Long-term Outcome After Vemurafenib / BRAF Inhibitors Interruption in Erdheim-chester Disease (LOVE)
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| ClinicalTrials.gov Identifier: NCT02089724 |
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Recruitment Status : Unknown
Verified October 2016 by Dr Cohen Aubart, Groupe Hospitalier Pitie-Salpetriere.
Recruitment status was: Recruiting
First Posted : March 18, 2014
Last Update Posted : October 28, 2016
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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.
| Condition or disease |
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| Erdheim-Chester Disease |
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.
| Study Type : | Observational |
| Estimated Enrollment : | 20 participants |
| Observational Model: | Cohort |
| Time Perspective: | Prospective |
| Official Title: | Long-term Outcome After Vemurafenib / BRAF Inhibitors Interruption in Erdheim-chester Disease |
| Study Start Date : | March 2014 |
| Estimated Primary Completion Date : | December 2016 |
| Estimated Study Completion Date : | April 2019 |
| Group/Cohort |
|---|
| vemurafenib/other BRAF inhibitors |
- PET scan response [ Time Frame: 6 months (M6) ]Modification of SUVmax between M0 and M6 will be used as the main evaluation criteria for each lesion. As assessed by PERCIST criteria, patients will be classified as complete metabolic responders (CMR; complete resolution of pathologic 18F-FDG uptake), partial metabolic responders (PMR; reduction of a minimum of 30% in activity of target lesions), stable metabolic disease (SMD; not CMR, PMR, or progressive metabolic disease (PMD; increase of a minimum of 30% in activity of target lesions or presentation of a new lesion). In contrast to the PERCIST suggestions, tumor SUVmax rather than peak SUV will be measured. Target lesion will be defined by the most active lesion on FDG-PET/CT study before treatment and, for each patient, one or two secondary target lesions among the most active lesions will also be studied. Side-by-side image review and analysis will be performed to ascertain that the SUVmax is derived from the same lesions on baseline and follow-up scans
- Specific organ assessment (cardiac, retroperitoneal, neurological) [ Time Frame: Months 6 and Months 12 ]
- PET scan [ Time Frame: Months 12 ]
- CRp value (mg/liter) [ Time Frame: Months 6 and Months 12 ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Non-Probability Sample |
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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02089724
| Contact: Julien Haroche, MD, PhD | +33 1 42 17 80 37 | julien.haroche@psl.aphp.fr | |
| Contact: Fleur Cohen Aubart, PD, PhD | +33 1 42 17 82 42 | fleur.cohen@psl.aphp.fr |
| United States, New York | |
| Memorial Sloan Kettering Cancer Center | Recruiting |
| New York, New York, United States, 10065 | |
| Contact: Eli L. Diamond, MD, PhD diamonel@mskcc.org | |
| Principal Investigator: Eli L. Diamond, MD, PhD | |
| Sub-Investigator: Omar Abdel-Wahab, MD | |
| France | |
| AP-HP, Groupe Hospitalier Pitié-Salpêtrière | Recruiting |
| Paris, France, 75013 | |
| Contact: Julien Haroche, MD, PhD +33 1 42 17 80 37 julien.haroche@psl.aphp.fr | |
| Contact: Fleur Cohen Aubart, MD, PhD +33 1 42 17 82 42 fleur.cohen@psl.aphp.fr | |
| Principal Investigator: Julien Haroche, MD, PhD | |
| Sub-Investigator: Fleur Cohen Aubart, MD, PhD | |
| Sub-Investigator: Zahir Amoura, MD, MSc | |
| Principal Investigator: | Julien Haroche, MD, PhD | Groupe Hospitalier Pitié-Salpêtrière | |
| Study Director: | Fleur Cohen Aubart, MD, PhD | Groupe Hospitalier Pitié-Salpêtrière | |
| Study Chair: | Eli L. Diamond, MD, PhD | Memorial Sloan Kettering Cancer Center |
| Responsible Party: | Dr Cohen Aubart, Groupe Hospitalier Pitie-Salpetriere |
| ClinicalTrials.gov Identifier: | NCT02089724 |
| Other Study ID Numbers: |
medint001 |
| First Posted: | March 18, 2014 Key Record Dates |
| Last Update Posted: | October 28, 2016 |
| Last Verified: | October 2016 |
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Erdheim-Chester Disease Histiocytosis, Non-Langerhans-Cell Histiocytosis Lymphatic Diseases |