Optimization of the Time and Dosage of Trametinib in BRAF Negative Juvenile Patients With Refractory Histiocytosis or After the Failure of Vemurafenib Treatment

Study Overview
=================
Brief Summary
-----------------
Prospective, interventional, open, randomized, single-center, non-commercial clinical trial to optimize treatment and dosage of trametinib in juvenile patients with histiocytosis resistant to conventional therapy and without the BRAF gene mutation or after the failure of vemurafenib treatment.

Detailed Description
-----------------
TRAM clinical study is part of the POLHISTIO project. The POLHISTIO project is a non-commercial clinical trial aimed at optimizing the diagnosis and treatment of juvenile patients with histiocytosis. The project objectives are defined as follows: 1) to estimate the nature and frequency of mutations in patients with histiocytosis in both tumor tissues and free-circulating DNA; 2) to compare molecular test results with clinical data; 3) to evaluate the diagnostic usefulness of the status of molecular analysis (MRD) as a prognostic factor compared with other recognized factors; 4) in the case of failure of conventional therapy - to modify treatment and to apply targeted treatment, based on molecular status of gene mutation. The project is intended to include patients from all over Poland.

Official Title
-----------------
Optimization of the Time and Dosage of Trametinib in BRAF Negative Juvenile Patients With Refractory Histiocytosis or After the Failure of Vemurafenib Treatment

Conditions
-----------------
Histiocytosis

Intervention / Treatment
-----------------
* Drug: Trametinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Lack of mutations in the BRAF gene in tumor tissues and/or circulating tumor DNA (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): Progression on the I and II line treatment, and involving of a minimum one risk organ; previous 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 treatment of 2 line, or Disease reactivation after an initial response to treatment with Vinblastine and prednisolone as the first line and no response to treatment of the second line using a minimum of 2 cycles of one of two drugs: Cytosine Arabinoside in 4-day cycles and/or Cladribine in 5-day cycles as a treatment of 2 line and the involving of a minimum one risk organ, or Third or subsequent reactivation of disease with or without risk organ involvement, or Progression during Vemurafenib therapy, or Reactivation of disease after Vemurafenib therapy has been completed, or The appearance of signs of neurodegenerative disorder (ND) in MRI of the central nervous system (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. Exclusion Criteria: Lack of inclusion criteria. Pregnancy and breastfeeding . Hypersensitivity to the study drug or any of its ingredients. Iritis, uveitis, obstruction of the retinal veins. Simultaneous treatment with other drugs which might interact with Trametinib. Persistent toxicity related to prior therapy, making it impossible to treat with Trametinib. Diagnosis of other malignancies before study inclusion. 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.

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R1 time of trametinib treatment<br>Patients with negative status of any mutation in ctDNA or 0-1 Disease Activity Score (DAS) in three consecutive tests in three month intervals. | Drug: Trametinib<br>* < 6 lat 0,032mg/kg, ≥ 6 lat 0,025mg/kg,<br>|
| Experimental: R2 time of trametinib treatment<br>Patients with negative status of any mutation in ctDNA or 0-1 Disease Activity Score (DAS) in in five consecutive tests in three month intervals. | Drug: Trametinib<br>* < 6 lat 0,032mg/kg, ≥ 6 lat 0,025mg/kg,<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | Event-free survival (EFS) was defined as the time interval from the date of diagnosis to the date of disease progression, recurrence, second malignancy, death or to date of last follow-up for patients without events. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular relapse (in ct DNA) | Molecular relapse was defined as the time interval from the date of any mutation negativization to the date of positive results of any mutation | 2 years | 
| Time to negative mutation test results (in ct DNA) | Time to negative mutation test results (in ct DNA) was defined as the time interval from the date of positive mutation to the date of negative results of any mutation | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Langerhans cell histiocytosis (LCH), histiocytosis, trametinib, paediatric patients