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Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03190915
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : June 22, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE June 16, 2017
First Posted Date  ICMJE June 19, 2017
Last Update Posted Date June 22, 2020
Actual Study Start Date  ICMJE October 6, 2017
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2020)
Objective response [ Time Frame: 4 cycles ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 16, 2017)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2019)
  • Incidence of adverse events [ Time Frame: Up to cycle 12 ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade.
  • Pharmacokinetic (PK) parameters of trametinib [ Time Frame: Up to cycle 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2017)
  • 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.
  • 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).
Current Other Pre-specified Outcome Measures
 (submitted: April 11, 2019)
  • Mutant allele burden [ Time Frame: Up to cycle 12 ]
    Will be measured by mass spectrometry. Will be analyzed descriptively. Values will be summarized with means, standard deviations, and 95% confidence intervals.
  • Trametinib concentrations [ Time Frame: Up to cycle 12 ]
    Will be measured by mass spectrometry. Will be analyzed descriptively. Values will be summarized with means, standard deviations, and 95% confidence intervals.
Original Other Pre-specified Outcome Measures
 (submitted: June 16, 2017)
  • 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.
  • 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.
 
Descriptive Information
Brief Title  ICMJE Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
Official Title  ICMJE A Phase 2 Study of the MEK Inhibitor Trametinib (NSC# 763093) in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
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.
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. Treatment repeats every 28 days for up to 12 cycles 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Juvenile Myelomonocytic Leukemia
  • Neurofibromatosis Type 1
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Drug: Trametinib
    Given PO
    Other Names:
    • GSK1120212
    • JTP-74057
    • MEK Inhibitor GSK1120212
    • Mekinist
Study Arms  ICMJE Experimental: Treatment (trametinib)
Patients receive trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: Trametinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 16, 2017)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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; >= 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 or a serum creatinine based on age/gender as follows (must be performed 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 (must be performed within 7 days prior to enrollment)
  • 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) (must be performed within 7 days prior to enrollment)
  • Serum albumin >= 2 g/dL (must be performed 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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03190915
Other Study ID Numbers  ICMJE NCI-2017-00921
NCI-2017-00921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1521
ADVL1521 ( Other Identifier: Children's Oncology Group )
ADVL1521 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
U54CA196519 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Elliot Stieglitz Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP