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

Conditions

Primary Haemophagocytic Lymphohistiocytosis

Keywords

Emapalumab

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.

Brossard P, Laveille C.

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Koo Wilson, Michał Pochopień, Jameel Nazir, Anupama Rao, Franco Locatelli

Blood2020-11-05

10.1182/blood-2020-140348

Sensitivity Analysis of Overall Response Rate (ORR) with Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis (HLH)

Franco Locatelli, Michael B. Jordan, Carl E. Allen, Simone Cesaro, Carmelo Rizzari et al. (19 authors)

Blood2020-11-05

10.1182/blood-2020-140692

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis

Franco Locatelli, Michael B. Jordan, Carl E. Allen, Simone Cesaro, Carmelo Rizzari et al. (20 authors)

New England Journal of Medicine2020-05-06478 citations

10.1056/nejmoa1911326

Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Franco Locatelli, Michael B. Jordan, Carl E. Allen, Simone Cesaro, Carmelo Rizzari et al. (18 authors)

Blood2018-11-2925 citations

10.1182/blood-2018-120810

Interventions

BIOLOGICALNI-0501

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 18 Years

Healthy volunteers

No

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

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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.
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.
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
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.

Countries

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

Participant flow

Pre-assignment details

Patients were screened within 1 week prior to the first administration of emapalumab (NI-0501). 66 patients were screened, and 45 were enrolled and treated.

Participants by arm

Arm	Count
NI-0501 All patients received emapalumab at a starting dose of 1 mg/kg every 3 days with possible escalation up to 10 mg/kg, for a minimum of 4 weeks.	45
Total	45

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Additional therapy when not allowed PP	4
Overall Study	Adverse Event	2
Overall Study	Death	3
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	NI-0501
Age, Continuous	1 years
Age, Customized ≥ 12 - <18 years	1 Participants
Age, Customized ≥ 2 - < 12 years	12 Participants
Age, Customized <2 years	32 Participants
HLH disease chracteristics at baseline ALT > 125 IU/L	21 Participants
HLH disease chracteristics at baseline CNS involvement	15 Participants
HLH disease chracteristics at baseline D-Dimers > 500 μg/L	33 Participants
HLH disease chracteristics at baseline Ferritin > 2000 μg/L	30 Participants
HLH disease chracteristics at baseline Ferritin > 500 μg/L	38 Participants
HLH disease chracteristics at baseline Fever	6 Participants
HLH disease chracteristics at baseline Fibrinogen < 1.5 g/L	20 Participants
HLH disease chracteristics at baseline LDH > 1000 IU/L	12 Participants
HLH disease chracteristics at baseline Neutrophil counts < 1 x10^9/L	25 Participants
HLH disease chracteristics at baseline Platelet counts < 100 x10^9/L	31 Participants
HLH disease chracteristics at baseline Splenomegaly	27 Participants
HLH disease chracteristics at baseline Total bilirubin > 25 μmol/L	13 Participants
HLH disease chracteristics at baseline Triglycerides > 3 mmol/L	29 Participants
Race/Ethnicity, Customized African Descent	3 Participants
Race/Ethnicity, Customized Asian	7 Participants
Race/Ethnicity, Customized LOther	5 Participants
Race/Ethnicity, Customized Mixed/multi-racial	0 Participants
Race/Ethnicity, Customized White	30 Participants
Region of Enrollment Europe	22 Participants
Region of Enrollment United States	23 Participants
Sex: Female, Male Female	23 Participants
Sex: Female, Male Male	22 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	10 / 45	5 / 30
other Total, other adverse events	41 / 45	28 / 30
serious Total, serious adverse events	28 / 45	20 / 30

Outcome results

Primary

Overall Response Rate (ORR) All Treated

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).

Time frame: End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Population: Primary analysis set: All Treated (all patients who received any part of an emapalumab infusion, data collected by regulatory cut-off: 20 July 2017)

Arm	Measure	Value (NUMBER)
NI-0501	Overall Response Rate (ORR) All Treated	64.7 percentage of participants

Comparison: Pre-specified null hypothesis that ORR is at most 40%p-value: 0.0031Exact binomial test

Primary

Overall Response Rate (ORR) at End of Treatment in Study NI-0501-04 (EOT 04) Follow-on Analysis Set: All Treated

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).

Time frame: End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Population: Follow-on analysis set: All Treated (45 patients who received any part of an emapalumab infusion, totality of the data collected in the NI-0501-04)

Arm	Measure	Value (NUMBER)
NI-0501	Overall Response Rate (ORR) at End of Treatment in Study NI-0501-04 (EOT 04) Follow-on Analysis Set: All Treated	60.0 percentage of participants

Comparison: Pre-specified null hypothesis that ORR is at most 40%.p-value: 0.0053Exact binomial test

Primary

Overall Response Rate (ORR) Follow-on Analysis Set:

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).

Time frame: End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Population: Follow-on analysis set: Second Line (34 patients who had previously received conventional HLH therapy before enrollment, totality of the data collected in the NI-0501-04 study)

Arm	Measure	Value (NUMBER)
NI-0501	Overall Response Rate (ORR) Follow-on Analysis Set:	58.8 percentage of participants

Comparison: Pre-specified null hypothesis that ORR is at most 40%p-value: 0.0205Exact binomial test

Primary

Overall Response Rate (ORR) Second Line

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).

Time frame: End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Population: Primary analysis set: Second Line (27 patients who had previously received conventional HLH therapy before enrollment, data collected by regulatory cut-off: 20 July 2017)

Arm	Measure	Value (NUMBER)
NI-0501	Overall Response Rate (ORR) Second Line	63.0 percentage of participants

Comparison: Pre-specified null hypothesis that ORR is at most 40%.p-value: 0.0134Exact binomial test

Secondary

Cumulative Duration of Response

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.

Time frame: 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)