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

NCT03585686 | Unknown Phase 2

• 1 other identifier: NCPHOI-2017-02
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Langerhans Cell Histiocytosis

Keywords

LCH; Langerhans; histiocytosis; vemurafenib; BRAF

Outcome Measures

Primary Outcomes (1)

• The overall response rate (ORR) proportion

  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.

  16 weeks

Secondary Outcomes (3)

• The reactivation/progression free survival

  1 year

• The proportion of of patients with severe adverse effects

  30 days

• Overall survival

  2 years

Study Arms (1)

vemurafenib

EXPERIMENTAL

vemurafenib, Cytarabine, 2-chlorodeoxyadenosine

Drug: Vemurafenib; Drug: Cytarabine; Drug: 2-chlorodeoxyadenosine

Interventions

Vemurafenib DRUG

vemurafenib 20 mg/kg/day

vemurafenib

Cytarabine DRUG

100 mg/m2/12 h, days 1-5

vemurafenib

2-chlorodeoxyadenosine DRUG

6 mg/m2/d, days 1-5

vemurafenib

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Federal Research Institute of Pediatric Hematology, Oncology and Immunology: lead

Study Sites (1)

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

Moscow, 117997, Russia

RECRUITING

Related Publications (1)

• Evseev D, Osipova D, Kalinina I, Raykina E, Ignatova A, Lyudovskikh E, Baidildina D, Popov A, Zhogov V, Semchenkova A, Litvin E, Kotskaya N, Cherniak E, Voronin K, Burtsev E, Bronin G, Vlasova I, Purbueva B, Fink O, Pristanskova E, Dzhukaeva I, Erega E, Novichkova G, Maschan A, Maschan M. Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH. Blood Adv. 2023 Sep 26;7(18):5246-5257. doi: 10.1182/bloodadvances.2022009067.

  PMID: 37216396 DERIVED

MeSH Terms

Conditions

Histiocytosis, Langerhans-Cell; Histiocytosis

Interventions

Vemurafenib; Cytarabine; Cladribine

Condition Hierarchy (Ancestors)

Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Deoxyadenosines; Deoxyribonucleosides; Ribonucleosides

Central Study Contacts

Dmitry Evseev, MD

CONTACT

+79175196374; dmitryevseev1991@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2018
• First Posted: July 13, 2018
• Study Start: June 26, 2018
• Primary Completion: April 1, 2023
• Study Completion: December 1, 2023
• Last Updated: March 16, 2023

Record last verified: 2023-03

Locations

RU (1)