ADVL1521: A Phase 2 Study of the MEK Inhibitor Trametinib in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

Why are we doing this research?

PURPOSE:

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 OBJECTIVES:

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

Study Type: Interventional
Intervention Model: Single Group Assignment

Masking: None (Open Label)
Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 2 years to 21 Years

ELIGIBILITY 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)

Conditions

  • Leukemia AML Relapse
  • Adult - Leukemia AML Relapse

Contact

For more information contact:
Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799