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.

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

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.

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.

Inclusion Criteria:

1. 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

2. 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)

3. 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)

4. Male and female patients

5. 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.

6. 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:

1. Pregnant (or planning to become pregnant) or lactating female patients
2. Body weight < 3 kg
3. 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
4. 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
5. Clinically manifested infections caused by typical and atypical Mycobacteria, Salmonella, Histoplasma capsulatum and Herpes Zoster on the day of HSCT
6. Active or clinical suspicion of latent tuberculosis
7. Concomitant diseases that in the opinion of the Investigator may interfere with the assessment of emapalumab safety or efficacy
8. Receipt of a Bacille Calmette-Guerin (BCG) vaccine within 3 months prior to HSCT
9. Receipt of a live or attenuated live (other than BCG) vaccine within 6 weeks prior to HSCT
10. Current or scheduled administration of therapies known to potentially trigger a cytokine release syndrome within 21 days from HSCT.
11. Patients having received IFNγ during the last 2 weeks prior to HSCT and/or who require treatment with IFNγ.
12. Patients having received emapalumab during the last 6 months prior to HSCT, unless it is known that emapalumab is no longer detectable.
13. 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.
14. Intolerance to antimicrobial and virus infection prophylaxis.
15. Hypersensitivity to emapalumab or any of the excipients.
16. 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.