Study to Investigate Safety, Efficacy of an Anti-IFNγ mAb in Children With Primary Haemophagocytic Lymphohistiocytosis

Phase 2

Completed

• Conditions: Primary Haemophagocytic Lymphohistiocytosis
• Interventions: Biological: NI-0501

• Registration Number: NCT01818492
• Lead Sponsor: Swedish Orphan Biovitrum

Brief Summary

The purpose of this study is to assess the safety, tolerability and efficacy of a new drug aimed at controlling disease activity in patients diagnosed with primary haemophagocytic lymphohistiocytosis. The new drug 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 current standard of care. Administration will be on top of a glucocorticosteroid, which is usually part of the current recommended treatment.

Detailed Description

The purpose of this study is to assess the safety, tolerability and efficacy of a new drug aimed at controlling disease activity in patients diagnosed with primary haemophagocytic lymphohistiocytosis. The new drug 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 current standard of care. Administration will be on top of a glucocorticosteroid, which is usually part of the current recommended treatment.

All participants in the NI-0501-04 study (NCT01818492) were invited to participate in the long-term follow-up study NI-0501-05 (NCT02069899). For the primary completion date, mentioned here, we refer to the NI-0501-04 study, even though in accordance with the NI-0501-04 study objectives, namely the assessment of long-term efficacy and safety endpoints, the study analyses also included data collected in the long-term follow-up study NI-0501-05. Hence these data are reported together. Study NI-0501-05 accepts patients from NI-0501-04 and NI-0501-06. Data collection for the patients from NI-0501-04 is completed.

The primary efficacy and safety analyses are based on the regulatory cut-off date of 20 July 2017. Refer to the publication in N Engl J Med 2020 May 7; 382 (19):1811-1822. Follow-on analyses have been conducted on all patients enrolled in the study, i.e. including the patients enrolled after the cut-off date of 20 July 2017. The results reported here refer to the totality of the 45 patients enrolled.

Study Timeline

• Study First Submitted: 2013-03-21
• Study First Submitted QC: 2013-03-25
• Study First Posted: 2013-03-26
• Study Start: 2013-07
• Primary Completion: 2019-01
• Study Completion: 2019-01
• Results First Submitted: 2020-06-26
• Results First Submitted QC: 2020-08-17
• Results First Posted: 2020-09-04
• Status Verified: 2021-04
• Last Update Submitted: 2023-01-23
• Last Update Posted: 2023-02-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

• Gender: male and female
• Age: up to and including 18 years at diagnosis of Haemophagocytic Lymphohistiocytosis
• Primary HLH patients
• Patient (if ≥ 18 years old), or patient's legal representative(s) must have signed informed consent

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Exclusion Criteria

• Diagnosis of secondary Haemophagocytic Lymphohistiocytosis consequent to a proven rheumatic or neoplastic disease.
• Body weight < 3 kg.
• Patients treated with biologics within a specific timeframe
• Active Mycobacteria, Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections.
• Presence of malignancy.
• Concomitant disease or malformation severely affecting the cardiovascular, pulmonary, liver or renal function

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
NI-0501	NI-0501	NI-0501 administered by IV infusion at a starting dose of 1 mg/kg.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) Second Line	End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)	Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm.; CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin \<2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen \>150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25.; PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology.; HI: improvement (\>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).
Overall Response Rate (ORR) All Treated	End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)	Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm.; CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin \<2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen \>150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25.; PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology.; HI: improvement (\>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).
Overall Response Rate (ORR) Follow-on Analysis Set:	End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)	Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm.; CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin \<2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen \>150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25.; PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology.; HI: improvement (\>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).
Overall Response Rate (ORR) at End of Treatment in Study NI-0501-04 (EOT 04) Follow-on Analysis Set: All Treated	End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)	Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm.; CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin \<2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen \>150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25.; PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology.; HI: improvement (\>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).

Secondary Outcome Measures

Name	Time	Method
Survival Pre-HSCT	Assessed up to HSCT, whenever HSCT occurred (up to approximately 6 months after treatment initiation)	Time from the date of first dose to the date of death, expressed in Kaplan-Meier survival probability estimates. Patients who receive HSCT will be censored at that date; patients who did not receive HSCT will be censored at last date of contact.; Where applicable, data were collected in both NI-0501-04 and long-term follow-up study NI-0501-05.
Number of Patients Able to Reduce Glucocorticoids	End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks.	Number of patients able to reduce glucocorticoids by 50% or more and between ≥30%-\<50%, of baseline dose at EOT 04.
Time to Response	Assessed up to End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)	Time from the date of the first dose of emapalumab to first achievement of response (at least HLH improvement)
Durability of First Response	Assessed up to End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)	Maintenance of response achieved any time during the study
Overall Survival	Time from the date of first dose to last dose, or 8 weeks after first dose.	Number of patients being alive at end of treatment or at week 8, pending on which comes first.
Cumulative Duration of Response	up to start of HSCT conditioning, whenever HSCT conditioning is scheduled (at least 4 weeks after treatment start), or End of Treatment 04/05 (if the patient did not have HSCT performed)	Percent of treatment time in response from the first achievement of an Overall Response until HSCT conditioning, or End of Treatment 04/05 (if the patient did not have HSCT performed) Where applicable, data were collected in both NI-0501-04 and long-term follow-up study NI-0501-05.
Survival Post-HSCT	Assessed up to Last Observation (up to 1 year after transplant, or up to approximately 18 months after treatment initiation)	Time from the date of first dose to the date of death, expressed in Kaplan-Meier survival probability estimates. Patients without an event will be censored at last assessment date in either the NI-0501-04 or NI-0501-05 study. Patients who do not proceed to HSCT will be excluded from this analysis.

Trial Locations

Locations (20)

Great Ormond Street Hospital - Department of Haematology; 🇬🇧 London, United Kingdom

Karolinska University Hospital; 🇸🇪 Stockholm, Sweden

Ospedale Pediatrico Bambino Gesu'; 🇮🇹 Roma, Italy

Hospital Universitario Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Sant Joan de Déu; 🇪🇸 Barcelona, Spain

Ospedale Donna Bambino - U.O.C. Oncoematologia Pediatrica; 🇮🇹 Verona, Italy

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

Alfred I. duPont Hospital for Children - Nemours Center for Cancer and Blood Disorders - Division of Pediatric Hematology Oncology; 🇺🇸 Wilmington, Delaware, United States

Dana-Farber Cancer Institute (DFCI); 🇺🇸 Boston, Massachusetts, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Cincinnati Children's Hospital - Division of Immunobiology - Department of Pediatrics; 🇺🇸 Cincinnati, Ohio, United States

Texas Children's Cancer Center; 🇺🇸 Houston, Texas, United States

University Children's Hospital; 🇩🇪 Münster, Germany

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

Azienda Ospedaliero Universitaria Meyer; 🇮🇹 Florence, Italy

Azienda Ospedaliera San Gerardo; 🇮🇹 Monza, Italy

Azienda Ospedaliera Padova - Clinica di Oncoematologia Pediatrica; 🇮🇹 Padua, Italy

Istituto Giannina Gaslini; 🇮🇹 Genoa, Italy

Hospital Universitario Niño Jesús; 🇪🇸 Madrid, Spain

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States