A Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation
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|ClinicalTrials.gov Identifier: NCT03585686|
Recruitment Status : Recruiting
First Posted : July 13, 2018
Last Update Posted : July 16, 2018
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|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 2020|
|Estimated Study Completion Date :||December 2020|
vemurafenib, Cytarabine, 2-chlorodeoxyadenosine
vemurafenib 20 mg/kg/day
100 mg/m2/12 h, days 1-5
6 mg/m2/d, days 1-5
- 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.
- 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.
- 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)
- 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03585686
|Contact: Dmitry Evseev, MDfirstname.lastname@example.org|
|Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology||Recruiting|
|Moscow, Russian Federation, 117997|
|Contact: Zhanna Shekhovtsova, MD 4956647078 ext 7538 email@example.com|
|Contact: Eugene Pashanov, PhD +79262205578 firstname.lastname@example.org|
|Sub-Investigator: Dmitry Evseev, MD|
|Principal Investigator: Michael Maschan, PhD|