Optimization of the Time and Dosage of Vemurafenib in BRAF Positive Juvenile Patients With Refractory Histiocytosis

NCT04943198 | Recruiting Phase 2 DMC

• 1 other identifier: BRAVO
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Prospective, interventional, open, randomized, single-center, non-commercial clinical trial to optimize treatment and dosage of vemurafenib in juvenile patients with histiocytosis resistant to conventional therapy and in whom the BRAF gene mutation has been found.

Conditions

Histiocytosis

Keywords

Langerhans cell histiocytosis (LCH); vemurafenib; children; refractory histiocytosis; paediatric patients

Outcome Measures

Primary Outcomes (1)

• event-free survival

  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 vemurafenib treatment

EXPERIMENTAL

vemurafenib will be given to 6 months after BRAF negativization

Drug: Vemurafenib

R2 time of vemurafenib treatment

EXPERIMENTAL

vemurafenib will be given to 12 months after BRAF negativization

Drug: Vemurafenib

Interventions

Vemurafenib DRUG

20 mg/kg/day

Also known as: Zelboraf

R1 time of vemurafenib treatment; R2 time of vemurafenib 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:

• The presence of mutations in the BRAF gene in tumor tissues and/or in circulating tumor DNA (ctDNA) at any stage of treatment or follow-up.
• 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
• Third or subsequent reactivation of disease with or without risk organ involvement, 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 Vemurafenib treatment) according with current legal regulations.
• Consent to the use of effective contraception throughout the Vemurafenib 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 Vemurafenib.
• Persistent toxicity related to prior therapy, making it impossible to treat with Vemurafenib.
• 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 (12)

• Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, Kuo FC, Ligon AH, Stevenson KE, Kehoe SM, Garraway LA, Hahn WC, Meyerson M, Fleming MD, Rollins BJ. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010 Sep 16;116(11):1919-23. doi: 10.1182/blood-2010-04-279083. Epub 2010 Jun 2.

  PMID: 20519626 BACKGROUND

• 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

• Donadieu J, Larabi IA, Tardieu M, Visser J, Hutter C, Sieni E, Kabbara N, Barkaoui M, Miron J, Chalard F, Milne P, Haroche J, Cohen F, Helias-Rodzewicz Z, Simon N, Jehanne M, Kolenova A, Pagnier A, Aladjidi N, Schneider P, Plat G, Lutun A, Sonntagbauer A, Lehrnbecher T, Ferster A, Efremova V, Ahlmann M, Blanc L, Nicholson J, Lambilliote A, Boudiaf H, Lissat A, Svojgr K, Bernard F, Elitzur S, Golan M, Evseev D, Maschan M, Idbaih A, Slater O, Minkov M, Taly V, Collin M, Alvarez JC, Emile JF, Heritier S. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol. 2019 Nov 1;37(31):2857-2865. doi: 10.1200/JCO.19.00456. Epub 2019 Sep 12.

  PMID: 31513482 BACKGROUND

• Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, Besnard S, Donadieu J, Amoura Z. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013 Feb 28;121(9):1495-500. doi: 10.1182/blood-2012-07-446286. Epub 2012 Dec 20.

  PMID: 23258922 BACKGROUND

• Haroche J, Cohen-Aubart F, Emile JF, Donadieu J, Amoura Z. Vemurafenib as first line therapy in BRAF-mutated Langerhans cell histiocytosis. J Am Acad Dermatol. 2015 Jul;73(1):e29-30. doi: 10.1016/j.jaad.2014.10.045. No abstract available.

  PMID: 26089069 BACKGROUND

• Heisig A, Sorensen J, Zimmermann SY, Schoning S, Schwabe D, Kvasnicka HM, Schwentner R, Hutter C, Lehrnbecher T. Vemurafenib in Langerhans cell histiocytosis: report of a pediatric patient and review of the literature. Oncotarget. 2018 Apr 24;9(31):22236-22240. doi: 10.18632/oncotarget.25277. eCollection 2018 Apr 24.

  PMID: 29774135 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

• Heritier S, Jehanne M, Leverger G, Emile JF, Alvarez JC, Haroche J, Donadieu J. Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis. JAMA Oncol. 2015 Sep;1(6):836-8. doi: 10.1001/jamaoncol.2015.0736. No abstract available.

  PMID: 26180941 BACKGROUND

• Raciborska A, Malas Z, Tysarowski A. [Vemurafenib in refractory langerhans histiocytosis]. Dev Period Med. 2018;22(4):376-378. doi: 10.34763/devperiodmed.20182204.376378. Polish.

  PMID: 30636236 BACKGROUND

• Szmulewitz RZ, Ratain MJ. Vemurafenib oral bioavailability: an insoluble problem. J Clin Pharmacol. 2014 Apr;54(4):375-7. doi: 10.1002/jcph.277. No abstract available.

  PMID: 24757719 BACKGROUND

• Vikingsson S, Stromqvist M, Svedberg A, Hansson J, Hoiom V, Green H. Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady state. Biomed Chromatogr. 2016 Aug;30(8):1234-9. doi: 10.1002/bmc.3672. Epub 2016 Jan 25.

  PMID: 26683023 BACKGROUND

• Zhang W, Heinzmann D, Grippo JF. Clinical Pharmacokinetics of Vemurafenib. Clin Pharmacokinet. 2017 Sep;56(9):1033-1043. doi: 10.1007/s40262-017-0523-7.

  PMID: 28255850 BACKGROUND

MeSH Terms

Conditions

Histiocytosis; Histiocytosis, Langerhans-Cell

Interventions

Vemurafenib

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

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 MD PhD

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)