Study to Investigate the Pharmacokinetics, Pharmacodynamics and Assess the Efficacy and Safety to Support Dose Selection of Emapalumab in Pre-empting Graft Failure in Patients at High Risk After HSCT.

Study Overview
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Brief Summary
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This study is designed as an open-label, single arm, proof of concept study in order to determine the appropriate emapalumab dosing regimen neutralizing IFNγ in patients at risk of GF. Patients presenting CXCL9 levels above a defined threshold and other clinical criteria will be eligible to receive emapalumab. Both children and adults, with malignant and non-malignant underlying diseases, receiving allo-HSCT who are at high risk of GF as defined in the inclusion criteria will be included in the study. The main objective of the study is to determine the appropriate emapalumab dose regimen neutralizing interferon gamma (IFNγ) activity to pre-empt graft failure post allo-HSCT in a population with various underlying diseases and at high risk of graft failure (GF). Maximum 3 cohorts are foreseen to determine the appropriate dose regimen to pre-emptively treat patients at risk of primary GF. Emapalumab will be administered by IV infusion and treatment will last up to 56 days (15 infusions) or until evidence of engraftment. The study is expected to last approximately 3 years from screening to the last follow-up phone call for each patient.

Detailed Description
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This study is designed as an open-label, single arm, proof of concept study in order to determine the appropriate emapalumab dosing regimen neutralizing IFNγ in patients at risk of GF. Patients presenting CXCL9 levels above a defined threshold and other clinical criteria will be eligible to receive emapalumab. Both children and adults, with malignant and non-malignant underlying diseases, receiving allo-HSCT who are at high risk of GF as defined in the inclusion criteria will be included in the study. The main objective of the study will be to determine the appropriate emapalumab dose regimen neutralizing interferon gamma (IFNγ) activity to pre-empt graft failure post allo-HSCT in a population with various underlying diseases and at high risk of graft failure (GF). Maximum 3 cohorts are foreseen to determine the appropriate dose regimen to pre-emptively treat patients at risk of primary GF. Emapalumab will be administered by IV infusion over 1 to 2 hours depending on the volume of the infusion. Treatment will last up to 56 days (15 infusions) or until evidence of engraftment. The study is comprised of the following study periods: screening (Day -21 to Day -8), allogeneic HSCT Day 0, monitoring period for primary GF (Day 1 up to Day 42), extended monitoring for secondary GF (up to Day 98), treatment period (up to 56 days) and follow-up period of 3 years after HSCT. The main objective of this proof of concept study is: • To determine the appropriate emapalumab dose regimen neutralizing interferon gamma (IFNγ) activity to pre-empt graft failure post allogeneic hematopoietic stem cell transplantation (HSCT) in a population with various underlying diseases and at high risk of graft failure (GF) The following objectives will support the dose selection: To describe the Pharmacokinetic (PK) and Pharmacodynamic (PD) profiles of emapalumab post allogeneic HSCT (allo-HSCT) To assess the efficacy of emapalumab to pre-empt GF post allo-HSCT To assess the safety of emapalumab to pre-empt GF post allo-HSCT To assess the immunogenicity of emapalumab post allo-HSCT Exploratory objectives will be: • To evaluate further data on the correlation between relevant biomarkers including C-X-C motif chemokine ligand 9 (CXCL9) levels and the risk of GF post allo-HSCT in a population with various underlying diseases and at high risk of GF also in the context of development of a diagnostic test. The study is expected to last approximately 3 years from screening to the last follow-up phone call for each patient.

Official Title
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An Open Label, Single Arm, Multicentre, Proof of Concept, Phase 2 Study to Investigate the Pharmacokinetics, Pharmacodynamics and Assess the Efficacy and Safety to Support Dose Selection of Emapalumab in Pre-empting Graft Failure in Patients at High Risk After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Graft Failure

Intervention / Treatment
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* Drug: Emapalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent form signed by the patient (as required by law) or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as applicable Recipients of allogeneic Hematopoietic Stem Cell Transplantation (HSCT) and at high risk of graft failure (GF) based on at least one of the following criteria: Receiving reduced intensity conditioning (RIC) or non-myeloablative conditioning (NMA) combined with a non-malignant disease or with a graft from Bone Marrow (BM) Ex vivo T cell depleted graft Graft from mismatched unrelated or haploidentical donor Graft from Umbilical Cord Blood (UCB) Patients requiring allo-HSCT with the following underlying diseases: Malignant disease with high risk of GF, i.e. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) with primary induction failure, second partial remission or relapse; Chronic Myeloid Leukemia (CML) in blastic phase (circulating blast or blast above 5% in biopsy); Non Hodgkin and Hodgkin Lymphoma and multiple myeloma with primary induction failure, second partial remission or relapse, myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) with splenomegaly, myelofibrosis with portal hypertension pre-transplant, MDS/MPD overlap syndromes Non-malignant hematological diseases (e.g. autoimmune and metabolic disorders, aplastic anemia, Sickle cell anemia, Fanconi anemia, Diamond-Blackfan anemia, thalassemia, osteopetrosis, Wiskott-Aldrich syndrome, severe combined immunodeficiency, Hemophagocytic lymphohistiocytosis and other immunoregulatory disorders) Male and female patients Children aged at least 1 year and adults. Once the appropriate dose has been determined in one of the three cohorts and safety has been assessed by the Independent Data Monitoring Committee (IDMC), children less than 1 year old may be included in the study. Females of child-bearing potential, defined as all women physiologically capable of becoming pregnant, require use of highly effective contraceptive measures from screening until 6 months after the last study drug administration Exclusion Criteria: Pregnant (or planning to become pregnant) or lactating female patients Body weight < 3 kg Underlying malignant disease with Karnofsky/Lansky performance status equal or less than 40 or an Eastern Cooperative Oncology Group (ECOG) performance status equal or less than 3 Patients presenting CXCL9 levels 10 times above the upper limit of the 95% interval (CI) of the normal range (reported in the CXCL9 assay laboratory manual) within 24 hours prior to HSCT Clinically manifested infections caused by typical and atypical Mycobacteria, Salmonella, Histoplasma capsulatum and Herpes Zoster on the day of HSCT Active or clinical suspicion of latent tuberculosis Concomitant diseases that in the opinion of the Investigator may interfere with the assessment of emapalumab safety or efficacy Receipt of a Bacille Calmette-Guerin (BCG) vaccine within 3 months prior to HSCT Receipt of a live or attenuated live (other than BCG) vaccine within 6 weeks prior to HSCT Current or scheduled administration of therapies known to potentially trigger a cytokine release syndrome within 21 days from HSCT. Patients having received IFNγ during the last 2 weeks prior to HSCT and/or who require treatment with IFNγ. Patients having received emapalumab during the last 6 months prior to HSCT, unless it is known that emapalumab is no longer detectable. Patients having received kinase inhibitors (Janus kinase inhibitors [JAKi] or bruton tyrosine kinase inhibitors [BTKi]) one week (or 5 half-lives whichever is greater) prior to HSCT. Intolerance to antimicrobial and virus infection prophylaxis. Hypersensitivity to emapalumab or any of the excipients. Ongoing participation in an interventional trial or administration of any investigational drug (within 3 half-lives of the investigational drug) with the exception of interventional trials involving supportive care such as probiotics or antiemetics, graft manipulation, or use of new combinations or new dosing of conventional therapies for conditioning and prophylaxis pre-HSCT.

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential dose cohorts. The first cohort of patients will receive a first emapalumab infusion of 6 mg/kg at TD0, followed by a second infusion at 3 mg/kg after 3 days. Subsequent infusions of 3 mg/kg will be every 3 or 4 days from previous dose until dose 15 or until engraftment. A maximum of 2 additional cohorts may be added to allow dosing regimen adaptation based on the PK/PD data observed from the previous cohort(s).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emapalumab<br>The first cohort of patients will receive a first infusion of 6 mg/kg at TD0, followed by a second infusion at 3 mg/kg after 3 days (treatment day 3 - TD3). Subsequent infusions of 3 mg/kg will be every 3 or 4 days from previous dose until dose 15 or until engraftment. A maximum of 2 additional cohorts may be added to allow dosing regimen adaptation based on the PK/PD data observed from the previous cohort(s). Efficacy and safety data will also be considered before adding additional cohorts. | Drug: Emapalumab<br>* Emapalumab is a fully human immunoglobulin G1 (IgG1) anti-IFNγ monoclonal antibody that binds to and neutralizes IFNγ. Emapalumab binds to both soluble and receptor (IFNγR1)-bound forms of IFNγ. Emapalumab is in development for treatment of primary and secondary HLH. The benefit expected from the targeted neutralization of IFNγ by emapalumab has been validated by the recent FDA approval of emapalumab for treatment of patients with pHLH who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. The safety profile has been assessed as acceptable. Emapalumab will be administered by intravenous infusion over 1 to 2 hours, depending on the volume of the infusion. The first infusion must be performed within 12 hours after CXCL9 levels have been measured above defined threshold. Treatment will last until maximum dose 15 (up to 56 days) or until evidence of engraftment, whichever comes first.<br>* Other names: NI-0501;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CXCL9 in Serum | Serum concentration of C-X-C Motif Chemokine Ligand 9 (CXCL9) | From start of treatment to EoS Visit, up to 34 weeks | 
| Primary Graft Failure (GF) | Number of participants with primary graft failure (GF) | From Hematopoietic stem-cell transplantation (HSCT) [Day 0] up to study termination, approximately 46 weeks | 
| Secondary GF | Number of participants with secondary GF | From HSCT (Day 0) up to study termination, approximately 46 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free & Total Interferon Gamma (IFNγ) in Serum | Serum concentration of free and total Interferon gamma (IFNγ) | From start of treatment to EoS Visit, up to 34 weeks | 
| Emapalumab in Serum - Peak | Peak emapalumab serum concentration | From start of treatment to EoS, up to 34 weeks | 
| Ctrough (Emapalumab) | Concentration just before administration | From start of treatment to EoS, up to 34 weeks | 
| Exploratory Biomarkers: Ferritin | Ferritin - serum concentration | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| ADA and nAbs | Number of participants developing antibodies against emapalumab (antidrug antibodies [ADA]) and Neutralizing antibodies (nAb) | From Start of treatment until EoS, up to 34 weeks | 
| Number of Participants With Mixed Donor Chimerism <10% and <20% | Based on unselected leukocytes and based on sorted T cells | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants Receiving Thrombopoietic Agents, Stem Cell Boost, Donor Lymphocyte Infusion (DLI) |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants Receiving a Second Allogeneic HSCT |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants With Poor Graft Function |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants With Event Free Engraftment | defined as absence of GF or graft support | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants With Acute and/or Chronic Mild to Severe Graft Versus Host Disease (GvHD) | (grade I to IV) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Biomarker Levels, in Particular IFNy and CXCL9, as Predictors of Primary and/or Secondary Graft Failure or Acute and/or Chronic GvHD |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Engraftment Syndrome | Number of participants with engraftment syndrome | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants With Endothelial Complications |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Participants With Relapse, Defined as Cumulative Incidence of Reoccurring Underlying Disease |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Survival Rate | Number of patients alive at the end of study. | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Body Temperature | Change from baseline in body temperature | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Heart Rate | Change from baseline in heart rate | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Blood Pressure | Change from baseline systolic and diastolic blood pressure | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Body Weight | Change from baseline in body weight | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology: Red Blood Cells (RBC) | Change from baseline in Hematology: red blood cells (RBC) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology: Hematocrit | Change from baseline in Hematology: hematocrit | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology: Hemoglobin | Change from baseline in Hematology: hemoglobin | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology: Platelets | Change from baseline in Hematology: platelets | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology: White Blood Cells (WBC) | Change from baseline in Hematology: white blood cells (WBC) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology Differential: Lymphocytes | Change from baseline in Hematology differential: lymphocytes | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology Differential: Monocytes | Change from baseline in Hematology differential: monocytes | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Hematology Differential: Neutrophils | Change from baseline in Hematology differential: neutrophils | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Ferritin | Change from baseline in Biochemistry: Ferritin | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Glucose | Change from baseline in Biochemistry: Glucose | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: C-reactive Protein | Change from baseline in Biochemistry: C-reactive protein | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Sodium | Change from baseline in Biochemistry: Sodium | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Potassium | Change from baseline in Biochemistry: Potassium | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Chloride | Change from baseline in Biochemistry: Chloride | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Calcium | Change from baseline in Biochemistry: Calcium | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Magnesium | Change from baseline in Biochemistry: Magnesium | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Phosphate | Change from baseline in Biochemistry: Phosphate | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Aspartate Aminotransferase (AST) | Change from baseline in Biochemistry: Aspartate aminotransferase (AST) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Alanine Aminotransferase (ALT) | Change from baseline in Biochemistry: alanine aminotransferase (ALT) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Gamma-glutamyl Transpeptidase (γGT) | Change from baseline in Biochemistry: gamma-glutamyl transpeptidase (γGT) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Alkaline Phosphatase (ALP) | Change from baseline in Biochemistry: alkaline phosphatase (ALP) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Lactate Dehydrogenase (LDH) | Change from baseline in Biochemistry: lactate dehydrogenase (LDH) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Bilirubin | Change from baseline in Biochemistry: bilirubin (total, direct and indirect) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Triglycerides | Change from baseline in Biochemistry: triglycerides | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Cholesterol | Change from baseline in Biochemistry: cholesterol (total and high-density lipoprotein [HDL]) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Albumin | Change from baseline in Biochemistry: Albumin | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Creatinine | Change from baseline in Biochemistry: Creatinine | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Biochemistry: Urea | Change from baseline in Biochemistry: Urea | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Activated Partial Thromboplastin (aPTT) | Change from baseline in Coagulation: activated partial thromboplastin (aPTT) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Prothrombin Time (PT) | Change from baseline in Coagulation: prothrombin time (PT) | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: Glucose | Change from baseline in Urinalysis: Glucose | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: Blood | Change from baseline in Urinalysis: Blood | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: Protein | Change from baseline in Urinalysis: Protein | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: Leucocytes | Change from baseline in Urinalysis: Leucocytes | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: Ketones | Change from baseline in Urinalysis: Ketones | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: pH | Change from baseline in Urinalysis: pH | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in Urinalysis: Specific Gravity | Change from baseline in Urinalysis: specific gravity | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Number of Subjects With Change in Donor Chimerism |  | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change in HLA Antibodies | Change from baseline in HLA antibodies against donor cells | From HSCT (Day 0) up to study termination, approximately 46 weeks | 
| Change From Baseline in Minimal Residual Disease (MRD) | Only in patients presenting malignant disease | From HSCT (Day 0) up to study termination, approximately 46 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HSCT, allo-HSCT, Graft failure, emapalumab, interferon gamma, CXCL9