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Report for Clinical Trial NCT03585686

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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

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.

NCT03585686 Langerhans Cell Histiocytosis
MeSH:Histiocytosis, Langerhans-Cell Histiocytosis
HPO:Histiocytosis

3 Interventions

Name: Vemurafenib

Description: vemurafenib 20 mg/kg/day
Type: Drug
Group Labels: 1

vemurafenib

Name: Cytarabine

Description: 100 mg/m2/12 h, days 1-5
Type: Drug
Group Labels: 1

vemurafenib

Name: 2-chlorodeoxyadenosine

Description: 6 mg/m2/d, days 1-5
Type: Drug
Group Labels: 1

vemurafenib


Primary Outcomes

Description: 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.

Measure: The overall response rate (ORR) proportion

Time: 16 weeks

Secondary Outcomes

Description: 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.

Measure: The reactivation/progression free survival

Time: 1 year

Description: The proportion of of patients with severe adverse effects of therapy according to CTCAE (ver 4.0)

Measure: The proportion of of patients with severe adverse effects

Time: 30 days

Description: OS is a time from the therapy start to death due to any cause or to the last evaluation.

Measure: Overall survival

Time: 2 years

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There is one SNP

SNPs


1 V600E

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. --- V600E ---

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

About 64% of all LCH are caused by clonal proliferation due to BRAF V600E mutation. --- V600E ---

Currently, there is a lot of information on BRAF V600E inhibitors in patients with LCH and other histiocytic disorders. --- V600E ---

Most of them report the dramatic efficacy of BRAF V600E inhibitors but after quick effect patients usually burden minimal disease activity ("plateau" effect). --- V600E ---

OS is a time from the therapy start to death due to any cause or to the last evaluation.. 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! --- V600E ---

In life-threatening cases, vemurafenib can be administered BEFORE BRAF V600E mutation confirmation. --- V600E ---

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 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! --- V600E ---

In life-threatening cases, the treatment can be started empirically, without BRAF V600E detection in any affected tissue. --- V600E ---

During that period their condition will be strictly monitored in order to control BRAF V600E inhibitor side effects. --- V600E ---

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. --- V600E ---



HPO Nodes


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