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Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

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ClinicalTrials.gov Identifier: NCT03190915
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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

Condition or disease Intervention/treatment Phase
Activating RAS Mutation Blasts Under 20 Percent of Bone Marrow Nucleated Cells Blasts Under 20 Percent of Peripheral Blood White Cells Juvenile Myelomonocytic Leukemia Monosomy 7 Neurofibromatosis Type 1 NF1 Gene Mutation PTPN11 Gene Mutation Splenomegaly Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Trametinib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

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 objective response rate to 12 cycles of trametinib in children with recurrent or refractory JMML.

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

VI. To measure the duration of response among responders.

TERTIARY OBJECTIVES:

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. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of the MEK Inhibitor Trametinib (NSC# 763093) in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
Actual Study Start Date : October 6, 2017
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 30, 2020


Arm Intervention/treatment
Experimental: Treatment (trametinib)
Patients receive trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist




Primary Outcome Measures :
  1. Objective response [ Time Frame: Up to 4 courses ]
    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.


Secondary Outcome Measures :
  1. Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to course 12 ]
    Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade.

  2. Pharmacokinetic (PK) parameters of trametinib [ Time Frame: Up to course 12 ]
    A descriptive analysis of pharmacokinetic parameters of trametinib will be performed to define systemic exposure, drug clearance, 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).


Other Outcome Measures:
  1. Mutant allele burden measured by mass spectrometry [ Time Frame: Up to course 12 ]
    Will be analyzed descriptively. Values will be summarized with means, standard deviations, and 95% confidence intervals.

  2. Trametinib concentrations measured by mass spectrometry [ Time Frame: Up to course 12 ]
    Will be analyzed descriptively. Values will be summarized with means, standard deviations, and 95% confidence intervals.



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Ages Eligible for Study:   1 Month to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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
  • 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
  • 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 or a serum creatinine based on age/gender as follows:

    • 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
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [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
  • 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; 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
  • Patients with a history of current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
  • Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension)
  • Uncontrolled systemic disease(s) such as hypertension or diabetes mellitus; blood pressure must be =< the 95th percentile for age, height, and gender
  • History of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib
  • Patients who are able to swallow capsules or liquid or able to use a nasogastric or G tube are eligible

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03190915


  Hide Study Locations
Locations
United States, Alabama
Children's Hospital of Alabama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Matthew A. Kutny         
United States, Arizona
Phoenix Childrens Hospital Recruiting
Phoenix, Arizona, United States, 85016
Contact: Site Public Contact    602-546-0920      
Principal Investigator: Jessica Boklan         
United States, Arkansas
Arkansas Children's Hospital Recruiting
Little Rock, Arkansas, United States, 72202-3591
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: David L. Becton         
United States, California
Kaiser Permanente Downey Medical Center Recruiting
Downey, California, United States, 90242
Contact: Site Public Contact    626-564-3455      
Principal Investigator: Robert M. Cooper         
Loma Linda University Medical Center Recruiting
Loma Linda, California, United States, 92354
Contact: Site Public Contact    909-558-3375      
Principal Investigator: Albert Kheradpour         
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Elyssa M. Rubin         
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Sheri L. Spunt         
UCSF Medical Center-Mission Bay Recruiting
San Francisco, California, United States, 94158
Contact: Site Public Contact    877-827-3222      
Principal Investigator: Elliot Stieglitz         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Kelly W. Maloney         
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Recruiting
Denver, Colorado, United States, 80218
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Jennifer J. Clark         
United States, Connecticut
Connecticut Children's Medical Center Recruiting
Hartford, Connecticut, United States, 06106
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Michael S. Isakoff         
United States, Delaware
Alfred I duPont Hospital for Children Recruiting
Wilmington, Delaware, United States, 19803
Contact: Site Public Contact    302-651-6884    dperry@nemours.org   
Principal Investigator: Scott M. Bradfield         
United States, Florida
Nemours Children's Clinic-Jacksonville Recruiting
Jacksonville, Florida, United States, 32207
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Scott M. Bradfield         
University of Miami Miller School of Medicine-Sylvester Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Site Public Contact    305-243-2647      
Principal Investigator: Julio C. Barredo         
Nicklaus Children's Hospital Recruiting
Miami, Florida, United States, 33155
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Enrique A. Escalon         
Nemours Children's Hospital Recruiting
Orlando, Florida, United States, 32827
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Scott M. Bradfield         
Saint Joseph's Hospital/Children's Hospital-Tampa Recruiting
Tampa, Florida, United States, 33607
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Mark J. Mogul         
United States, Georgia
Children's Healthcare of Atlanta - Egleston Recruiting
Atlanta, Georgia, United States, 30322
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Melinda G. Pauly         
United States, Indiana
Riley Hospital for Children Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Site Public Contact    800-248-1199      
Principal Investigator: Kamnesh R. Pradhan         
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center Recruiting
Iowa City, Iowa, United States, 52242
Contact: Site Public Contact    800-237-1225      
Principal Investigator: Mariko Sato         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Vlad C. Radulescu         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Yana Pikman         
United States, Michigan
C S Mott Children's Hospital Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Rajen Mody         
United States, Minnesota
Children's Hospitals and Clinics of Minnesota - Minneapolis Recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Michael K. Richards         
University of Minnesota/Masonic Cancer Center Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Emily G. Greengard         
United States, Missouri
The Childrens Mercy Hospital Recruiting
Kansas City, Missouri, United States, 64108
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Jaszianne A. Tolbert         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Robert J. Hayashi         
United States, New York
The Steven and Alexandra Cohen Children's Medical Center of New York Recruiting
New Hyde Park, New York, United States, 11040
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Julie I. Krystal         
Mount Sinai Hospital Recruiting
New York, New York, United States, 10029
Contact: Site Public Contact    212-824-7309    CCTO@mssm.edu   
Principal Investigator: Pillai Pallavi Madhusoodhan         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: James I. Geller         
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Mark A. Ranalli         
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Site Public Contact    405-271-8777    ou-clinical-trials@ouhsc.edu   
Principal Investigator: Rene Y. McNall-Knapp         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Site Public Contact    503-494-1080    trials@ohsu.edu   
Principal Investigator: Bill H. Chang         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Elizabeth Fox         
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Jean M. Tersak         
United States, South Carolina
BI-LO Charities Children's Cancer Center Recruiting
Greenville, South Carolina, United States, 29605
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Nichole L. Bryant         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Jeffrey E. Rubnitz         
The Children's Hospital at TriStar Centennial Recruiting
Nashville, Tennessee, United States, 37203
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Haydar A. Frangoul         
United States, Texas
UT Southwestern/Simmons Cancer Center-Dallas Recruiting
Dallas, Texas, United States, 75390
Contact: Site Public Contact    214-648-7097    canceranswerline@UTSouthwestern.edu   
Principal Investigator: Kathleen (Wiertel) Ludwig         
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Site Public Contact    713-798-1354    burton@bcm.edu   
Principal Investigator: Rachel E. Rau         
Methodist Children's Hospital of South Texas Recruiting
San Antonio, Texas, United States, 78229
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Vinod K. Gidvani-Diaz         
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Julie R. Park         
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Site Public Contact    414-955-4727    MACCCTO@mcw.edu   
Principal Investigator: Michael J. Burke         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Elliot Stieglitz Children's Oncology Group

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03190915     History of Changes
Other Study ID Numbers: NCI-2017-00921
NCI-2017-00921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1521
ADVL1521 ( Other Identifier: Childrens Oncology Group )
ADVL1521 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Leukemia, Myelomonocytic, Juvenile
Splenomegaly
Monosomy
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Hypertrophy
Pathological Conditions, Anatomical
Aneuploidy