Clinical Trials /

Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

NCT03190915

Description:

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.

Related Conditions:
  • Juvenile Myelomonocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
  • Official Title: A Phase 2 Study of the MEK Inhibitor Trametinib (NSC# 763093) in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00921
  • SECONDARY ID: NCI-2017-00921
  • SECONDARY ID: ADVL1521
  • SECONDARY ID: ADVL1521
  • SECONDARY ID: ADVL1521
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03190915

Conditions

  • 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

Interventions

DrugSynonymsArms
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (trametinib)

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:

      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.

      EXPLORATORY 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib)ExperimentalPatients 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.
  • Trametinib

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 (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 (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

          -  Patients who are able to swallow capsules or liquid or able to use a nasogastric or G
             tube are eligible
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response
Time Frame:Up to 4 cycles
Safety Issue:
Description: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

Measure:Incidence of adverse events
Time Frame:Up to cycle 12
Safety Issue:
Description: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.
Measure:Pharmacokinetic (PK) parameters of trametinib
Time Frame:Up to cycle 12
Safety Issue:
Description: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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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