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.
- Registration Number
- NCT04731298
- Lead Sponsor
- Swedish Orphan Biovitrum
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 2
-
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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Emapalumab Emapalumab 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.
- Primary Outcome Measures
Name Time Method CXCL9 in Serum From start of treatment to EoS Visit, up to 34 weeks Serum concentration of C-X-C Motif Chemokine Ligand 9 (CXCL9)
Primary Graft Failure (GF) From Hematopoietic stem-cell transplantation (HSCT) [Day 0] up to study termination, approximately 46 weeks Number of participants with primary graft failure (GF)
Secondary GF From HSCT (Day 0) up to study termination, approximately 46 weeks Number of participants with secondary GF
- Secondary Outcome Measures
Name Time Method Change in Heart Rate From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in heart rate
Free & Total Interferon Gamma (IFNγ) in Serum From start of treatment to EoS Visit, up to 34 weeks Serum concentration of free and total Interferon gamma (IFNγ)
Emapalumab in Serum - Peak From start of treatment to EoS, up to 34 weeks Peak emapalumab serum concentration
Ctrough (Emapalumab) From start of treatment to EoS, up to 34 weeks Concentration just before administration
Exploratory Biomarkers: Ferritin From HSCT (Day 0) up to study termination, approximately 46 weeks Ferritin - serum concentration
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 Acute and/or Chronic Mild to Severe Graft Versus Host Disease (GvHD) From HSCT (Day 0) up to study termination, approximately 46 weeks (grade I to IV)
ADA and nAbs From Start of treatment until EoS, up to 34 weeks Number of participants developing antibodies against emapalumab (antidrug antibodies \[ADA\]) and Neutralizing antibodies (nAb)
Number of Participants With Mixed Donor Chimerism <10% and <20% From HSCT (Day 0) up to study termination, approximately 46 weeks Based on unselected leukocytes and based on sorted T cells
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 From HSCT (Day 0) up to study termination, approximately 46 weeks defined as absence of GF or graft support
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 From HSCT (Day 0) up to study termination, approximately 46 weeks Number of participants with engraftment syndrome
Survival Rate From HSCT (Day 0) up to study termination, approximately 46 weeks Number of patients alive at the end of study.
Change in Body Temperature From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in body temperature
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 Change in Blood Pressure From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline systolic and diastolic blood pressure
Change in Body Weight From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in body weight
Change in Hematology: Hemoglobin From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology: hemoglobin
Change in Hematology: Platelets From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology: platelets
Change in Hematology: Red Blood Cells (RBC) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology: red blood cells (RBC)
Change in Hematology: Hematocrit From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology: hematocrit
Change in Hematology: White Blood Cells (WBC) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology: white blood cells (WBC)
Change in Hematology Differential: Lymphocytes From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology differential: lymphocytes
Change in Hematology Differential: Monocytes From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology differential: monocytes
Change in Hematology Differential: Neutrophils From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Hematology differential: neutrophils
Change in Biochemistry: Ferritin From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Ferritin
Change in Biochemistry: Glucose From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Glucose
Change in Biochemistry: C-reactive Protein From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: C-reactive protein
Change in Biochemistry: Sodium From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Sodium
Change in Biochemistry: Potassium From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Potassium
Change in Biochemistry: Phosphate From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Phosphate
Change in Biochemistry: Aspartate Aminotransferase (AST) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Aspartate aminotransferase (AST)
Change in Biochemistry: Bilirubin From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: bilirubin (total, direct and indirect)
Change in Biochemistry: Albumin From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Albumin
Change in Biochemistry: Cholesterol From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: cholesterol (total and high-density lipoprotein \[HDL\])
Change in Biochemistry: Creatinine From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Creatinine
Change in Biochemistry: Urea From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Urea
Activated Partial Thromboplastin (aPTT) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Coagulation: activated partial thromboplastin (aPTT)
Prothrombin Time (PT) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Coagulation: prothrombin time (PT)
Change in Urinalysis: pH From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: pH
Number of Subjects With Change in Donor Chimerism From HSCT (Day 0) up to study termination, approximately 46 weeks Change in HLA Antibodies From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in HLA antibodies against donor cells
Change From Baseline in Minimal Residual Disease (MRD) From HSCT (Day 0) up to study termination, approximately 46 weeks Only in patients presenting malignant disease
Change in Urinalysis: Glucose From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: Glucose
Change in Urinalysis: Protein From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: Protein
Change in Urinalysis: Specific Gravity From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: specific gravity
Change in Urinalysis: Blood From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: Blood
Change in Biochemistry: Alanine Aminotransferase (ALT) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: alanine aminotransferase (ALT)
Change in Biochemistry: Lactate Dehydrogenase (LDH) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: lactate dehydrogenase (LDH)
Change in Biochemistry: Triglycerides From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: triglycerides
Change in Urinalysis: Leucocytes From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: Leucocytes
Change in Biochemistry: Gamma-glutamyl Transpeptidase (γGT) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: gamma-glutamyl transpeptidase (γGT)
Change in Urinalysis: Ketones From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Urinalysis: Ketones
Change in Biochemistry: Alkaline Phosphatase (ALP) From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: alkaline phosphatase (ALP)
Change in Biochemistry: Chloride From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Chloride
Change in Biochemistry: Calcium From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Calcium
Change in Biochemistry: Magnesium From HSCT (Day 0) up to study termination, approximately 46 weeks Change from baseline in Biochemistry: Magnesium
Trial Locations
- Locations (5)
CHU Sainte-Justine
🇨🇦Montréal, Quebec, Canada
The Rambam Academic Hospital
🇮🇱Haifa, Israel
Hadassah Hebrew University
🇮🇱Jerusalem, Israel
Kids Cancer Centre Sydney Children's Hospital
🇦🇺Randwick, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Australia