A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Emapalumab in Adult Patients With HLH

Study Overview
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Brief Summary
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Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by uncontrolled hyperinflammation which may develop on the background of several clinical conditions (e.g. autoimmune disease, infection, malignancy). Emapalumab (previously referred to as NI-0501) is a monoclonal antibody neutralizing interferon-gamma (IFN-gamma), a key cytokine driving the inflammation and tissue damage seen in HLH. The purpose of this study is to assess the efficacy, safety and pharmacokinetics of emapalumab in adult patients with secondary HLH.

Detailed Description
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Study NI-0501-10 is an open-label, single arm, multicenter, Phase 2/3 interventional study. The study enrolls adult patients with hemophagocytic lymphohistiocytosis (HLH), specifically newly diagnosed patients with malignancy-associated HLH (M-HLH), and newly diagnosed or previously treated patients with non-malignancy-associated HLH.

Official Title
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A Phase 2/3, Open-label, Single Arm, Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Emapalumab in Adult Patients With Hemophagocytic Lymphohistiocytosis

Conditions
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Hemophagocytic Lymphohistiocytoses

Intervention / Treatment
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* Drug: Emapalumab-Lzsg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients of age 18 and older at the time of HLH diagnosis Fulfilment of 5 of the 8 HLH-2004 clinical criteria Patients diagnosed with malignancy-associated HLH must be treatment naïve; patients diagnosed with HLH driven by any other etiology or idiopathic can be either treatment naïve or treatment experienced Patients with non-malignancy-associated or idiopathic HLH who have already received conventional therapy for HLH must have failed prior treatment as per the treating physician's judgement Informed consent signed by the patient or by the patient's legally authorized representative(s) (as required by local law) Willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug, if female and of childbearing potential. Exclusion Criteria: Primary HLH Current or scheduled administration of therapies known to trigger the cytokine release syndrome (e.g. chimeric antigen receptor (CAR)-modified T cells, bispecific T cell-engaging antibodies) Current or scheduled administration of PD-1/PD-L1/CTLA-4 inhibitors Life-expectancy associated with the underlying disease (triggering HLH) < 3 months Ongoing participation in an investigational trial, or administration of any investigational treatment within 30 days History of hypersensitivity or allergy to any components of emapalumab Active mycobacteria, Histoplasma capsulatum, or Leishmania infections Evidence of latent tuberculosis Receipt of a bacille Calmette-Guerin (BCG) vaccine within 12 weeks prior to Screening Receipt of a live or attenuated live (other than BCG) vaccine within 6 weeks prior to Screening

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: Emapalumab<br>Patients were administered Emapalumab-Lzsg by intravenous (i.v.) infusion over a period of 1 to 2 hours, at an initial dose of 6 mg/kg and continued at 3 mg/kg, every 3 days for the first 2 weeks (Study Day [SD] 15), and then twice-a-week. If the treating physician deemed appropriate, the dose of emapalumab could be increased (up to 10 mg/kg), guided by clinical and laboratory response. | Drug: Emapalumab-Lzsg<br>* Patients were administered Emapalumab-Lzsg by intravenous (i.v.) infusion over a period of 1 to 2 hours, at an initial dose of 6 mg/kg and continued at 3 mg/kg, every 3 days for the first 2 weeks (Study Day [SD] 15), and then twice-a-week. If the treating physician deemed appropriate, the dose of emapalumab could be increased (up to 10 mg/kg), guided by clinical and laboratory response.<br>* Other names: NI-0501;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response | Achievement of either a Complete or Partial Response Complete Response is adjudicated if the following are observed: No fever = body temperature <37.5°C Normal spleen size No cytopenia = Absolute Neutrophil Counts >=1.0x10^9/L and platelet count >=100x10^9/L [absence of G-CSF and transfusion support must be documented for at least 4 days to report no cytopenia] No hyperferritinemia = serum level is <2000 µg/L No evidence of coagulopathy, i.e., normal D-Dimer and/or normal (>150 mg/dL) fibrinogen levels No neurological and CSF abnormalities attributed to HLH No sustained worsening of sCD25 (as indicated by at least two consecutive measurements that are >2-fold higher than baseline) Partial Response is adjudicated if there is an improvement (>50% change from baseline or normalization) of at least 3 HLH clinical and laboratory criteria (including Central Nervous System abnormalities). | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response on Treatment | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Week 4; End of Treatment Visit (on average of 12 weeks) | 
| Overall Response | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | End of Treatment Visit (on average of 12 weeks) | 
| Overall Survival | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | End of Treatment Visit (on average of 12 weeks) | 
| Time to Complete Response or Partial Response | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Week 4; End of Treatment visit (on average of 12 weeks) | 
| Duration of Response | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Up to 1 year after last emapalumab administration | 
| Hemophagocytic Lymphohistiocytosis Relapse | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Up to 1 year after last emapalumab administration | 
| Incidence, Severity, Causality and Outcomes of Serious Adverse Events and Non-serious Adverse Events | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Up to 1 year after last emapalumab administration | 
| Serum Concentrations of Emapalumab | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Up to 1 year after last emapalumab administration | 
| Serum Biomarker Levels | Levels of interferon-gamma, C-X-C chemokine ligand 9, soluble CD25, interleukin-6. | Up to 1 year after last emapalumab administration | 
| Incidence of Anti-Drug Antibodies Against Emapalumab | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. | Up to 1 year after last emapalumab administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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interferon gamma, emapalumab, adult HLH, malignancy-associated HLH, CXCL9