Clinical trial NCT02089724: Long-term Outcome After Vemurafenib / BRAF Inhibitors Interruption in Erdheim-chester Disease
Official title: Long-term Outcome After Vemurafenib / BRAF Inhibitors Interruption in Erdheim-chester Disease
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Erdheim-Chester Disease
Lead sponsor: Groupe Hospitalier Pitie-Salpetriere
Sponsor class: OTHER
Collaborators: name: Memorial Sloan Kettering Cancer Center
First posted: 2014-03-18
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study population description is patients with Erdheim-Chester disease who have been treated with vemurafenib or other BRAF inhibitor

Brief summary: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. Diagnosis of ECD is based on clinical symptoms, imaging and histology with infiltration of tissues by foamy CD68 positive CD1a negative histiocytes.

Because half of the ECD patients carry a BRAFV600E mutation, we recently proposed vemurafenib, an inhibitor of mutant BRAF, as a possible targeted therapy. We have treated more than10 patients with refractory ECD with life-threatening manifestations associated with the BRAFV600E mutation and observed a short and long term efficacy.

However, vemurafenib may have several side effects and long term administration of this drug has not been evaluated. In other diseases such as melanoma, duration of administration is usually shorter, due to bad prognosis of the disease and progression despite treatment.

As in long-term follow-up, ECD patients with vemurafenib seem to have a stable disease, we want to evaluate the possibility of treatment interruption as this is what we do in our current practice. Other BRAF inhibitors, such as dabrafenib, have recently been proposed for treating BRAF mutated histiocytoses. Other BRAF inhibitor interruption treatment should also be prospectively evaluated.

Detailed description: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. Diagnosis of ECD is based on clinical symptoms, imaging and histology with infiltration of tissues by foamy CD68 positive+ CD1a negative histiocytes. The clinical course mainly depends on the extent and distribution of the disease, and ranges from asymptomatic bone lesions to life-threatening manifestations. The overall mortality remains high (22% of the 100 ECD patients seen at our institution in August 2013).

Due to the rare nature of the disease (500 cases worldwide have been reported since 1930) no prospective therapeutic trial has been performed. Interferon alpha (IFN alpha), in its standard or pegylated forms, is the first line therapy for ECD. However, long-term IFN alpha treatment can lead to severe side effects. Moreover, some patients with CNS and/or cardiovascular infiltrations, the two lethal organ involvement, develop secondary resistance to high doses of IFN alpha. For refractory patients, anakinra, cladribine, tyrosine kinase inhibitors, or infliximab have been proposed as second line treatments. The optimal second line therapeutic strategy remains however to be defined, mostly because these treatments have been evaluated in only small numbers of patients.

Because half of the ECD patients carry a BRAFV600E mutation, we recently proposed vemurafenib, an inhibitor of mutant BRAF, as a possible targeted therapy. We have treated 10 patients with refractory ECD with life-threatening manifestations associated with the BRAFV600E mutation and observed a short and long term efficacy (median follow-up 9 months).

However, vemurafenib may have several side effects and long term administration of this drug has not been evaluated. In other diseases such as melanoma, duration of administration is usually shorter, due to bad prognosis of the disease and progression despite treatment.

As in long-term follow-up, ECD patients with vemurafenib seem to have a stable disease, we want to evaluate the possibility of treatment interruption as this is what we do in our current practice. Other BRAF inhibitors, such as dabrafenib, have recently been proposed for treating BRAF mutated histiocytoses.

Eligibility criteria: Inclusion Criteria:

* Age superior or equal to 18 years
* Clinical and radiological presentation concordant with ECD
* Presence of histological proof of ECD
* Treatment with vemurafenib or other BRAF inhibitor
* Agreement to participate

Exclusion Criteria:

* Pregnancy
* Patients who exceed the safe weight limit of the PET/CT bed (220 kg) or who cannot fit through the PET/CT bore (diameter 70 cm).

Primary outcomes:
measure: PET scan response
timeFrame: 6 months (M6)
Secondary outcomes:
measure: Specific organ assessment (cardiac, retroperitoneal, neurological)
timeFrame: Months 6 and Months 12
measure: PET scan
timeFrame: Months 12
measure: CRp value (mg/liter)
timeFrame: Months 6 and Months 12
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Paris
country: France
facility: AP-HP, Groupe Hospitalier Pitié-Salpêtrière
Study officials:
affiliation: Groupe Hospitalier Pitié-Salpêtrière
name: Julien Haroche, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Groupe Hospitalier Pitié-Salpêtrière
name: Fleur Cohen Aubart, MD, PhD
role: STUDY_DIRECTOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Eli L. Diamond, MD, PhD
role: STUDY_CHAIR
References:
citation: Haroche J, Arnaud L, Cohen-Aubart F, Hervier B, Charlotte F, Emile JF, Amoura Z. Erdheim-Chester disease. Curr Rheumatol Rep. 2014 Apr;16(4):412. doi: 10.1007/s11926-014-0412-0.
citation: Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, Besnard S, Donadieu J, Amoura Z. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013 Feb 28;121(9):1495-500. doi: 10.1182/blood-2012-07-446286. Epub 2012 Dec 20.
citation: Haroche J, Charlotte F, Arnaud L, von Deimling A, Helias-Rodzewicz Z, Hervier B, Cohen-Aubart F, Launay D, Lesot A, Mokhtari K, Canioni D, Galmiche L, Rose C, Schmalzing M, Croockewit S, Kambouchner M, Copin MC, Fraitag S, Sahm F, Brousse N, Amoura Z, Donadieu J, Emile JF. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood. 2012 Sep 27;120(13):2700-3. doi: 10.1182/blood-2012-05-430140. Epub 2012 Aug 9.