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.
Condition: Graft Failure
Intervention: Emapalumab
Intervention description: 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Intervention model: Sequential Assignment
Intervention 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)
Enrollment: 2.0
Sex: All
Minimum age: 1 Year
Healthy volunteers: No
Keywords: HSCT; allo-HSCT; Graft failure; emapalumab; interferon gamma; CXCL9

Summary:

      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.
    

Eligibility criteria:

        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.