Hemophagocytic Lymphohistiocytoses
Conditions
Keywords
interferon gamma, emapalumab, adult HLH, malignancy-associated HLH, CXCL9
Brief summary
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by uncontrolled hyperinflammation which may develop on the background of several clinical conditions (e.g. autoimmune disease, infection, malignancy). Emapalumab (previously referred to as NI-0501) is a monoclonal antibody neutralizing interferon-gamma (IFN-gamma), a key cytokine driving the inflammation and tissue damage seen in HLH. The purpose of this study is to assess the efficacy, safety and pharmacokinetics of emapalumab in adult patients with secondary HLH.
Detailed description
Study NI-0501-10 is an open-label, single arm, multicenter, Phase 2/3 interventional study. The study enrolls adult patients with hemophagocytic lymphohistiocytosis (HLH), specifically newly diagnosed patients with malignancy-associated HLH (M-HLH), and newly diagnosed or previously treated patients with non-malignancy-associated HLH.
Interventions
DRUGEmapalumab-Lzsg
Patients were administered Emapalumab-Lzsg by intravenous (i.v.) infusion over a period of 1 to 2 hours, at an initial dose of 6 mg/kg and continued at 3 mg/kg, every 3 days for the first 2 weeks (Study Day \[SD\] 15), and then twice-a-week. If the treating physician deemed appropriate, the dose of emapalumab could be increased (up to 10 mg/kg), guided by clinical and laboratory response.
Sponsors
Light Chain Bioscience - Novimmune SA
Swedish Orphan Biovitrum
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients of age 18 and older at the time of HLH diagnosis * Fulfilment of 5 of the 8 HLH-2004 clinical criteria * Patients diagnosed with malignancy-associated HLH must be treatment naïve; patients diagnosed with HLH driven by any other etiology or idiopathic can be either treatment naïve or treatment experienced * Patients with non-malignancy-associated or idiopathic HLH who have already received conventional therapy for HLH must have failed prior treatment as per the treating physician's judgement * Informed consent signed by the patient or by the patient's legally authorized representative(s) (as required by local law) * Willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug, if female and of childbearing potential.
Exclusion criteria
* Primary HLH * Current or scheduled administration of therapies known to trigger the cytokine release syndrome (e.g. chimeric antigen receptor (CAR)-modified T cells, bispecific T cell-engaging antibodies) * Current or scheduled administration of PD-1/PD-L1/CTLA-4 inhibitors * Life-expectancy associated with the underlying disease (triggering HLH) \< 3 months * Ongoing participation in an investigational trial, or administration of any investigational treatment within 30 days * History of hypersensitivity or allergy to any components of emapalumab * Active mycobacteria, Histoplasma capsulatum, or Leishmania infections * Evidence of latent tuberculosis * Receipt of a bacille Calmette-Guerin (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | Week 4 | Achievement of either a Complete or Partial Response Complete Response is adjudicated if the following are observed: * No fever = body temperature \<37.5°C * Normal spleen size * No cytopenia = Absolute Neutrophil Counts \>=1.0x10\^9/L and platelet count \>=100x10\^9/L \[absence of G-CSF and transfusion support must be documented for at least 4 days to report no cytopenia\] * No hyperferritinemia = serum level is \<2000 µg/L * No evidence of coagulopathy, i.e., normal D-Dimer and/or normal (\>150 mg/dL) fibrinogen levels * No neurological and CSF abnormalities attributed to HLH * No sustained worsening of sCD25 (as indicated by at least two consecutive measurements that are \>2-fold higher than baseline) Partial Response is adjudicated if there is an improvement (\>50% change from baseline or normalization) of at least 3 HLH clinical and laboratory criteria (including Central Nervous System abnormalities). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | End of Treatment Visit (on average of 12 weeks) | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Overall Survival | End of Treatment Visit (on average of 12 weeks) | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Time to Complete Response or Partial Response | Week 4; End of Treatment visit (on average of 12 weeks) | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Duration of Response | Up to 1 year after last emapalumab administration | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Best Response on Treatment | Week 4; End of Treatment Visit (on average of 12 weeks) | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Incidence, Severity, Causality and Outcomes of Serious Adverse Events and Non-serious Adverse Events | Up to 1 year after last emapalumab administration | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Serum Concentrations of Emapalumab | Up to 1 year after last emapalumab administration | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Serum Biomarker Levels | Up to 1 year after last emapalumab administration | Levels of interferon-gamma, C-X-C chemokine ligand 9, soluble CD25, interleukin-6. |
| Incidence of Anti-Drug Antibodies Against Emapalumab | Up to 1 year after last emapalumab administration | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
| Hemophagocytic Lymphohistiocytosis Relapse | Up to 1 year after last emapalumab administration | As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description. |
Countries
United States
Participant flow
Recruitment details
This Phase 2/3, open-label, single arm study was conducted in adult patients with hemophagocytic lymphohistiocytosis (HLH) at a single center in the United States of America.
Pre-assignment details
The study consisted of a screening (up to 2 weeks), treatment period (until clinically satisfactory response was achieved), and follow-up period (1 year). A total of 7 patients were enrolled in the study and treated.
Participants by arm
| Arm | Count |
|---|---|
| Emapalumab Patients were administered emapalumab 6 mg/kg IV infusion for 1 to 2 hours, and continued at 3 mg/kg every 3 days for the first 2 weeks, and then twice-a-week until clinically satisfactory response was achieved.
If the treating physician deemed appropriate, the dose of emapalumab could be increased (up to 10 mg/kg), guided by clinical and laboratory response. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 2 |
| Overall Study | Lack of insurance and citizenship | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Emapalumab |
|---|---|
| Age, Continuous | 50 years |
| Age, Customized >= 18 and 64 years | 6 Participants |
| Age, Customized >= 65 and 84 years | 1 Participants |
| Age, Customized >= 85 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Height | 168.59 centimeter STANDARD_DEVIATION 12.234 |
| Race/Ethnicity, Customized Race Other | 3 Participants |
| Race/Ethnicity, Customized Race White | 4 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
| Weight | 80.84 kg STANDARD_DEVIATION 11.855 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 5 / 7 |
Outcome results
Primary
Overall Response
Achievement of either a Complete or Partial Response Complete Response is adjudicated if the following are observed: * No fever = body temperature \<37.5°C * Normal spleen size * No cytopenia = Absolute Neutrophil Counts \>=1.0x10\^9/L and platelet count \>=100x10\^9/L \[absence of G-CSF and transfusion support must be documented for at least 4 days to report no cytopenia\] * No hyperferritinemia = serum level is \<2000 µg/L * No evidence of coagulopathy, i.e., normal D-Dimer and/or normal (\>150 mg/dL) fibrinogen levels * No neurological and CSF abnormalities attributed to HLH * No sustained worsening of sCD25 (as indicated by at least two consecutive measurements that are \>2-fold higher than baseline) Partial Response is adjudicated if there is an improvement (\>50% change from baseline or normalization) of at least 3 HLH clinical and laboratory criteria (including Central Nervous System abnormalities).
Time frame: Week 4
Population: Since the study was prematurely terminated, no data was collected for the primary efficacy endpoint.
Secondary
Best Response on Treatment
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Week 4; End of Treatment Visit (on average of 12 weeks)
Population: Since the study was prematurely terminated, no data was collected for the secondary efficacy endpoints.
Secondary
Duration of Response
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Up to 1 year after last emapalumab administration
Population: Since the study was prematurely terminated, no data was collected for the secondary efficacy endpoints.
Secondary
Hemophagocytic Lymphohistiocytosis Relapse
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Up to 1 year after last emapalumab administration
Population: Since the study was prematurely terminated, no data was collected for the secondary efficacy endpoints.
Secondary
Incidence of Anti-Drug Antibodies Against Emapalumab
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Up to 1 year after last emapalumab administration
Population: Since the study was prematurely terminated, no data was collected for the secondary Pharmacodynamic endpoints.
Secondary
Incidence, Severity, Causality and Outcomes of Serious Adverse Events and Non-serious Adverse Events
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Up to 1 year after last emapalumab administration
Population: Since the study was prematurely terminated, no data was collected for the secondary safety endpoints.
Secondary
Overall Response
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: End of Treatment Visit (on average of 12 weeks)
Population: Since the study was prematurely terminated, no data was collected for the secondary efficacy endpoints.
Secondary
Overall Survival
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: End of Treatment Visit (on average of 12 weeks)
Population: Since the study was prematurely terminated, no data was collected for the secondary efficacy endpoints.
Secondary
Serum Biomarker Levels
Levels of interferon-gamma, C-X-C chemokine ligand 9, soluble CD25, interleukin-6.
Time frame: Up to 1 year after last emapalumab administration
Population: Since the study was prematurely terminated, no data was collected for the secondary Pharmacodynamic endpoints.
Secondary
Serum Concentrations of Emapalumab
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Up to 1 year after last emapalumab administration
Population: Since the study was prematurely terminated, no data was collected for the secondary Pharmacokinetic endpoints.
Secondary
Time to Complete Response or Partial Response
As no data are reported for this outcome measure, additional method is not applicable in the outcome measure description.
Time frame: Week 4; End of Treatment visit (on average of 12 weeks)
Population: Since the study was prematurely terminated, no data was collected for the secondary efficacy endpoints.