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HistiocytosisPhase 2BRAVONCT04943198

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

A Phase 2 study testing Vemurafenib in people with Histiocytosis, run by Anna Raciborska at 1 site in Poland.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 1 year to 18 years
Conditions the study is for
Histiocytosis
What is being tested?
Vemurafenib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
1 sitePoland
Study dates
1 Apr 2021to 30 Jun 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
Show all 10Show fewer
  • 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.

Who cannot join

  • Lack of inclusion criteria.
  • 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.
  • Diagnosis of other malignancies before study inclusion.
  • 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.

Trial locations and contacts

1 site in 1 country.

Poland1 site
  • Mother and Child Institute

    Warsaw, Mazovian, 01-211

Other trials in Poland

About this study

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.

Read the detailed description

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
Histiocytosis
Being tested
Vemurafenib
Keywords
Langerhans cell histiocytosis (LCH), vemurafenib, children, refractory histiocytosis, paediatric patients
Medical subject headings
Histiocytosis, Histiocytosis, Langerhans-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VemurafenibDrug

    Also called Zelboraf

    20 mg/kg/day

Study groups in NCT04943198
Study groupRoleWhat they receive
R1 time of vemurafenib treatmentExperimentalvemurafenib will be given to 6 months after BRAF negativization
Receives: Drug: Vemurafenib
R2 time of vemurafenib treatmentExperimentalvemurafenib will be given to 12 months after BRAF negativization
Receives: Drug: Vemurafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 years

Secondary outcomes (2)
  1. Molecular relapse (in ct DNA)

    Molecular relapse was defined as the time interval from the date of BRAF negativization to the date of positive results of BRAF mutation

    Measured: 2 years

  2. 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 BRAF mutation to the date of negative results of BRAF mutation

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Jun 2021
  2. Study start1 Apr 2021
  3. Primary completion30 Jun 2027 (estimated)
  4. Study completion30 Jun 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04943198
Sponsor's protocol ID
BRAVO
Acronym
BRAVO
Status last verified
Oct 2026
First submitted
21 Jun 2021
Last updated
7 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 20519626
  • 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.

    PubMed 29544202
  • 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.

    PubMed 31513482
  • 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.

    PubMed 23258922
  • 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.

    PubMed 26089069
  • 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.

    PubMed 29774135
  • 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.

    PubMed 29165815
  • 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.

    PubMed 26180941
  • 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.

    PubMed 30636236
  • 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.

    PubMed 24757719
  • 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.

    PubMed 26683023
  • 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.

    PubMed 28255850

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vemurafenib in people with Histiocytosis, run by Anna Raciborska at 1 site in Poland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 7 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Poland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

event-free survival (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04943198, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2026.

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