Clinical trial NCT04731298: 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.
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Graft Failure
Keywords: HSCT
allo-HSCT
Graft failure
emapalumab
interferon gamma
CXCL9
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
name: Cytel Inc.
name: Q2 Solutions
name: ABF Pharmaceutical Services GmbH
name: Cromsource
name: BioMérieux
First posted: 2021-01-29
Enrollment: 2
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
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).
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: CXCL9 in Serum
timeFrame: From start of treatment to EoS Visit, up to 34 weeks
measure: Primary Graft Failure (GF)
timeFrame: From Hematopoietic stem-cell transplantation (HSCT) [Day 0] up to study termination, approximately 46 weeks
measure: Secondary GF
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcomes:
measure: Free & Total Interferon Gamma (IFNγ) in Serum
timeFrame: From start of treatment to EoS Visit, up to 34 weeks
measure: Emapalumab in Serum - Peak
timeFrame: From start of treatment to EoS, up to 34 weeks
measure: Ctrough (Emapalumab)
timeFrame: From start of treatment to EoS, up to 34 weeks
measure: Exploratory Biomarkers: Ferritin
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: ADA and nAbs
timeFrame: From Start of treatment until EoS, up to 34 weeks
measure: Number of Participants With Mixed Donor Chimerism <10% and <20%
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants Receiving Thrombopoietic Agents, Stem Cell Boost, Donor Lymphocyte Infusion (DLI)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants Receiving a Second Allogeneic HSCT
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants With Poor Graft Function
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants With Event Free Engraftment
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants With Acute and/or Chronic Mild to Severe Graft Versus Host Disease (GvHD)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Biomarker Levels, in Particular IFNy and CXCL9, as Predictors of Primary and/or Secondary Graft Failure or Acute and/or Chronic GvHD
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Engraftment Syndrome
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants With Endothelial Complications
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Participants With Relapse, Defined as Cumulative Incidence of Reoccurring Underlying Disease
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Survival Rate
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Body Temperature
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Heart Rate
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Blood Pressure
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Body Weight
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology: Red Blood Cells (RBC)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology: Hematocrit
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology: Hemoglobin
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology: Platelets
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology: White Blood Cells (WBC)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology Differential: Lymphocytes
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology Differential: Monocytes
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Hematology Differential: Neutrophils
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Ferritin
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Glucose
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: C-reactive Protein
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Sodium
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Potassium
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Chloride
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Calcium
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Magnesium
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Phosphate
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Aspartate Aminotransferase (AST)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Alanine Aminotransferase (ALT)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Gamma-glutamyl Transpeptidase (γGT)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Alkaline Phosphatase (ALP)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Lactate Dehydrogenase (LDH)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Bilirubin
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Triglycerides
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Cholesterol
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Albumin
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Creatinine
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Biochemistry: Urea
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Activated Partial Thromboplastin (aPTT)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Prothrombin Time (PT)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: Glucose
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: Blood
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: Protein
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: Leucocytes
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: Ketones
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: pH
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in Urinalysis: Specific Gravity
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Number of Subjects With Change in Donor Chimerism
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change in HLA Antibodies
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
measure: Change From Baseline in Minimal Residual Disease (MRD)
timeFrame: From HSCT (Day 0) up to study termination, approximately 46 weeks
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
city: Randwick
country: Australia
facility: Kids Cancer Centre Sydney Children's Hospital
city: Montréal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Haifa
country: Israel
facility: The Rambam Academic Hospital
city: Jerusalem
country: Israel
facility: Hadassah Hebrew University
Study officials:
affiliation: The Rambam Academic Hospital
name: Tsila Zuckerman, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Justine's Hospital
name: Henrique Bittencourt, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hadassah Hebrew University
name: Polina Stepensky, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Peter MacCallum Cancer Centre, Australia
name: Ashvind Prabahran, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Kids Cancer Centre Sydney Children's Hospital
name: Richard Mitchell, Dr
role: PRINCIPAL_INVESTIGATOR
References: