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

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

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, including 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).

Study Overview

• Status: Completed
• Conditions: Primary Hemophagocytic Lymphohistiocytosis
• Intervention / Treatment: Drug: Emapalumab

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada, QC H3T 1C5
    • Hopital Ste-Justine Research Center
  • Toronto, Canada, ON M5G 1X8
    • Hospital for Sick Children
  • Vancouver, Canada, V6H 3V4
    • Children's and Women's Health Centre of British Columbia
• Germany
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Freiburg, Germany, 79106
    • Medical Center- University of Freiburg
  • Hamburg, Germany, 20246
    • Universitätsklinikum Eppendorf
• Italy
  • Genova, Italy, 16147
    • Istituto Giannina Gaslini
  • Monza, Italy, 20900
    • Fondazione MBBM, Ospedale San Gerardo
  • Rome, Italy, 00165
    • Ospedale Pediatrico Bambino Gesu
  • Verona, Italy, 37126
    • Ospedale della Donna e del Bambino
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28009
    • Hospital Universitario Niño Jesus
• Sweden
  • Stockholm, Sweden, 14186
    • Karolinska University Hospital Huddinge
• Switzerland
  • Zürich, Switzerland, CH-8032
    • University Children's Hospital Zurich
• United Kingdom
  • Leeds, United Kingdom, LS1 3EX
    • Leeds Children's Hospital
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045-7106
      • Children's Hospital Colorado
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. duPont Hospital for Children - Nemours Center for Cancer and Blood Disorders - Division of Pediatric Hematology Oncology
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute (DFCI)
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Helen Devos Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital - Feigin Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Main 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.

Main 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.

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: Emapalumab	Drug: Emapalumab; Emapalumab will be administered by intravenous infusion, twice weekly.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response at Week 8 or End of Treatment (if Earlier)	The overall response rate (ORR) 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 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
Time to Response	Time to first response at any time during the study.	Up to 18 months
Number of Patients Proceeding to HSCT	Number of patients able to proceed to HSCT when deemed indicated.	Up to 18 months
Overall Survival at End of Study	Number of patients surviving to the end of the study.	Up to 18 months
Overall Survival to HSCT	Number of patients surviving to HSCT.	From start of treatment to HSCT or from start of treatment until 1 year after EOT for patient who did not undergo HSCT
Overall Survival for Patients Receiving HSCT	Number of patients surviving post HSCT.	Up to 1 year post HSCT
Event-free Survival	Number of patients experiencing event-free survival, the duration of which was defined as time from HSCT to date of (whichever occurs first): death from any cause, graft failure, or HLH reactivation.	Up to 1 year post HSCT
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. Summarized by number of patients experiencing each category of response duration.	Up to 18 months
Number of Patients Reducing Glucocorticoids by 50% or More of the Baseline Dose During Emapalumab Treatment	Number of patients able to reduce glucocorticoids by 50% or more of the baseline dose during emapalumab treatment.	Up to 6 months
Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life Inventory™	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
Quality of Life Assessed Through Behavioral, Affective and Somatic Experiences Scales (BASES)	Assessment of the quality of life using the BASES questionnaire, which 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. Subscale scores were calculated using a 5-point Likert scale from 1 to 5 for all questions. Scores for all questions in each subscale were added up and divided by the number of patients in the analysis population to reach the mean score. Subscale scores were calculated for the following domains: Physical Discomfort (5 questions, '1' = best response, total range 5-25); Cooperation/Compliance (5 questions, '1' = best response, total range 5-25); Mood/Behavior (7 questions, '5' = best response, total range 7-35); Quality of Interactions (3 questions, '1' = best response, total range 3-15); Activity/Sleep (2 questions, '5' = best response for patient's activity level and '1' = best response for patient's sleeping, total range 2-10)	Up to 6 months
Incidence, Severity, Causality and Outcomes of AEs (Serious and Non-serious)	Incidence of adverse events. SAE = serious adverse event; TEAE = treatment-emergent adverse event	Up to 18 months
Evolution of Laboratory Parameters Change From Baseline to EOT/Week 8	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, urea nitrogen), 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], aPTT ratio, prothrombin time, prothrombin international normalized ratio [INR]), D-dimer, fibrinogen	To Week 8 or End of treatment if before Week 8.
Number of Patients Who Discontinued Emapalumab Treatment	Number of patients who discontinued emapalumab treatment for safety reasons.	Up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Concentrations of Emapalumab	The serum concentration of emapalumab will be measured as a function of time to determine the emapalumab PK profile.	Up to Week 8, with data presented at Baseline and EOT/W8
Change in Pharmacodynamic Parameters	Levels (in ng/L) of total IFNγ (interferon gamma), markers of its neutralization (CXCL9 and CXCL10), and sCD25.	Up to 18 months with data presented at Baseline and EOT/W8
Number of Patients Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity	The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).	Up to 1 year follow up post end of treatment with assessments at first dose of emapalumab, Week 4, Week 8, EOT and following treatment at day 100 and at the 1 year follow up visit, with data presented at study day 21 and EOT/Week 8.

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2019
• Primary Completion (Actual): August 18, 2021
• Study Completion (Actual): September 14, 2022

Study Registration Dates

• First Submitted: October 5, 2017
• First Submitted That Met QC Criteria: October 12, 2017
• First Posted (Actual): October 18, 2017

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Interferon-gamma; NI-0501; primary HLH; emapalumab
• Additional Relevant MeSH Terms: Lymphatic Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: NI-0501-09

Drug and device information, study documents

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