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.

Phase 2TerminatedNCT04731298

Swedish Orphan Biovitrum2 enrolled

Overview

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.

Interventions

EmapalumabDRUG

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.

Eligibility

Sex: ALLMin age: 1 Year

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

CXCL9 in Serum

Serum concentration of C-X-C Motif Chemokine Ligand 9 (CXCL9)

Time frame: From start of treatment to EoS Visit, up to 34 weeks

Primary Graft Failure (GF)

Number of participants with primary graft failure (GF)

Time frame: From Hematopoietic stem-cell transplantation (HSCT) [Day 0] up to study termination, approximately 46 weeks

Secondary GF

Number of participants with secondary GF

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Secondary Outcomes

Free & Total Interferon Gamma (IFNγ) in Serum

Serum concentration of free and total Interferon gamma (IFNγ)

Time frame: From start of treatment to EoS Visit, up to 34 weeks

Emapalumab in Serum - Peak

Peak emapalumab serum concentration

Time frame: From start of treatment to EoS, up to 34 weeks

Ctrough (Emapalumab)

Concentration just before administration

Time frame: From start of treatment to EoS, up to 34 weeks

Exploratory Biomarkers: Ferritin

Ferritin - serum concentration

Time frame: 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)

Time frame: 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

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Number of Participants Receiving Thrombopoietic Agents, Stem Cell Boost, Donor Lymphocyte Infusion (DLI)

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Number of Participants Receiving a Second Allogeneic HSCT

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Number of Participants With Poor Graft Function

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Engraftment Syndrome

Number of participants with engraftment syndrome

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Number of Participants With Endothelial Complications

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Number of Participants With Relapse, Defined as Cumulative Incidence of Reoccurring Underlying Disease

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Survival Rate

Number of patients alive at the end of study.

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Body Temperature

Change from baseline in body temperature

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Heart Rate

Change from baseline in heart rate

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Blood Pressure

Change from baseline systolic and diastolic blood pressure

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Body Weight

Change from baseline in body weight

Time frame: 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)

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Hematology: Hematocrit

Change from baseline in Hematology: hematocrit

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Hematology: Hemoglobin

Change from baseline in Hematology: hemoglobin

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Hematology: Platelets

Change from baseline in Hematology: platelets

Time frame: 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)

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Hematology Differential: Lymphocytes

Change from baseline in Hematology differential: lymphocytes

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Hematology Differential: Monocytes

Change from baseline in Hematology differential: monocytes

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Hematology Differential: Neutrophils

Change from baseline in Hematology differential: neutrophils

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Ferritin

Change from baseline in Biochemistry: Ferritin

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Glucose

Change from baseline in Biochemistry: Glucose

Time frame: 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

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Sodium

Change from baseline in Biochemistry: Sodium

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Potassium

Change from baseline in Biochemistry: Potassium

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Chloride

Change from baseline in Biochemistry: Chloride

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Calcium

Change from baseline in Biochemistry: Calcium

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Magnesium

Change from baseline in Biochemistry: Magnesium

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Phosphate

Change from baseline in Biochemistry: Phosphate

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Triglycerides

Change from baseline in Biochemistry: triglycerides

Time frame: 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 \[HDL\])

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Albumin

Change from baseline in Biochemistry: Albumin

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Creatinine

Change from baseline in Biochemistry: Creatinine

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Biochemistry: Urea

Change from baseline in Biochemistry: Urea

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Activated Partial Thromboplastin (aPTT)

Change from baseline in Coagulation: activated partial thromboplastin (aPTT)

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Prothrombin Time (PT)

Change from baseline in Coagulation: prothrombin time (PT)

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: Glucose

Change from baseline in Urinalysis: Glucose

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: Blood

Change from baseline in Urinalysis: Blood

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: Protein

Change from baseline in Urinalysis: Protein

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: Leucocytes

Change from baseline in Urinalysis: Leucocytes

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: Ketones

Change from baseline in Urinalysis: Ketones

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: pH

Change from baseline in Urinalysis: pH

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in Urinalysis: Specific Gravity

Change from baseline in Urinalysis: specific gravity

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Number of Subjects With Change in Donor Chimerism

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

Change in HLA Antibodies

Change from baseline in HLA antibodies against donor cells

Time frame: 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

Time frame: From HSCT (Day 0) up to study termination, approximately 46 weeks

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.

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes