"A Phase 2 Study of the MEK inhibitor Trametinib (IND #119346, NSC# 763093) in Children with Relapsed or Refractory Juvenile Myelomonocytic Leukemia "

Protocol # :
Juvenile Myelomonocytic Leukemia
Neurofibromatosis Type 1
Disease Sites
Myeloid and Monocytic Leukemia
Principal Investigator
Pikman, Yana
Site Investigator
Pikman, Yana
Site Research Nurses
Cuttle, Annette, B.

Trial Description

This phase II trial studies how well trametinib works in treating patients with juvenile
myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment
(refractory). Trametinib may stop the growth of tumor cells by blocking some of the enzymes
needed for cell growth.

Eligibility Requirements

Inclusion Criteria:

- Patients must be >= 1 month and < 22 years of age at the time of study entry

- 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

- 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 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

- >= 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 (within 7 days prior to enrollment) or a serum creatinine based on
age/gender as follows (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 (within 7 days prior to

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
ULN (=< 135 U/L) (within 7 days prior to enrollment) (for the purpose of this study,
the ULN for SGPT is 45 U/L)

- Serum albumin >= 2 g/dL (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

- 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 are not eligible

- Patients with a history of or current evidence/risk of retinal vein occlusion (RVO) or
central serous retinopathy (CSR) are not eligible

- Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g.,
uncontrolled glaucoma or ocular hypertension

- Patients with uncontrolled systemic disease(s) such as hypertension or diabetes
mellitus are not eligible; blood pressure must be =< the 95th percentile for age,
height, and gender

- Patients with a history of allergic reaction attributed to compounds of similar
chemical or biologic composition to the MEK inhibitor, trametinib are not eligible

- Patients with a clinical diagnosis of Noonan syndrome are not eligible; Note: patients
with Casitas B-lineage lymphoma (CBL) syndrome, also known as Noonan-like syndrome,
are eligible to enroll