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

Primary Hemophagocytic Lymphohistiocytosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03312751
• Other study ID #: NI-0501-09
• Status: Completed
• Phase: Phase 3
• Start date: February 6, 2019
• Est. completion date: September 14, 2022

Study information

• Verified date: March 2024
• Source: Swedish Orphan Biovitrum
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: September 14, 2022
• Est. primary completion date: August 18, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lymphohistiocytosis, Hemophagocytic
• Primary Hemophagocytic Lymphohistiocytosis

Intervention

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

Locations

Country	Name	City	State
Canada	Hopital Ste-Justine Research Center	Montréal
Canada	Hospital for Sick Children	Toronto
Canada	Children's and Women's Health Centre of British Columbia	Vancouver
Germany	Universitätsklinikum Essen	Essen
Germany	Medical Center- University of Freiburg	Freiburg
Germany	Universitätsklinikum Eppendorf	Hamburg
Italy	Istituto Giannina Gaslini	Genova
Italy	Fondazione MBBM, Ospedale San Gerardo	Monza
Italy	Ospedale Pediatrico Bambino Gesù	Rome
Italy	Ospedale della Donna e del Bambino	Verona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario Niño Jesús	Madrid
Sweden	Karolinska University Hospital Huddinge	Stockholm
Switzerland	University Children's Hospital Zurich	Zürich
United Kingdom	Leeds Children's Hospital	Leeds
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dana-Farber Cancer Institute (DFCI)	Boston	Massachusetts
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Spectrum Health Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	Texas Children's Hospital - Feigin Center	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Phoenix Children Hospital	Phoenix	Arizona
United States	Seattle Children's Hospital	Seattle	Washington
United States	Alfred I. duPont Hospital for Children - Nemours Center for Cancer and Blood Disorders - Division of Pediatric Hematology Oncology	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Swedish Orphan Biovitrum

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Italy,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Change in Pharmacodynamic Parameters	Levels (in ng/L) of total IFN? (interferon gamma), markers of its neutralization (CXCL9 and CXCL10), and sCD25.	Up to 18 months with data presented at Baseline and EOT/W8
Other	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.
Primary	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	Overall Survival at End of Study	Number of patients surviving to the end of the study.	Up to 18 months
Secondary	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
Secondary	Overall Survival for Patients Receiving HSCT	Number of patients surviving post HSCT.	Up to 1 year post HSCT
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to Response	Time to first response at any time during the study.	Up to 18 months
Secondary	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
Secondary	Number of Patients Proceeding to HSCT	Number of patients able to proceed to HSCT when deemed indicated.	Up to 18 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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 [?GT], 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.
Secondary	Number of Patients Who Discontinued Emapalumab Treatment	Number of patients who discontinued emapalumab treatment for safety reasons.	Up to 6 months