Optimization of the Time and Dosage of Trametinib in BRAF Negative Juvenile Patients

Phase 2

Recruiting

• Conditions: Histiocytosis
• Interventions: Drug: Trametinib

• Registration Number: NCT04943224
• Lead Sponsor: Anna Raciborska

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.

Study Timeline

• Study Start: 2021-04-01
• Study First Submitted: 2021-06-21
• Study First Submitted QC: 2021-06-28
• Study First Posted: 2021-06-29
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-09
• Last Update Posted: 2025-04-13
• Primary Completion: 2026-03-30
• Study Completion: 2026-03-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

1. 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.

2. Failure of the treatment (at least one of below needs to apply in order for this requirement to be satisfied):

   1. 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 second-line treatment or
   2. 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

   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 central nervous system (CNS).

3. Signing of informed consent for trial participation (including for Trametinib treatment) according with current legal regulations.

4. 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.

5. Participation in HISTIOGEN trial.

Exclusion Criteria

1. Lack of inclusion criteria.
2. Pregnancy and breastfeeding .
3. Hypersensitivity to the study drug or any of its ingredients.
4. Iritis, uveitis, obstruction of the retinal veins.
5. Simultaneous treatment with other drugs which might interact with Trametinib.
6. Persistent toxicity related to prior therapy, making it impossible to treat with Trametinib.
7. Diagnosis of other malignancies before study inclusion.
8. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
R1 time of trametinib treatment	Trametinib	Patients with negative status of any mutation in ctDNA or 0-1 Disease Activity Score (DAS) in three consecutive tests in three month intervals.
R2 time of trametinib treatment	Trametinib	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.

Primary Outcome Measures

Name	Time	Method
Event-free survival (EFS)	2 years	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.

Secondary Outcome Measures

Name	Time	Method
Molecular relapse (in ct DNA)	2 years	Molecular relapse was defined as the time interval from the date of any mutation negativization to the date of positive results of any mutation
Time to negative mutation test results (in ct DNA)	2 years	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

Trial Locations

Locations (1)

Mother and Child Institute; 🇵🇱 Warsaw, Mazovian, Poland