Clinical trial NCT05063110: Treatment of Non Severe Hemophagocytosis Lymphohistiocytosis With ITACITINIB
Official title: Treatment of Non Severe Hemophagocytosis Lymphohistiocytosis With ITACITINIB a Phase II Prospective Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Adults Patients Having Non Severe HLH
Keywords: Hemophagocytosis lymphohistiocytosis
JAK 1
Itacitinib
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Incyte Corporation
First posted: 2021-09-30
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This project aims to test the effectiveness of ITACITINIB in sporadic Hemophagocytosis Lymphohistiocytosis (HLHs)

Detailed description: 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

Eligibility criteria: 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

Primary outcomes:
measure: Efficacy of ITACITINIB
timeFrame: At day 15
Secondary outcomes:
measure: Response rate of ITACITINIB at D8 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria
timeFrame: day 8
measure: Efficacy at the day of etiologic treatment if patients received at least 7 days of treatment (ITACITINIB taken until J15)
timeFrame: At day 15
measure: Toxicity of ITACITINIB
timeFrame: 21 months
measure: Rescue therapy
timeFrame: 21 months
measure: Reduction of plasma cytokines level between D0 and D15 and correlation to the therapeutic response to D15
timeFrame: At day 15
measure: Clinical, biological, associated diseases characteristics of patients having CR, PR, Progression
timeFrame: 21 months
measure: Overall survival at 3
timeFrame: 3 months
measure: Response rate of ITACITINIB at D30 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria
timeFrame: day 30
measure: Response rate of ITACITINIB at D90 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria
timeFrame: day 90
Other outcomes:
Locations:
city: Bobigny
country: France
facility: Hôpital Avicenne
Study officials:
References:
citation: Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. 2005 Feb;203:165-79. doi: 10.1111/j.0105-2896.2005.00224.x.
citation: Pachlopnik Schmid J, Ho CH, Chretien F, Lefebvre JM, Pivert G, Kosco-Vilbois M, Ferlin W, Geissmann F, Fischer A, de Saint Basile G. Neutralization of IFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol Med. 2009 May;1(2):112-24. doi: 10.1002/emmm.200900009.
citation: Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood. 2005 Feb 15;105(4):1648-51. doi: 10.1182/blood-2004-08-2997. Epub 2004 Oct 5.
citation: Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2013 May 23;32(21):2601-13. doi: 10.1038/onc.2012.347. Epub 2012 Aug 6.
citation: Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood. 2016 Jul 7;128(1):60-71. doi: 10.1182/blood-2016-02-700013. Epub 2016 May 24.