Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

• Register: ClinicalTrials.gov
• Last refreshed on: 20 November 2023
• Main ID: NCT03190915
• Date of registration: 16/06/2017
• Prospective Registration: Yes
• Primary sponsor: National Cancer Institute (NCI)
• Public title: Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
• Scientific title: A Phase 2 Study of the MEK Inhibitor Trametinib (NSC# 763093) in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
• Date of first enrolment: September 9, 2018
• Target sample size: 10
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03190915
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

United States

Contacts

• Name: Elliot Stieglitz
• Affiliation: Children's Oncology Group

Key inclusion & exclusion criteria

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
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 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; >= 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
enrollment)

- 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 w


Age minimum: 1 Month
Age maximum: 21 Years
Gender: All

Health Condition(s) or Problem(s) studied

Juvenile Myelomonocytic Leukemia

Neurofibromatosis Type 1

Intervention(s)

Procedure: Bone Marrow Aspiration and Biopsy

Drug: Trametinib

Primary Outcome(s)

Objective response [Time Frame: 12 cycles (1 cycle = 28 days)]

Secondary Outcome(s)

Incidence of adverse events [Time Frame: Up to cycle 12 (1 cycle = 28 days)]

Complete Response [Time Frame: 12 cycles (1 cycle = 28 days)]

Duration of Response [Time Frame: 2-year]

Mutant allele burden [Time Frame: Up to cycle 12 (1 cycle = 28 days)]

Pharmacokinetic (PK) parameters of trametinib [Time Frame: Up to cycle 12 (1 cycle = 28 days)]

Trametinib concentrations [Time Frame: Up to cycle 12 (1 cycle = 28 days)]

Secondary ID(s)

NCI-2017-00921

U10CA180886

U54CA196519

ADVL1521

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Children's Oncology Group