Treatment of Non Severe Hemophagocytosis Lymphohistiocytosis With ITACITINIB (HLH-JAK)

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

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

Study Overview

• Status: Recruiting
• Conditions: Adults Patients Having Non Severe HLH
• Intervention / Treatment: Drug: Itacitinib

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

• Study Type: Interventional
• Enrollment (Anticipated): 63
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Coralie BLOCH-QUEYRAT, MD; Phone Number: 0148957732; Email: coralie.bloch-queyrat@aphp.fr
• Study Contact Backup: Name: Zahia Ben Abdesselam, Project Manager; Phone Number: 0148957435; Email: zahia.ben-abdesselam@aphp.fr

Study Locations

• France
  • Bobigny, France, 93000
    • Recruiting
    • Hopital Avicenne
    • Contact: BLOCH Coralie, Dr; Email: coralie.bloch-queyrat@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment arm; 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; Administration of 300 mg of ITACITINIB per os every day for 30 days.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Incyte Corporation

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): February 1, 2024

Study Registration Dates

• First Submitted: September 2, 2021
• First Submitted That Met QC Criteria: September 22, 2021
• First Posted (Actual): September 30, 2021

Study Record Updates

• Last Update Posted (Actual): August 23, 2022
• Last Update Submitted That Met QC Criteria: August 22, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Itacitinib; Hemophagocytosis lymphohistiocytosis; JAK 1
• Other Study ID Numbers: APHP 201454; 2021-000407-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No