New Therapeutic Target for Toxic Epidermal Necrolysis (TEN) Using Anti-CD38+ Monoclonal Antibodies.
Trial statusNot yet recruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorHospices Civils de Lyon
About this trial
Toxic Epidermal Necrolysis (TEN) are rare diseases that are dermatologic emergencies characterized by widespread epidermal necrosis and sloughing of skin. A hundred patients are affected each year in France. The main symptom is bullous and skin detachment \> 10% which gradually progresses to extensive necrosis of the 100% BSA epidermis. The mortality rate is around 15-20% due to visceral inflammatory injuries and serious bacterial infections. The morbidity is also very important (92% at 1 year), especially ophthalmologic with high risk of blindness. There is currently no effective treatment.
Our team recently demonstrated that the severity of the disease correlates with the quantity and quality of CD8+ T lymphocytes which are activated in the active phase of disease. An activation marker has been identified, the CD38 receptor, which is very strongly expressed on the T clones responsible for the disease in the skin or blood of patients The CD38 receptor is the target of several commercial therapeutic antibodies, including DARATUMUMAB, which is currently used for the treatment of myeloma. DARATUMUMAB is a depleting antibody that eliminates cells strongly expressing this receptor.
The hypothesis is that a single intravenous infusion of DARATUMUMAB upon hospital admission of a patient with drug-induced NET would eliminate pathogenic T cells, thereby slowing disease progression, severity (% BSA with skin detachment, mortality rate) and sequelae.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Adult, over 18 years old, with drug-induced SJS/NET, proven or very strongly suspected (indirect argument of certainty) and confirmed by the evaluator.
SJS or NET or overlap syndrome evolving for less than 7 days prior to inclusion and with a progression of the detachment or rash observed within 48 hours prior to DARATUMUMAB treatment.
Negative hepatitis B screening (HBs, anti HBs and HBc).
The patient (or a trusted support person, family member, or close relative in case of emergency) must be capable of understanding the objectives of the trial and must have given free, informed, and express consent.
Disqualifiers
Patient with Lyell syndrome induced by immunotherapy.
Known hypersensitivity to the active substance (DARZALEX) or to one of the excipients (L-histidine, L-histidine hydrochloride monohydrate, L-methionine, Polysorbate 20 Sorbitol -E420).
Patient with known hereditary fructose intolerance (HFI).
Patient with known history of chronic obstructive pulmonary disease (COPD).
Trial design
Design model
Single group
Treatments tested in this trial
DARATUMUMAB (DARZALEX®)
DrugA single injection of DARZALEX 16 mg/kg body weight administered by intravenous infusion (day 1) in addition to standard symptomatic treatment of NET until re-epidermalization.
Treatment groups
9 Participants
are divided into 1 treatment groupGroup A: ExperimentalExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
From baseline up to 24 hours after end of infusion: tolerance criteria defined as occurence of infusion related reactions, Cytokine release syndrome, main hemostasis parameters or variation in main biological parameters (blood ionogram).
Tolerance criteria according to NCI-CTCAE v5 criteria is defined as occurence of infusion related reactions; Cytokine release syndrome is characterized by increased levels of serum pro-inflammatory mediators; Main hemostasis parameters (prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), thromobin time (TT), and D-dimer (DD); Variation in main biological parameters (blood ionogram).
Time frame
At baseline and 24 hours after completion of the infusion of DARZALEX. If a clinical symptom or reaction is observed during infusion, an additional blood samples will be taken after a single intravenous infusion of DARZALEX 16 mg/kg body weight at day 1.2
Efficacy defined as stop of disease progression at Day 6
The cessation of disease progression at day 6 (D6) will be assessed by evaluating the change in the percentage of body surface area with skin detachment (detached and/or bullous surfaces, and/or associated with Nikolsky's sign) between the baseline (before daratumumab administration) and day 6 (D6), according to the following rules : * ≤ 2% for Stevens-Johnson Syndrome, * ≤ 5% for overlap syndrome * ≤ 10% for Lyell syndrome And without any new lesion with skin detachment. The percentage of body surface area with skin detachment will be evaluated based on the stable burn table using the E-Burn® application Day 6 after an intravenous injection of darzalex (16mg/kg) in addition to the reference symptomatic treatment (Day 1 = infusion of darzalex treatment)
Time frame
Day 6 after an intravenous injection of darzalex (16mg/kg)3
The occurrence of grade 3 or higher cardiovascular, renal, thyroid, or intestinal adverse events within two months of injection (seven times the nine-day half-life of daratumumab)
Occurrence of grade \>=3 cardiovascular, renal, thyroid or intestinal adverse events, according to NCI-CTCAE v5 criteria.
Time frame
Up to 2 months after the DARATUMUMAB infusion.Secondary outcomes
1
Measure time between index date (onset of first symptom) and initiation of DARATUMUMAB treatment (Day 1)
Total number of days between the unique intravenous infusion of DARATUMUMAB at day 1 and onset of first symptoms leading to the diagnosis of TEN (Toxic Epidermal Necrolysis)
Time frame
From date of onset of first symptoms leading to the diagnosis of TEN (Toxic Epidermal Necrolysis) until the unique infusion of DARATUMUMAB treatment at (Day 1)]2
Stop TEN progression delay: Time in days from start of DARATUMUMAB injection (Day 1) to cessation of progression
Total number of days between intravenous infusion of DARATUMUMAB (day 1) and the documented stopping progression of TEN
Time frame
From the date of DARATUMUMAB infusion (Day 1) until the documented date of stopping progression of TEN, assessed up to 12 months or date of death from any cause3
Complete re-epidermalization delay: Time in days from start of DARATUMUMAB infusion (Day 1) to complete re-epidermalization
The complete re-epidermalization is defined as disappearance of skin erosions AND return to normal skin. The complete re-epidermalization is the total number of days between DARATUMUMAB injection (day 1) to complete re-epidermalization.
Time frame
From the date of DARATUMUMAB infusion (day 1) until the documented date of complete re-epidermization, assessed up to 12 months or date of death from any cause.4
Hospital stay : measure the length of stay in one of the intensive care, burn, or internal medicine departments at Hôpital Édouard Herriot.
Length of stay in E. Herriot hospital units care: Time between admission and discharge from E Herriot hospital
Time frame
From admission to end of 12-month follow-up periodSponsors and contacts
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Source ClinicalTrials.gov
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