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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 : January 15, 2018
Sponsor:
Information provided by (Responsible Party):

Study Description
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 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.

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 Design

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 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


Arms and Interventions

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


Outcome Measures

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 4.0 [ Time Frame: Up to course 12 ]
    Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade.

  2. Pharmacokinetic 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.


Eligibility Criteria

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Ages Eligible for Study:   2 Years 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 (1x10^9/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 (10x10^9/ 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 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 acute myeloid leukemia (AML) with more than 20% blasts at relapse 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)

      • 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]) =< 110 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 msec

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
  • 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 are unable to swallow capsules or liquid are not eligible
  • 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, diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes)
Contacts and Locations

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


  Show 24 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Elliot Stieglitz Children's Oncology Group
More Information

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: January 15, 2018
Last Verified: October 2017

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
Neurofibroma
Neurofibromatosis 1
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 Neoplasms
Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Hypertrophy
Pathological Conditions, Anatomical
Aneuploidy