Ignite Creation Date:
2024-05-06 @ 11:43 AM
Last Modification Date:
2024-10-26 @ 12:49 PM
Study NCT ID:
NCT03585686
Status:
RECRUITING
Last Update Posted:
2023-03-16
First Post:
2018-07-06
Brief Title:
A Combination of Vemurafenib Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation
Sponsor:
Federal Research Institute of Pediatric Hematology Oncology and Immunology
Organization:
Federal Research Institute of Pediatric Hematology Oncology and Immunology
Study Overview
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
Status:
RECRUITING
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 GBadalyan-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
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 GBadalyan-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
Detailed Description:
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 GBadalyan-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 mgkgd 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 antibacterialantifungal 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 shouldnt 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
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 GBadalyan-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 mgkgd 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 antibacterialantifungal 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 shouldnt 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None