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.

NCT04731298 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: NI-0501-12
• Study Type: interventional
• Target: 2
• Locations: 3 countries
• Sites: 5

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.

Conditions

Graft Failure

Keywords

HSCT; allo-HSCT; Graft failure; emapalumab; interferon gamma; CXCL9

Outcome Measures

Primary Outcomes (3)

• CXCL9 in Serum

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

  From start of treatment to EoS Visit, up to 34 weeks

• Primary Graft Failure (GF)

  Number of participants with primary graft failure (GF)

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

• Secondary GF

  Number of participants with secondary GF

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

Secondary Outcomes (60)

• Free & Total Interferon Gamma (IFNγ) in Serum

  From start of treatment to EoS Visit, up to 34 weeks

• Emapalumab in Serum - Peak

  From start of treatment to EoS, up to 34 weeks

• Ctrough (Emapalumab)

  From start of treatment to EoS, up to 34 weeks

• Exploratory Biomarkers: Ferritin

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

• ADA and nAbs

  From Start of treatment until EoS, up to 34 weeks

Study Arms (1)

Emapalumab

EXPERIMENTAL

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.

Drug: Emapalumab

Interventions

Emapalumab DRUG

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.

Also known as: Gamifant®, NI-0501

Emapalumab

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Swedish Orphan Biovitrum: lead
• PRA Health Sciences: collaborator
• Cytel Inc.: collaborator
• Q2 Solutions: collaborator
• ABF Pharmaceutical Services GmbH: collaborator
• Cromsource: collaborator
• BioMérieux: collaborator

Study Sites (5)

Peter MacCallum Cancer Centre

Melbourne, 3000, Australia

Location

Kids Cancer Centre Sydney Children's Hospital

Randwick, 2031, Australia

Location

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

The Rambam Academic Hospital

Haifa, 31096, Israel

Location

Hadassah Hebrew University

Jerusalem, 91120, Israel

Location

MeSH Terms

Interventions

Emapalumab

Limitations and Caveats

The study was prematurely terminated with only 2 patients enrolled. Both patients were in the non-emapalumab treated arm, i.e. no patients received study treatment (emapalumab). Consequently, the majority of analyses were not performed and no conclusion on the efficacy of emapalumab on this patient population could be drawn from the study.

Results Point of Contact

• Title: Emmanuel Monnet
• Organization: Sobi

Emmanuel.Monnet@sobi.com

+41225519156

Study Officials

• Tsila Zuckerman, Dr

  The Rambam Academic Hospital

  PRINCIPAL INVESTIGATOR

• Henrique Bittencourt, Dr

  St. Justine's Hospital

  PRINCIPAL INVESTIGATOR

• Polina Stepensky, Dr

  Hadassah Hebrew University

  PRINCIPAL INVESTIGATOR

• Ashvind Prabahran, Dr

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

• Richard Mitchell, Dr

  Kids Cancer Centre Sydney Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: November 13, 2020
• First Posted: January 29, 2021
• Study Start: May 25, 2021
• Primary Completion: April 21, 2022
• Study Completion: April 21, 2022
• Last Updated: December 28, 2023
• Results First Posted: December 28, 2023

Record last verified: 2023-12

Locations

CA (1); IL (2); AU (2)