Langerhans Cell HistiocytosisPhase 2NCT03585686
A Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation
A Phase 2 study testing Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in people with Langerhans Cell Histiocytosis, run by Federal Research Institute of Pediatric Hematology, Oncology and Immunology at 1 site in Russia.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Langerhans Cell Histiocytosis
- What is being tested?
- Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteRussia
- Study dates
- 26 Jun 2018to Dec 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- withdrawal of informed consent
- QTc > 0.5 s or long QT syndrome
- use of antiarrhythmic medication
- persistent electrolytic disorders
Trial locations and contacts
1 site in 1 country.
Russia1 site, 1 recruiting
- Recruiting
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Moscow, 117997
Zhanna Shekhovtsova, MD, 4956647078 ext. 7538, zhanna.shekhovtsova@fccho-moscow.ru
Eugene Pashanov, PhD, +79262205578, e.pashanov@gmail.com
About this study
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
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.
Read more
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.
Read the 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 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 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 mg/kg/d 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 antibacterial/antifungal 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 shouldn't 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.
- Conditions
- Langerhans Cell Histiocytosis
- Being tested
- Vemurafenib, Cytarabine, 2-chlorodeoxyadenosine
- Keywords
- LCH, Langerhans, histiocytosis, vemurafenib, BRAF
- Medical subject headings
- Histiocytosis, Langerhans-Cell, Histiocytosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VemurafenibDrug
vemurafenib 20 mg/kg/day
CytarabineDrug
100 mg/m2/12 h, days 1-5
2-chlorodeoxyadenosineDrug
6 mg/m2/d, days 1-5
| Study group | Role | What they receive |
|---|---|---|
| vemurafenib | Experimental | vemurafenib, Cytarabine, 2-chlorodeoxyadenosine Receives: Drug: Vemurafenib; Drug: Cytarabine; Drug: 2-chlorodeoxyadenosine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 16 weeks
Secondary outcomes (3)
The reactivation/progression free survival
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.
Measured: 1 year
The proportion of of patients with severe adverse effects
The proportion of of patients with severe adverse effects of therapy according to CTCAE (ver 4.0)
Measured: 30 days
Overall survival
OS is a time from the therapy start to death due to any cause or to the last evaluation.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jul 2018
- Study start26 Jun 2018
- Primary completionApr 2023 (estimated)
- Study completionDec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Langerhans Cell HistiocytosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Federal Research Institute of Pediatric Hematology, Oncology and Immunology
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03585686
- Sponsor's protocol ID
- NCPHOI-2017-02
- Status last verified
- Mar 2023
- First submitted
- 6 Jul 2018
- Last updated
- 16 Mar 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 37216396
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03585686
- Acronym / sponsor ID
- NCPHOI-2017-02
- Conditions
- Langerhans Cell Histiocytosis
- Keywords
- LCH, Langerhans, histiocytosis, vemurafenib, BRAF
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Federal Research Institute of Pediatric Hematology, Oncology and ImmunologyUniversity, hospital or other
- Study start
- 26 Jun 2018 (actual)
- Primary completion
- Apr 2023 (estimated)
- Study completion
- Dec 2023 (estimated)
- First posted
- 13 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 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 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 mg/kg/d 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 antibacterial/antifungal 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 shouldn't 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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| vemurafenib | Experimental | Drug: Vemurafenib, Drug: Cytarabine, Drug: 2-chlorodeoxyadenosinevemurafenib, Cytarabine, 2-chlorodeoxyadenosine |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (4 listed)
- withdrawal of informed consent
- QTc > 0.5 s or long QT syndrome
- use of antiarrhythmic medication
- persistent electrolytic disorders
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vemurafenibvemurafenib 20 mg/kg/day | Drug | vemurafenib |
| Cytarabine100 mg/m2/12 h, days 1-5 | Drug | vemurafenib |
| 2-chlorodeoxyadenosine6 mg/m2/d, days 1-5 | Drug | vemurafenib |
Primary outcome
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.
3 secondary outcomes
The reactivation/progression free survival
Time frame: 1 year
The proportion of of patients with severe adverse effects
Time frame: 30 days
Overall survival
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2023.
- Derived from this study: PubMed 37216396Evseev 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in people with Langerhans Cell Histiocytosis, run by Federal Research Institute of Pediatric Hematology, Oncology and Immunology at 1 site in Russia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 16 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Russia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Dmitry Evseev, MD (+79175196374, dmitryevseev1991@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The overall response rate (ORR) proportion (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03585686, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2023.