Study to Assess the Efficacy and Safety of Emapalumab in Primary Haemophagocytic Lymphohistiocytosis

Study Overview
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Brief Summary
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The purpose of this study is to expand the knowledge on the efficacy and safety of emapalumab (previously known as NI-0501) as a treatment for primary haemophagocytic lymphohistiocytosis (HLH) patients, with special focus on long-term outcomes and quality of life assessments. Emapalumab can be administered as the first-line therapy to patients not previously treated with the current standard of care, or can be given to patients who have either failed or were unable to tolerate the available standard of care. Emapalumab is to be administered until the start of conditioning for hematopoietic stem cell transplantation (HSCT), with an anticipated duration ranging from a minimum of 4 weeks to approximately 12 weeks and not exceeding 6 months. After treatment completion, patients will continue in the study for long-term follow-up until 1 year after either HSCT or last emapalumab infusion (if HSCT is not performed).

Official Title
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An Open-label, Single Arm, Multicenter Study to Broaden Access to Emapalumab, an Anti-Interferon Gamma (Anti-IFNγ) Monoclonal Antibody, and to Assess Its Efficacy, Safety, Impact on Quality of Life, and Long-term Outcome in Pediatric Patients With Primary Hemophagocytic Lymphohistiocytosis

Conditions
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Primary Hemophagocytic Lymphohistiocytosis

Intervention / Treatment
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* Drug: Emapalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary HLH patients with active disease. Treatment naïve patients or patients having already received HLH conventional therapy, but having not responded, not achieved a satisfactory response or worsened, or reactivated, or are unable to tolerate current standard of care. Informed consent signed by the patient or by the patient's legally authorized representative. Received guidance on contraception. Exclusion Criteria: Diagnosis of secondary HLH consequent to a proven rheumatic, metabolic or neoplastic disease. Active mycobacteria, Histoplasma capsulatum, Shigella, Salmonella, Campylobacter or Leishmania infections. Evidence of latent tuberculosis. Presence of malignancy. Concomitant disease or malformation severely affecting cardiovascular, pulmonary, central nervous system (CNS), liver, or renal function, that in the opinion of the Investigator may significantly affect the likelihood to respond to treatment and/or the assessment of emapalumab safety and/or efficacy. History of hypersensitivity or allergy to any component of the study regimen. Receipt of a 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. Pregnant or lactating female patients.

Ages Eligible for Study
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Maximum 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> | Drug: Emapalumab<br>* Emapalumab will be administered by intravenous infusion, twice weekly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response at Week 8 or End of Treatment (if earlier) | Number of patients achieving either Complete or Partial Response or HLH Improvement, at Week 8 or EOT (whichever occurs earlier). | Up to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Number of patients surviving, including survival to HSCT and survival after either HSCT or last emapalumab infusion (if HSCT was not performed). | Up to 18 months | 
| Event-free Survival | The duration of event-free survival was defined as time from HSCT to date of (whichever occurs first): death from any cause, graft failure, or HLH reactivation. | Up to 18 months | 
| Overall Response at Start of Conditioning | Number of patients achieving either a Complete or Partial Response or HLH Improvement, at start of conditioning (or at last emapalumab infusion if HSCT is not performed). | Up to 6 months | 
| Duration of Response | Duration of response, i.e., maintenance of the response achieved at any time during the study (with censoring time at start of conditioning for patients with no event) calculated only for patients showing confirmed overall response. | Up to 18 months | 
| Time to Response | Time to first response at any time during the study. | Up to 18 months | 
| Number of Patients Reducing Glucocorticoids by 50% or More | Number of patients able to reduce glucocorticoids by 50% or more of the baseline dose during emapalumab treatment. | Up to 6 months | 
| Number of Patients Proceeding to HSCT | Number of patients able to proceed to HSCT when deemed indicated. | Up to 18 months | 
| Change in PedsQL Score | Assessment of the quality of life using the PedsQL Pediatric Quality of Life Inventory. The PedsQL uses a 100-point scale ranging from 0 to 100 with higher values indicating better quality of life. | Up to 6 months | 
| Change in BASES Score | Assessment of the quality of life using BASES, the Behavioral, Affective and Somatic Experiences questionnaires. The BASES questionnaire is a validated 38-item questionnaire; a reduced nonvalidated 22-item version of the questionnaire is used in an exploratory nature for the secondary endpoint. BASES subscale scores were calculated using a 5-point Likert scale from 1 to 5 for all items and they will be weighted equally to calculate subscale scores for the following domains: Physical Discomfort (5 items - where 1 is considered best response) Cooperation/Compliance (5 items - where 1 is considered best response) Mood/Behavior (7 items - where 5 is considered best response) Quality of Interactions (3 items - where 1 is considered best response) Activity/Sleep (2 items - where 5 is considered best response for patient's activity level and 1 is considered best response for patient's sleeping) | Up to 6 months | 
| Incidence, Severity, Causality and Outcomes of AEs (serious and non-serious) | Incidence of adverse events. | Up to 18 months | 
| Evolution of Laboratory Parameters | Number of patients experiencing shifts from baseline in the following relevant laboratory parameters are reported: Biochemistry: glucose ferritin, C-reactive protein (CRP), liver function (alkaline phosphatase [ALP], alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma glutamyl transferase [γGT], lactate dehydrogenase [LDH], bilirubin, renal function (albumin, creatinine, urea), triglycerides Complete blood count: basophils, basophils/leukocytes, eosinophils, eosinophils/leukocytes, hematocrit, hemoglobin, large unstained cells, lymphocytes, lymphocytes/leukocytes, monocytes, monocytes/leukocytes, neutrophils band form, neutrophils band form/leukocytes, platelets, erythrocytes, leukocytes Coagulation tests (activated partial thromboplastin time [aPTT], prothrombin time), D-dimer, fibrinogen | Up to 6 months | 
| Number of Patients who Discontinued Emapalumab Treatment | Number of patients who discontinued emapalumab treatment for safety reasons. | Up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interferon-gamma, NI-0501, primary HLH, emapalumab