PFF Clinical Trial Finder

A Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation

Study Purpose

Langerhans cell histiocytosis (LCH) is a disease caused by clonal expansion, proliferation, and dissemination of cells that are phenotypically close to Langerhans cells in different tissues and organs. The clinical presentation of LCH varies greatly from one solid bone tumor to multisystem lesion that involves liver, spleen and bone marrow. The basis of LCH is the clonal proliferation of the pathological cells. These cells express CD1a and CD207 markers on their surface and originate from myeloid progenitors. The main event in life circle of these cells is the MEK-ERK cascade mutation. The most common mutation is the substitution of valine for glutamic acid in position 600 of BRAF gene. The influence of this mutation was confirmed by G.Badalyan-Very et al. in 2010. About 64% of all LCH are caused by clonal proliferation due to BRAF V600E mutation. Despite generally good results of therapy of monosystemic LCH, the treatment of LCH with risk organs lesion is still a challenge: 5-years survival is as low as 40-50%. Combination of cytarabine and 2-chlorodeoxyadenosine was supposed to improve the results, but the cost was a very high toxicity, that limits the application of the regimen in patients with severe infections. Currently, there is a lot of information on BRAF V600E inhibitors in patients with LCH and other histiocytic disorders. Most of them report the dramatic efficacy of BRAF V600E inhibitors but after quick effect patients usually burden minimal disease activity ("plateau" effect). However, discontinuation of the therapy results in quick disease reactivation. Considering this a trial that combines targeted therapy (vemurafenib) and low-dose chemotherapy (cytarabine and 2-chlorodeoxyadenosine) in order to achieve complete response with manageable toxicity is proposed.

Recruitment Criteria

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Accepts Healthy Volunteers
No

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Study Type
Interventional
Eligible Ages N/A - 18 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - 0-18 years old - histologically verified diagnosis of LCH (CD1a+/CD207+) - verified BRAF V600E mutation in the biopsy specimen AND/OR CD34+ isolate (NB! In life-threatening cases, vemurafenib can be administered BEFORE BRAF V600E mutation confirmation.
It's recommended to stop vemurafenib therapy if no clinically significant positive dynamic was achieved after 7 days of intake) - QTc < 0.5 s - no previously documented cardiac diseases - signed informed consent

Exclusion Criteria:

- withdrawal of informed consent - QTc > 0.5 s or long QT syndrome - use of antiarrhythmic medication - persistent electrolytic disorders

Trial Details

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

Trial ID:
NCT03585686

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase
Phase 2

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Lead Sponsor
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

The person who is responsible for the scientific and technical direction of the entire clinical study.

Principal Investigator
N/A
Principal Investigator Affiliation N/A

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Agency Class
Other
Overall Status Recruiting
Countries Russian Federation

The disease, disorder, syndrome, illness, or injury that is being studied.

Conditions
Langerhans Cell Histiocytosis
Additional Details

Langerhans cell histiocytosis (LCH) is a disease caused by clonal expansion, proliferation, and dissemination of cells that are phenotypically close to Langerhans cells to different tissues and organs. The clinical presentation of LCH varies greatly from one solid bone tumor to multisystem lesion that involves liver, spleen and bone marrow. The basis of LCH is the clonal proliferation of the pathological cells. These cells express CD1a and CD207 markers on their surface and originate from myeloid progenitors. The main event in life circle of these cells is the MEK-ERK cascade mutation. The most common mutation is the substitution of valine for glutamic acid in position 600 of BRAF gene. The influence of this mutation was confirmed by G.Badalyan-Very et al. in 2010. About 64% of all LCH are caused by clonal proliferation due to BRAF V600E mutation. Despite generally good results of therapy of monosystemic LCH, the treatment of LCH with risk organs lesion is still a challenge: 5-years survival is as low as 40-50%. Combination of cytarabine and 2-chlorodeoxyadenosine was supposed to improve the results, but the cost was very high toxicity, that limits the application of the regimen in patients with severe infections. Currently, there is a lot of information on BRAF V600E inhibitors in patients with LCH and other histiocytic disorders. Most of them report the dramatic efficacy of BRAF V600E inhibitors but after quick effect patients usually burden minimal disease activity ("plateau" effect). However, discontinuation of the therapy results in quick disease reactivation. Considering this a trial that combines targeted therapy (vemurafenib) and low-dose chemotherapy (cytarabine and 2-chlorodeoxyadenosine) in order to achieve complete response with manageable toxicity is proposed. Patients who met the eligibility criteria evaluate their condition using DAS score on Day 0 and start the therapy with oral intake of vemurafenib 20 mg/kg/d rounded off to a whole capsule from day 1 to day 28. NB! In life-threatening cases, the treatment can be started empirically, without BRAF V600E detection in any affected tissue. During that period their condition will be strictly monitored in order to control BRAF V600E inhibitor side effects. Moreover, serum levels of vemurafenib should be evaluated on any two points after day 3 and before day 28. Serum concentration should be measured with the mass-spectrometry method in the positive ionization regimen. On day 28 condition must be evaluated with DAS again and vemurafenib intake should be stopped. On day 29, Ara-C + 2-CdA course №1 should be started. It takes 5 days, on day 34 vemurafenib intake should be continued. Each patient should undergo 3 courses of Ara-C + 2-CdA with 28 days between each course. After each course, G-CSF stimulation and proper antibacterial/antifungal therapy are to be applied. Before each course, patients condition should be evaluated with DAS scale. After Ara-C + 2-CdA, №3 patient should undergo a more thorough evaluation that includes bone marrow aspiration. After that vemurafenib intake should be stopped and mono 2-CdA course starts. After 5 days of the course, vemurafenib intake shouldn't be restarted. After 3 courses of mono 2-CdA, all specific therapy stops. On each DAS evaluation point, serum for digital droplet polymerase chain reaction (ddPCR) should also be collected. With the help of ddPCR, it could be possible to analyze cell-free DNA (cfDNA) harboring BRAF V600E mutation and thus to create a method of disease activity control. Taking into account the small potential number of the included patients the analysis of data will be based on Simon two-step design. All reactivation-free survival and overall survival rates will be evaluated with standard Kaplan-Mayer method. All severe side effects will be evaluated with standard CTCAE scale. All operations with patients' data, informed consents will be performed according to the internal SOPs.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Moscow, Russian Federation

Status

Recruiting

Address

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Moscow, , 117997

Site Contact

Zhanna Shekhovtsova, MD

zhanna.shekhovtsova@fccho-moscow.ru

4956647078 #7538

Terms of Service

The PFF does not promote or represent that any investigational new drugs mentioned are safe or effective. The content provided on clinical trials is for informational purposes only and is not a substitute for medical consultation with your healthcare provider. We do not recommend or endorse any specific study and you are advised to discuss the information shown with your healthcare provider. While we believe the information presented on this website to be accurate at the time of writing, we do not guarantee that its contents are correct, complete, or applicable to any particular individual situation. We strongly encourage individuals to seek out appropriate medical advice and treatment from their physicians. We cannot guarantee the availability of any clinical trial listed and will not be responsible if you are considered ineligible to participate in a given clinical trial. We are also not liable for any injury arising as a result of participation. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. For a full description of terms please refer to our Terms, Conditions & Privacy.

Back to Top
footer_txt_bblBook a PFF Ambassador for your event.   Call 844.TalkPFF >