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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03585686
Recruitment Status : Recruiting
First Posted : July 13, 2018
Last Update Posted : April 7, 2020
Information provided by (Responsible Party):
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Langerhans Cell Histiocytosis Drug: Vemurafenib Drug: Cytarabine Drug: 2-chlorodeoxyadenosine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Prospective Non-randomized Phase II Clinical Trial of Vemurafenib in Combination With Cytarabine and 2-chlorodeoxyadenosine in Children With Langerhans-cell Hisitocytosis With BRAF V600E Mutation
Actual Study Start Date : June 26, 2018
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : December 2021

Arm Intervention/treatment
Experimental: vemurafenib
vemurafenib, Cytarabine, 2-chlorodeoxyadenosine
Drug: Vemurafenib
vemurafenib 20 mg/kg/day

Drug: Cytarabine
100 mg/m2/12 h, days 1-5

Drug: 2-chlorodeoxyadenosine
6 mg/m2/d, days 1-5

Primary Outcome Measures :
  1. The overall response rate (ORR) proportion [ Time Frame: 16 weeks ]
    ORR is the sum of complete response rate (CRR) and partial response rate (PRR) which define as DAS score 0-1 and 2-3 respectfully.

Secondary Outcome Measures :
  1. The reactivation/progression free survival [ Time Frame: 1 year ]
    RFS is a time from the therapy start to reactivation, progression or death due to any cause or to last evaluation up to the time of analysis. Analysis will be made with Kaplan-Mayer method with 95% confidence interval.

  2. The proportion of of patients with severe adverse effects [ Time Frame: 30 days ]
    The proportion of of patients with severe adverse effects of therapy according to CTCAE (ver 4.0)

  3. Overall survival [ Time Frame: 2 years ]
    OS is a time from the therapy start to death due to any cause or to the last evaluation.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03585686

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Contact: Dmitry Evseev, MD +79175196374

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Russian Federation
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology Recruiting
Moscow, Russian Federation, 117997
Contact: Zhanna Shekhovtsova, MD    4956647078 ext 7538   
Contact: Eugene Pashanov, PhD    +79262205578   
Sub-Investigator: Dmitry Evseev, MD         
Principal Investigator: Michael Maschan, PhD         
Sponsors and Collaborators
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
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Responsible Party: Federal Research Institute of Pediatric Hematology, Oncology and Immunology Identifier: NCT03585686    
Other Study ID Numbers: NCPHOI-2017-02
First Posted: July 13, 2018    Key Record Dates
Last Update Posted: April 7, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Federal Research Institute of Pediatric Hematology, Oncology and Immunology:
Additional relevant MeSH terms:
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Histiocytosis, Langerhans-Cell
Lymphatic Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors