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

Histiocytosis Clinical Trial

— TRAM  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04943224
• Other study ID #: TRAM
• Status: Recruiting
• Phase: Phase 2
• Start date: April 1, 2021
• Est. completion date: June 23, 2026

Study information

• Verified date: January 2024
• Source: Institute of Mother and Child, Warsaw, Poland
• Contact: Katarzyna Maleszewska
• Phone: +48 22 32 77 205
• Email: klinika.onkologii[@]imid.med.pl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: June 23, 2026
• Est. primary completion date: March 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Histiocytosis

Intervention

Drug:
• Trametinib
< 6 lat 0,032mg/kg, = 6 lat 0,025mg/kg,

Locations

Country	Name	City	State
Poland	Mother and Child Institute	Warsaw	Mazovian

Sponsors (4)

Lead Sponsor	Collaborator
Anna Raciborska	Lukasiewicz Research Network, Maria Sklodowska-Curie National Research Institute of Oncology, Wroclaw University of Environmental and Life Sciences

Country where clinical trial is conducted

Poland, 

References & 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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