • Age: Maximum serum creatinine (mg/dL)

    • 1 month to < 6 months: 0.4 (male) 0.4 (female)
    • 6 months to < 1 year: 0.5 (male) 0.5 (female)
    • 1 to < 2 years: 0.6 (male) 0.6 (female)
    • 2 to < 6 years: 0.8 (male) 0.8 (female)
    • 6 to < 10 years: 1 (male) 1 (female)
    • 10 to < 13 years: 1.2 (male) 1.2 (female)
    • 13 to < 16 years: 1.5 (male) 1.4 (female)
    • >= 16 years: 1.7 (male) 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• 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)
• Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA)
• Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs
• Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed

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
  • 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-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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (trametinib); Patients receive trametinib PO 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 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.	Drug: Trametinib; Given PO; Other Names: GSK1120212; JTP-74057; MEK Inhibitor GSK1120212; GSK 1120212; GSK-1120212; GSK 212; GSK-212; GSK212; JTP 74057; JTP74057; Procedure: Bone Marrow Aspiration and Biopsy; Undergo bone marrow aspiration or biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response	Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design. A responder is defined as a patient who achieves a best response of PR or CR on the study prior to having an overall response of PD; all others will be considered non-responders. The definitions of response are based on a publication (PMID: 25552679) entitled "Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia". Patients can be categorized as having experienced complete remission, partial remission, stable disease, or progressive disease based on a combination of clinical and molecular variables.	12 cycles (1 cycle = 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response	Complete Response rates will be calculated as the percent of evaluable patients who had an overall best response of Complete Response, and confidence intervals will be constructed accounting for the two-stage design.	12 cycles (1 cycle = 28 days)
Incidence of Adverse Events	Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will report the percentage of patients within each disease stratum who experienced a grade 3 or higher toxicity with attribution of possible, probable, or definite while on protocol therapy or within 30 days of the last dose of therapy.	Up to cycle 12 (1 cycle = 28 days)
Pharmacokinetic (PK) Parameters of Trametinib	A descriptive analysis of pharmacokinetic parameters of trametinib will be performed to define systemic exposure, drug clearance, Trametinib concentrations, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).	Up to cycle 12 (1 cycle = 28 days)
Trametinib Concentrations	Will be measured by mass spectrometry. Will be analyzed descriptively. Values will be summarized with means and standard deviations.	Up to cycle 12 (1 cycle = 28 days)
Mutant Allele Burden	Will be measured by next-generation sequencing. The percent change in mutant allele burden will be analyzed descriptively. Values will be summarized with means and standard deviations.	Up to cycle 12 (1 cycle = 28 days)
Duration of Response	Duration of response (Aim 1.2.5) will be defined as the time from first occurrence of PR or CR until the first occurrence of PD, death, or going off study. Patients who progress will be considered to have had an event, patients who die prior to progressing will be considered to have a competing event, and patients who go off study prior to progressing will be censored at time of last contact. The analysis will be done using the method of Gray.	Up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mutant allele burden	Will be measured by mass spectrometry. Will be analyzed descriptively. Values will be summarized with means, standard deviations, and 95% confidence intervals.	Up to cycle 12 (1 cycle = 28 days)
Trametinib concentrations	Will be measured by mass spectrometry. Will be analyzed descriptively. Values will be summarized with means, standard deviations, and 95% confidence intervals.	Up to cycle 12 (1 cycle = 28 days)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Children's Oncology Group
• Investigators: Principal Investigator: Elliot Stieglitz, Children's Oncology Group

Publications and helpful links

General Publications

• McCullough KB, Kuhn AK, Patnaik MM. Treatment advances for pediatric and adult onset neoplasms with monocytosis. Curr Hematol Malig Rep. 2021 Jun;16(3):256-266. doi: 10.1007/s11899-021-00622-8. Epub 2021 Mar 16.
• Stieglitz E, Lee AG, Angus SP, Davis C, Barkauskas DA, Hall D, Kogan SC, Meyer J, Rhodes SD, Tasian SK, Xuei X, Shannon K, Loh ML, Fox E, Weigel BJ. Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children's Oncology Group. Cancer Discov. 2024 Sep 4;14(9):1590-1598. doi: 10.1158/2159-8290.CD-23-1376.

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2018
• Primary Completion (Actual): March 31, 2023
• Study Completion (Estimated): October 3, 2026

Study Registration Dates

• First Submitted: June 16, 2017
• First Submitted That Met QC Criteria: June 16, 2017
• First Posted (Actual): June 19, 2017

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 23, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Heredodegenerative Disorders, Nervous System; Nerve Sheath Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Leukemia; Neurofibroma; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Neurofibromatoses; Leukemia, Myelomonocytic, Juvenile; Neurofibromatosis 1; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Biopsy; trametinib; omipalisib
• Other Study ID Numbers: NCI-2017-00921 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180886 (U.S. NIH Grant/Contract); ADVL1521 (Other Identifier: CTEP); U54CA196519 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No