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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04731298




Registration number
NCT04731298
Ethics application status
Date submitted
13/11/2020
Date registered
29/01/2021
Date last updated
28/12/2023

Titles & IDs
Public title
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.
Scientific 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
Secondary ID [1] 0 0
NI-0501-12
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Graft Failure 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Emapalumab

Experimental: 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.


Treatment: Drugs: Emapalumab
Emapalumab is a fully human immunoglobulin G1 (IgG1) anti-IFN? monoclonal antibody that binds to and neutralizes IFN?. Emapalumab binds to both soluble and receptor (IFN?R1)-bound forms of IFN?.

Emapalumab is in development for treatment of primary and secondary HLH. The benefit expected from the targeted neutralization of IFN? 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
CXCL9 in Serum
Timepoint [1] 0 0
From start of treatment to EoS Visit, up to 34 weeks
Primary outcome [2] 0 0
Primary Graft Failure (GF)
Timepoint [2] 0 0
From Hematopoietic stem-cell transplantation (HSCT) [Day 0] up to study termination, approximately 46 weeks
Primary outcome [3] 0 0
Secondary GF
Timepoint [3] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [1] 0 0
Free & Total Interferon Gamma (IFN?) in Serum
Timepoint [1] 0 0
From start of treatment to EoS Visit, up to 34 weeks
Secondary outcome [2] 0 0
Emapalumab in Serum - Peak
Timepoint [2] 0 0
From start of treatment to EoS, up to 34 weeks
Secondary outcome [3] 0 0
Ctrough (Emapalumab)
Timepoint [3] 0 0
From start of treatment to EoS, up to 34 weeks
Secondary outcome [4] 0 0
Exploratory Biomarkers: Ferritin
Timepoint [4] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [5] 0 0
ADA and nAbs
Timepoint [5] 0 0
From Start of treatment until EoS, up to 34 weeks
Secondary outcome [6] 0 0
Number of Participants With Mixed Donor Chimerism <10% and <20%
Timepoint [6] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [7] 0 0
Number of Participants Receiving Thrombopoietic Agents, Stem Cell Boost, Donor Lymphocyte Infusion (DLI)
Timepoint [7] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [8] 0 0
Number of Participants Receiving a Second Allogeneic HSCT
Timepoint [8] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [9] 0 0
Number of Participants With Poor Graft Function
Timepoint [9] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [10] 0 0
Number of Participants With Event Free Engraftment
Timepoint [10] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [11] 0 0
Number of Participants With Acute and/or Chronic Mild to Severe Graft Versus Host Disease (GvHD)
Timepoint [11] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [12] 0 0
Biomarker Levels, in Particular IFNy and CXCL9, as Predictors of Primary and/or Secondary Graft Failure or Acute and/or Chronic GvHD
Timepoint [12] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [13] 0 0
Engraftment Syndrome
Timepoint [13] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [14] 0 0
Number of Participants With Endothelial Complications
Timepoint [14] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [15] 0 0
Number of Participants With Relapse, Defined as Cumulative Incidence of Reoccurring Underlying Disease
Timepoint [15] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [16] 0 0
Survival Rate
Timepoint [16] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [17] 0 0
Change in Body Temperature
Timepoint [17] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [18] 0 0
Change in Heart Rate
Timepoint [18] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [19] 0 0
Change in Blood Pressure
Timepoint [19] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [20] 0 0
Change in Body Weight
Timepoint [20] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [21] 0 0
Change in Hematology: Red Blood Cells (RBC)
Timepoint [21] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [22] 0 0
Change in Hematology: Hematocrit
Timepoint [22] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [23] 0 0
Change in Hematology: Hemoglobin
Timepoint [23] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [24] 0 0
Change in Hematology: Platelets
Timepoint [24] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [25] 0 0
Change in Hematology: White Blood Cells (WBC)
Timepoint [25] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [26] 0 0
Change in Hematology Differential: Lymphocytes
Timepoint [26] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [27] 0 0
Change in Hematology Differential: Monocytes
Timepoint [27] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [28] 0 0
Change in Hematology Differential: Neutrophils
Timepoint [28] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [29] 0 0
Change in Biochemistry: Ferritin
Timepoint [29] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [30] 0 0
Change in Biochemistry: Glucose
Timepoint [30] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [31] 0 0
Change in Biochemistry: C-reactive Protein
Timepoint [31] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [32] 0 0
Change in Biochemistry: Sodium
Timepoint [32] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [33] 0 0
Change in Biochemistry: Potassium
Timepoint [33] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [34] 0 0
Change in Biochemistry: Chloride
Timepoint [34] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [35] 0 0
Change in Biochemistry: Calcium
Timepoint [35] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [36] 0 0
Change in Biochemistry: Magnesium
Timepoint [36] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [37] 0 0
Change in Biochemistry: Phosphate
Timepoint [37] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [38] 0 0
Change in Biochemistry: Aspartate Aminotransferase (AST)
Timepoint [38] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [39] 0 0
Change in Biochemistry: Alanine Aminotransferase (ALT)
Timepoint [39] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [40] 0 0
Change in Biochemistry: Gamma-glutamyl Transpeptidase (?GT)
Timepoint [40] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [41] 0 0
Change in Biochemistry: Alkaline Phosphatase (ALP)
Timepoint [41] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [42] 0 0
Change in Biochemistry: Lactate Dehydrogenase (LDH)
Timepoint [42] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [43] 0 0
Change in Biochemistry: Bilirubin
Timepoint [43] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [44] 0 0
Change in Biochemistry: Triglycerides
Timepoint [44] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [45] 0 0
Change in Biochemistry: Cholesterol
Timepoint [45] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [46] 0 0
Change in Biochemistry: Albumin
Timepoint [46] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [47] 0 0
Change in Biochemistry: Creatinine
Timepoint [47] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [48] 0 0
Change in Biochemistry: Urea
Timepoint [48] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [49] 0 0
Activated Partial Thromboplastin (aPTT)
Timepoint [49] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [50] 0 0
Prothrombin Time (PT)
Timepoint [50] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [51] 0 0
Change in Urinalysis: Glucose
Timepoint [51] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [52] 0 0
Change in Urinalysis: Blood
Timepoint [52] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [53] 0 0
Change in Urinalysis: Protein
Timepoint [53] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [54] 0 0
Change in Urinalysis: Leucocytes
Timepoint [54] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [55] 0 0
Change in Urinalysis: Ketones
Timepoint [55] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [56] 0 0
Change in Urinalysis: pH
Timepoint [56] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [57] 0 0
Change in Urinalysis: Specific Gravity
Timepoint [57] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [58] 0 0
Number of Subjects With Change in Donor Chimerism
Timepoint [58] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [59] 0 0
Change in HLA Antibodies
Timepoint [59] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks
Secondary outcome [60] 0 0
Change From Baseline in Minimal Residual Disease (MRD)
Timepoint [60] 0 0
From HSCT (Day 0) up to study termination, approximately 46 weeks

Eligibility
Key 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
Minimum age
1 Year
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 IFN? during the last 2 weeks prior to HSCT and/or who require treatment with IFN?.
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.

Study design
Purpose of the study
Prevention
Allocation to intervention
NA
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 0 0
Kids Cancer Centre Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Quebec
Country [2] 0 0
Israel
State/province [2] 0 0
Haifa
Country [3] 0 0
Israel
State/province [3] 0 0
Jerusalem

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Swedish Orphan Biovitrum
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
PRA Health Sciences
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Cytel Inc.
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/industry
Name [3] 0 0
Q2 Solutions
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Commercial sector/industry
Name [4] 0 0
ABF Pharmaceutical Services GmbH
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Commercial sector/industry
Name [5] 0 0
Cromsource
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Commercial sector/industry
Name [6] 0 0
BioMérieux
Address [6] 0 0
Country [6] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Tsila Zuckerman, Dr
Address 0 0
The Rambam Academic Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

Results publications and other study-related documents

No documents have been uploaded by study researchers.