To test the safety, efficacy and tolerability of a drug called trametinib and determine the duration of treatment in children with histiocytic cell hyperplasia refractory to conventional therapy.

Prior treatment

• Simultaneous treatment with other drugs which might interact with Trametinib.
• Persistent toxicity related to prior therapy, making it impossible to treat with Trametinib.

Other illness

• Hypersensitivity to the study drug or any of its ingredients.
• Diagnosis of other malignancies before study inclusion.

Lab values

• Other acute or persistent disorders, behaviors or abnormal laboratory test results, which might increase the risk related to the participation in this clinical trial or to taking the study drug, or which might influence the interpretation of the study results, or which, in the investigator's opinion, disqualify a patient from participating in the trial.

Other

• Lack of inclusion criteria.
• Pregnancy and breastfeeding .
• Iritis, uveitis, obstruction of the retinal veins.

• Lack of mutations in the BRAF gene in tumor tissues and/or ctDNA at any stage of treatment or follow-up, or failure of Vemurafenib treatment in BRAF positive patients.
• Failure of the treatment (at least one of below needs to apply in order for this requirement to be satisfied): a. Progression on the I and/or II line treatment, including at least one risk organ; prior treatment should include a minimum of 6 weeks of weekly Vinblastine with a minimum of 28 days prednisolone or minimum 2 cycles of Cytosine Arabinoside in 4-day cycles and/or Cladribine in 5- day cycles as a 2nd line treatment, minimum 2 cycles, or other secondline treatment or b. Disease reactivation after an initial response to treatment with Vimblastine and prednisolone as the first line and/or no response to second line treatment using one of two drugs: Cytosine Arabinoside in 4- day cycles and/or Cladribine in 5-day cycles, minimum 2 cycles, or other I/ II line treatment or occurrence of involvement of at least one risk organ or c. Third or subsequent reactivation of disease with or without risk organ involvement, or d. Progression during Vemurafenib therapy, or e. Reactivation of disease after Vemurafenib therapy has been completed, or f. The appearance of signs of neurodegenerative disorder (ND) in MRI of the CNS.
• Signing of informed consent for trial participation (including for Trametinib treatment) according with current legal regulations.
• Consent to the use of effective contraception throughout the Trametinib administration period and a minimum of 1 year after discontinuation in patients at puberty and sexual maturity.
• Participation in HISTIOGEN trial.