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

NCT ID: NCT04943198

Last Updated: 2025-04-13

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

25 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-04-01

Study Completion Date

2026-03-30

Brief Summary

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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.

Detailed Description

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BRAVO 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.

Conditions

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Histiocytosis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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R1 time of vemurafenib treatment

vemurafenib will be given to 6 months after BRAF negativization

Group Type EXPERIMENTAL

Vemurafenib

Intervention Type DRUG

20 mg/kg/day

R2 time of vemurafenib treatment

vemurafenib will be given to 12 months after BRAF negativization

Group Type EXPERIMENTAL

Vemurafenib

Intervention Type DRUG

20 mg/kg/day

Interventions

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Vemurafenib

20 mg/kg/day

Intervention Type DRUG

Other Intervention Names

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Zelboraf

Eligibility Criteria

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Inclusion Criteria

1. 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.
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
3. Third or subsequent reactivation of disease with or without risk organ involvement, or
4. Reactivation of disease after Vemurafenib therapy has been completed, or
5. 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 Vemurafenib treatment) according with current legal regulations.
4. 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.
5. Participation in HISTIOGEN trial.

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 Vemurafenib.
6. Persistent toxicity related to prior therapy, making it impossible to treat with Vemurafenib.
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.
Minimum Eligible Age

1 Year

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Maria Sklodowska-Curie National Research Institute of Oncology

OTHER

Sponsor Role collaborator

Łukasiewicz Research Network

UNKNOWN

Sponsor Role collaborator

Wrocław University of Environmental and Life Sciences

UNKNOWN

Sponsor Role collaborator

Anna Raciborska

OTHER

Sponsor Role lead

Responsible Party

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Anna Raciborska

Prof Ass MD PhD

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Anna Raciborska

Role: PRINCIPAL_INVESTIGATOR

Mother and Child Institute

Locations

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Mother and Child Institute

Warsaw, Mazovian, Poland

Site Status RECRUITING

Countries

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Poland

Central Contacts

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Katarzyna Maleszewska

Role: CONTACT

+48 22 32 77 205

Facility Contacts

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Katarzyna Maleszewska

Role: primary

+48 22 32 77 205

References

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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.

Reference Type BACKGROUND
PMID: 20519626 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29544202 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31513482 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23258922 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26089069 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29774135 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29165815 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26180941 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 30636236 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24757719 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26683023 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28255850 (View on PubMed)

Other Identifiers

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BRAVO

Identifier Type: -

Identifier Source: org_study_id

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