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

NCT04943224 | Recruiting Phase 2

• 1 other identifier: TRAM
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Histiocytosis

Keywords

Langerhans cell histiocytosis (LCH); histiocytosis; trametinib; paediatric patients

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Molecular relapse (in ct DNA)

  2 years

• Time to negative mutation test results (in ct DNA)

  2 years

Study Arms (2)

R1 time of trametinib treatment

EXPERIMENTAL

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

R2 time of trametinib treatment

EXPERIMENTAL

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

Interventions

Trametinib DRUG

\< 6 lat 0,032mg/kg, ≥ 6 lat 0,025mg/kg,

Also known as: Mekinist

R1 time of trametinib treatment; R2 time of trametinib treatment

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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/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
• 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).
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Anna Raciborska: lead
• Maria Sklodowska-Curie National Research Institute of Oncology: collaborator
• Łukasiewicz Research Network: collaborator
• Wrocław University of Environmental and Life Sciences: collaborator

Study Sites (1)

Mother and Child Institute

Warsaw, Mazovian, 01-211, Poland

RECRUITING

Related Publications (10)

• Cardoso E, Mercier T, Wagner AD, Homicsko K, Michielin O, Ellefsen-Lavoie K, Cagnon L, Diezi M, Buclin T, Widmer N, Csajka C, Decosterd L. Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Apr 15;1083:124-136. doi: 10.1016/j.jchromb.2018.02.008. Epub 2018 Feb 8.

  PMID: 29544202 BACKGROUND

• Cox DS, Allred A, Zhou Y, Infante JR, Gordon MS, Bendell J, Jones S, Burris H 3rd, Orford K. Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Clin Pharmacol Drug Dev. 2015 Jul;4(4):287-94. doi: 10.1002/cpdd.152. Epub 2014 Oct 27.

  PMID: 27136909 BACKGROUND

• Crombag MBS, van Doremalen JGC, Janssen JM, Rosing H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR. Therapeutic drug monitoring of small molecule kinase inhibitors in oncology in a real-world cohort study: does age matter? Br J Clin Pharmacol. 2018 Dec;84(12):2770-2778. doi: 10.1111/bcp.13725. Epub 2018 Sep 26.

  PMID: 30068020 BACKGROUND

• Farnault L, Helias-Rodzewicz Z, Venton G, Fanciullino R, Gabriel S, Mescam L, Haroche J, Donadieu J, Emile JF. Response to trametinib of histiocytosis with an activating PTPN11 mutation. Leuk Lymphoma. 2020 Jan;61(1):194-197. doi: 10.1080/10428194.2019.1650175. Epub 2019 Aug 8. No abstract available.

  PMID: 31393194 BACKGROUND

• Herbrink M, de Vries N, Rosing H, Huitema ADR, Nuijen B, Schellens JHM, Beijnen JH. Development and validation of a liquid chromatography-tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs. Biomed Chromatogr. 2018 Apr;32(4). doi: 10.1002/bmc.4147. Epub 2017 Dec 19.

  PMID: 29165815 BACKGROUND

• Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA 3rd, Messersmith WA. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):773-81. doi: 10.1016/S1470-2045(12)70270-X. Epub 2012 Jul 16.

  PMID: 22805291 BACKGROUND

• Lian T, Li C, Wang H. Trametinib in the treatment of multiple malignancies harboring MEK1 mutations. Cancer Treat Rev. 2019 Dec;81:101907. doi: 10.1016/j.ctrv.2019.101907. Epub 2019 Oct 14.

  PMID: 31715422 BACKGROUND

• Lorillon G, Jouenne F, Baroudjian B, de Margerie-Mellon C, Vercellino L, Meignin V, Lebbe C, Vassallo R, Mourah S, Tazi A. Response to Trametinib of a Pulmonary Langerhans Cell Histiocytosis Harboring a MAP2K1 Deletion. Am J Respir Crit Care Med. 2018 Sep 1;198(5):675-678. doi: 10.1164/rccm.201802-0275LE. No abstract available.

  PMID: 29694792 BACKGROUND

• Nelson DS, van Halteren A, Quispel WT, van den Bos C, Bovee JV, Patel B, Badalian-Very G, van Hummelen P, Ducar M, Lin L, MacConaill LE, Egeler RM, Rollins BJ. MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes Chromosomes Cancer. 2015 Jun;54(6):361-8. doi: 10.1002/gcc.22247. Epub 2015 Mar 31.

  PMID: 25899310 BACKGROUND

• Ouellet D, Kassir N, Chiu J, Mouksassi MS, Leonowens C, Cox D, DeMarini DJ, Gardner O, Crist W, Patel K. Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. Cancer Chemother Pharmacol. 2016 Apr;77(4):807-17. doi: 10.1007/s00280-016-2993-y. Epub 2016 Mar 3.

  PMID: 26940938 BACKGROUND

MeSH Terms

Conditions

Histiocytosis; Histiocytosis, Langerhans-Cell

Interventions

trametinib

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Anna Raciborska

  Mother and Child Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Katarzyna Maleszewska

CONTACT

+48 22 32 77 205; klinika.onkologii@imid.med.pl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof Ass

Study Record Dates

• First Submitted: June 21, 2021
• First Posted: June 29, 2021
• Study Start: April 1, 2021
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1)