Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
NCT ID: NCT03190915
Last Updated: 2025-10-29
Study Results
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View full resultsBasic Information
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ACTIVE_NOT_RECRUITING
PHASE2
10 participants
INTERVENTIONAL
2018-09-09
2026-10-03
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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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.
Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration or biopsy
Trametinib
Given PO
Interventions
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Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration or biopsy
Trametinib
Given PO
Other Intervention Names
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Eligibility Criteria
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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
* 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
* 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
1 Month
21 Years
ALL
No
Sponsors
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Children's Oncology Group
NETWORK
National Cancer Institute (NCI)
NIH
Responsible Party
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Principal Investigators
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Elliot Stieglitz
Role: PRINCIPAL_INVESTIGATOR
Children's Oncology Group
Locations
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Children's Hospital of Alabama
Birmingham, Alabama, United States
Phoenix Childrens Hospital
Phoenix, Arizona, United States
Arkansas Children's Hospital
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
Downey, California, United States
Loma Linda University Medical Center
Loma Linda, California, United States
Kaiser Permanente-Oakland
Oakland, California, United States
Children's Hospital of Orange County
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States
UCSF Medical Center-Mission Bay
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, United States
Connecticut Children's Medical Center
Hartford, Connecticut, United States
Alfred I duPont Hospital for Children
Wilmington, Delaware, United States
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Nemours Children's Clinic-Jacksonville
Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
Nicklaus Children's Hospital
Miami, Florida, United States
Arnold Palmer Hospital for Children
Orlando, Florida, United States
Nemours Children's Hospital
Orlando, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta, Georgia, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
Saint Jude Midwest Affiliate
Peoria, Illinois, United States
Riley Hospital for Children
Indianapolis, Indiana, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
C S Mott Children's Hospital
Ann Arbor, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, United States
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park, New York, United States
Mount Sinai Hospital
New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, United States
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Dayton Children's Hospital
Dayton, Ohio, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Oregon Health and Science University
Portland, Oregon, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, United States
Saint Jude Children's Research Hospital
Memphis, Tennessee, United States
The Children's Hospital at TriStar Centennial
Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas
Austin, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, United States
Methodist Children's Hospital of South Texas
San Antonio, Texas, United States
Primary Children's Hospital
Salt Lake City, Utah, United States
Seattle Children's Hospital
Seattle, Washington, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States
Countries
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References
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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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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NCI-2017-00921
Identifier Type: REGISTRY
Identifier Source: secondary_id
ADVL1521
Identifier Type: OTHER
Identifier Source: secondary_id
ADVL1521
Identifier Type: OTHER
Identifier Source: secondary_id
NCI-2017-00921
Identifier Type: -
Identifier Source: org_study_id
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