Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

ID: NCT03190915
Status: Recruiting
Phase: Phase 2
Start Date: October 06, 2017
First Submitted: June 16, 2017
Last Updated: February 22, 2018
Results: N/A
Sponsors & Collaborators: National Cancer Institute (NCI)
Location: United States
Conditions: Activating RAS Mutation, Juvenile Myelomonocytic Leukemia, Monosomy 7, Neurofibromatosis Type 1, NF1 Gene Mutation, PTPN11 Gene Mutation, Splenomegaly
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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.

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.
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 Names
Other: Pharmacological Study
Other Names
Drug: Trametinib
Other Names
GSK1120212 JTP-74057 MEK Inhibitor GSK1120212 Mekinist
Phase 2

Tracking Information

First Submitted DateJune 16, 2017
Last Update Posted DateFebruary 22, 2018
Actual Start DateOctober 06, 2017
Anticipated Completion DateDecember 30, 2020
Actual Primary Completion DateDecember 30, 2020
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • 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.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • 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).

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleTrametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
Official TitleA Phase 2 Study of the MEK Inhibitor Trametinib 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 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 TypeInterventional
Study PhasePhase 2
Estimated Enrollment
24
Allocation
Not Available
Interventional Model
Single Group Assignment
Masking
None (Open Label)
Primary Purpose
Treatment
Conditions
Activating RAS Mutation
Juvenile Myelomonocytic Leukemia
Monosomy 7
Neurofibromatosis Type 1
NF1 Gene Mutation
PTPN11 Gene Mutation
Splenomegaly
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Other: Laboratory Biomarker Analysis

Correlative studies

Other Names
Other: Pharmacological Study

Correlative studies

Other Names
Drug: Trametinib

Given PO

Other Names
GSK1120212
JTP-74057
MEK Inhibitor GSK1120212
Mekinist
Study Groups/Cohorts
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.

Study Arms
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

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 : Pharmacological Study
Correlative studies

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.
Drug : Trametinib
Given PO

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
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 : Pharmacological Study
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.
Drug : Trametinib

Recruitment Information

Recruitment Status:Recruiting
Enrollment24
Completion DateDecember 30, 2020
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)
GenderAll
Age2 Years to 21 Years
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
United States

Administrative Information

NCT Number:NCT03190915
Other Study ID Numbers
NCI-2017-00921
NCI-2017-00921
ADVL1521
ADVL1521
ADVL1521
U10CA180886
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
National Cancer Institute (NCI)
Collaborators
Not Available
Investigators
Principal Investigator
Elliot Stieglitz
Children's Oncology Group