Treatment of Non Severe Hemophagocytosis Lymphohistiocytosis With ITACITINIB

Study Overview
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Brief Summary
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This project aims to test the effectiveness of ITACITINIB in sporadic Hemophagocytosis Lymphohistiocytosis (HLHs)

Detailed Description
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This project aims to test the effectiveness of ITACITINIB in sporadic Hemophagocytosis Lymphohistiocytosis (HLHs). The existence of an IFN-γ signature, in HLHs, is a strong rational for testing the use of a JAK1 inhibitor in the treatment of HLHs. We hypothesize that ITACITINIB, an inhibitor of JAK-1, may be a therapeutic of interest in the treatment of non-severe HLHs in replacement of corticosteroids by inhibiting the production and effects of IFN-γ but also those of other pro-inflammatory cytokines. The use JAK-1 inhibitor instead of corticosteroids in patients with HLHs without any sign of severity is justified by its probable lesser toxicity and higher efficiency. In this proof of concept study, because of the vital risk associated with severe HLH and the efficacy of Etoposide in this setting, we will first include only patients with moderate HLHs

Official Title
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Treatment of Non Severe Hemophagocytosis Lymphohistiocytosis With ITACITINIB a Phase II Prospective Trial

Conditions
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Adults Patients Having Non Severe HLH

Intervention / Treatment
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* Drug: Itacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients age > 18 years, Patient is willing to provide written informed consent prior to enrolment and agrees to follow the protocol Patient known to have systemic juvenile idiopathic arthritis are classified as having HLH Negative pregnancy test for woman of childbearing potential, woman of childbearing potential should have reliable contraception for the duration of the study Be either affiliated to, or a beneficiary of, a social security category Exclusion Criteria: Organ failure: confusion, organic kidney failure KDIGO 2 criteria, liver failure (Factor V < 50%), heart failure, respiratory failure. Fibrinogen < 0.50 g/l, platelets <20G/L Indication to intensive care unit transfer on an organ failure requiring assistance (dialysis, Ventilation (assisted or VNI), shock regardless of the origin. Breastfeeding women Patient participating in another investigational therapeutic study Women with a positive pregnancy test or not willing to take contraceptive measures Known allergies, hypersensitivity, or intolerance to any of the ITACITINIB or excipients, or similar compounds Current or history of recurrent infections, including HBV, HCV Participants with active HBV or HCV infection that requires treatment or who are at risk for HBV reactivation (ie Positive HBs Ag serology) Candidates positive for HCV antibody and positive PCR RNA HCV HIV infection with positive viral charge Protected adults (including individual under guardianship by court order) Vulnerable adults, under a safeguard of justice measure Adults deprived of their liberty by judicial or administrative decision Persons under psychiatric care without their consent Persons admitted to social institution for purposes other this research Adults under legal protection (guardianship or curatorship) Persons unable to express their consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>300 mg of ITACITINIB will be administrated per os every day for 30 days, dose with reduction to 200 mg per safety is allowed if AEs are observed or if co-administered a strong CYP3A inhibitor | Drug: Itacitinib<br>* Administration of 300 mg of ITACITINIB per os every day for 30 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of ITACITINIB | Efficacy at day 15 of ITACITINIB treatment in non-severe adults HLH | At day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate of ITACITINIB at D8 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria | Response rate at D8 of treatment | day 8 | 
| Efficacy at the day of etiologic treatment if patients received at least 7 days of treatment (ITACITINIB taken until J15) | Rate of complete response to ITACITINIB treatment for HLHs in adults without any sign of severity at the day of etiologic treatment if patients have been treated by ITACITINIB at least during seven days. Response to ITACITINIB is evaluated at the day of etiologic treatment on the major and minor diagnostic criteria of HLH | At day 15 | 
| Toxicity of ITACITINIB | Toxicity of ITACITINIB not related to evolution of HLH (cytopenia, worsening of hepatic balance, secondary infections) | 21 months | 
| Rescue therapy | In the case of worsening, treatment will be stopped and switch for HLH specific treatment as VP16, (etoposide) | 21 months | 
| Reduction of plasma cytokines level between D0 and D15 and correlation to the therapeutic response to D15 | Range of decrease in plasma rate of IFN-Gamma, IP-10, Il-1, Il-6, IL-10, TNF-alpha, between D0 and D15 of ITACITINIB treatment in each patient group: response and progression | At day 15 | 
| Clinical, biological, associated diseases characteristics of patients having CR, PR, Progression | Clinical, biological, associated diseases and evolutions characteristics of patients in each response | 21 months | 
| Overall survival at 3 | Overall survival at 3 | 3 months | 
| Response rate of ITACITINIB at D30 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria | Response rate at D30 of treatment | day 30 | 
| Response rate of ITACITINIB at D90 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria | Response rate at D90 of treatment | day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophagocytosis lymphohistiocytosis, JAK 1, Itacitinib