|
|
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 |
|
|
|
|
|
Somatic mutation in RAS or PTPN11 |
|
|
|
|
|
criteria are not present) |
|
|
|
|
|
Clinical diagnosis of NF1 or NF1 gene mutation |
|
|
|
|
|
Homozygous mutation in CBL |
|
|
|
|
|
Monosomy 7 |
|
|
|
|
|
Circulating myeloid precursors |
|
|
|
|
|
JMML category 3 (at least two of the following if no category 2 criteria are |
|
|
|
|
|
White blood cell count, > 10 000 (10 x 10^9/ uL) |
|
|
|
|
|
met) |
|
|
|
|
|
Increased hemoglobin F for age |
|
|
|
|
|
Clonal cytogenetic abnormality |
|
|
|
|
|
GM-CSF hypersensitivity |
|
|
|
|
|
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 |
|
|
|
|
|
Patients with refractory or relapsed JMML must have had at least one cycle of |
|
|
|
|
|
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 |
|
|
|
|
|
intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid |
|
|
|
|
|
Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy |
|
|
|
|
|
(DNA) demethylating agent with persistence of disease, defined by clinical |
|
|
|
|
|
symptoms or the presence of a clonal abnormality; frontline therapy is defined |
|
|
|
|
|
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 |
|
|
|
|
|
as one cycle of intravenous chemotherapy that includes of any of the following |
|
|
|
|
|
Monoclonal antibodies |
|
|
|
|
|
agents: fludarabine, cytarabine, or any anthracycline but specifically |
|
|
|
|
|
At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines |
|
|
|
|
|
excludes oral 6-mercaptopurine; frontline therapy will also include any |
|
|
|
|
|
At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody |
|
|
|
|
|
conditioning regimen as part of a stem cell transplant; patients who transform |
|
|
|
|
|
Radiotherapy |
|
|
|
|
|
to AML at any point with more than 20% blasts are not eligible for this trial |
|
|
|
|
|
>= 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 |
|
|
|
|
|
Patients must not be known to be refractory to red blood cell or platelet transfusions |
|
|
|
|
|
Hematopoietic growth factors: at least 14 days after the last dose of a |
|
|
|
|
|
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 |
|
|
|
|
|
long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting |
|
|
|
|
|
Age: Maximum serum creatinine (mg/dL) |
|
|
|
|
|
growth factor; for agents that have known adverse events occurring beyond 7 |
|
|
|
|
|
month to < 6 months: 0.4 (male) 0.4 (female) |
|
|
|
|
|
days after administration, this period must be extended beyond the time during |
|
|
|
|
|
months to < 1 year: 0.5 (male) 0.5 (female) |
|
|
|
|
|
which adverse events are known to occur |
|
|
|
|
|
to < 2 years: 0.6 (male) 0.6 (female) |
|
|
|
|
|
to < 6 years: 0.8 (male) 0.8 (female) |
|
|
|
|
|
to < 10 years: 1 (male) 1 (female) |
|
|
|
|
|
to < 13 years: 1.2 (male) 1.2 (female) |
|
|
|
|
|
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]) =< 3 x ULN (=< 135 U/L) (for the purpose of this study, the ULN for SGPT is 45 U/L) |
|
|
|
|
|
Serum albumin >= 2 g/dL |
|
|
|
|
|
Stem cell transplant or rescue without TBI: no evidence of active graft versus |
|
|
|
|
|
Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA) |
|
|
|
|
|
(vs.) host disease and >= 3 months must have elapsed since transplant; >= 4 |
|
|
|
|
|
Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs |
|
|
|
|
|
weeks must have elapsed since any donor lymphocyte infusion |
|
|
|
|
|
Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed |
|
|
|
|
|
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
|
|
|
|
|
|
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 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
|
|
|
|
|
|
Investigational drugs: patients who are currently receiving another
|
|
|
|
|
|
investigational drug are not eligible
|
|
|
|