Clinical trial NCT03327857: Neihulizumab (ALTB-168) in Patients With Steroid-refractory Acute Graft-versus-host Disease or Treatment-refractory Acute Graft-versus-host Disease
Official title: A Phase I Study of Neihulizumab (ALTB-168) in Patients With Steroid-refractory Acute Graft-versus-host Disease (SR-aGVHD) or Treatment-refractory Acute Graft-versus-host Disease (TR-aGVHD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Steroid-refractory Acute Graft-versus-Host Disease
Treatment-refractory Acute Graft-versus-Host Disease
Lead sponsor: AltruBio Inc.
Sponsor class: INDUSTRY
First posted: 2017-11-01
Enrollment: 37
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A Phase I study to establish the pharmacokinetics, pharmacodynamics, safety and efficacy profiles of Neihulizumab in patients with steroid-refractory or treatment refractory acute graft-versus-host disease (SR/TR-aGVHD)

Detailed description: Neihulizumab (ALTB-168) is an immune checkpoint agonist antibody that regulates T cell homeostasis. The unique mechanism of action provides a natural regulation of T cell homeostasis that induces cell death preferentially in late-stage activated T cells without affecting resting T cells and early-activated T cells. Because pathogenic T cells underlying the inflammatory conditions are usually in late-stage activated state, eliminating this population of cells can potentially result in controlling autoimmune inflammation of T cell associated diseases, such as GvHD.

Eligibility criteria: Inclusion Criteria (must meet all of the following criteria):

1. Patients must have clinical aGVHD and pathologic findings consistent with the diagnosis by biopsy of at least 1 involved site, and

   1. progressed after 3 days of treatment with methylprednisolone (MP) 2 mg/kg/day equivalent, or
   2. did not improve after 7 days of treatment with MP 2 mg/kg/day equivalent, or
   3. progressed to involve a new organ after treatment with MP 1 mg/kg/day equivalent for skin and upper gastrointestinal (GI) GVHD, or
   4. recurred during or after a steroid taper
2. For single dose phase: Patients must have erythematous manifestations of cutaneous aGVHD. Characteristics of the rash must indicate active inflammation (red coloration) as distinct from resolving inflammation (brown coloration).
3. For single dose phase: Providers and patients must be willing to defer new systemic or cutaneous topical treatment of aGVHD for at least 36 hr after administration of Neihulizumab.
4. Patient must give informed consent and sign an approved consent form prior to any study procedures.
5. Females of childbearing potential must have a negative pregnancy test result before enrollment. Males and females of childbearing potential must agree to use a highly effective method of birth control during the study for at least 30 days after enrollment in the study.

Exclusion Criteria (may not meet any of the following criteria):

1. For single dose phase: Prior administration of anti-lymphocyte globulin or anti- thymocyte globulin for treatment of aGVHD.
2. For multiple dose phase: Has received any systemic treatment in addition to corticosteroids for aGVHD.
3. Stage 4 lower GI GVHD, defined by the presence of ileus, severe abdominal pain, or overt GI bleeding.
4. Uncontrolled infections not responding to antimicrobial therapy or requiring intensive critical care or vasopressors.
5. Evidence of end-organ cytomegalovirus (CMV) or adenovirus infection.
6. Known to have adenovirus, or Epstein Barr virus (EBV) viremia from screening according to institutional standard practice. Patients receiving appropriate antiviral treatment for CMV, HHV6 or hepatitis viremia are eligible on a case-by-case basis.
7. HIV infection or a known HIV-related malignancy.
8. Tuberculosis, history of tuberculosis or a known positive Quantiferon test for tuberculosis.
9. Unplanned donor lymphocyte infusion (DLI) for residual or relapsed malignancy or mixed chimerism. DLI as part of the planned HCT protocol is allowed.
10. Known relapsed or progressive malignancy after transplant, posttransplant lymphoproliferative disease or any secondary malignancy diagnosed after HCT.
11. Absolute neutrophil count (ANC) \<1000/mm3.
12. Total serum bilirubin concentration \>3.0 mg/dL UNLESS attributed to GVHD.
13. Creatinine clearance \< 30 mL/min calculated by Cockcroft-Gault equation.
14. Sodium (Na) concentration \< 130 mmol/L.
15. Karnofsky Performance Status (KPS) or Lansky Performance Status \< 20%.
16. Intensive care unit (ICU) care, life expectancy of less than 28 days, ongoing or unresolved hepatic sinusoidal obstruction syndrome, unstable hemodynamics, or evidence of current or previous clinically significant disease, medical condition or finding (including vital signs and ECG) that in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data.
17. History of allergy or hypersensitivity to any systemically administered antibody agent or its excipients.
18. Pregnancy or nursing.
19. Less than 12 years of age.

Primary outcomes:
measure: Pharmacokinetics of Neihulizumab - AUC
timeFrame: Up to Day 56
measure: Pharmacokinetics of Neihulizumab - Cmax
timeFrame: Up to Day 56
measure: Pharmacokinetics of Neihulizumab - tmax
timeFrame: Up to Day 56
measure: Pharmacokinetics of Neihulizumab - Lambda-z
timeFrame: Up to Day 56
measure: Pharmacokinetics of Neihulizumab - t1/2
timeFrame: Up to Day 56
measure: Pharmacokinetics of Neihulizumab - MRT
timeFrame: Up to Day 56
measure: Pharmacokinetics of Neihulizumab - Vz and Vss
timeFrame: Up to Day 56
Secondary outcomes:
measure: Adverse Events (AEs)
timeFrame: Up to Day 180
measure: To measure the Receptor Occupancy (RO)
timeFrame: Up to Day 56
measure: To measure regenerating islet-derived 3-alpha (REG3α) and suppression of tumorigenicity 2 (ST2) as Pharmacodynamics (PD) biomarkers.
timeFrame: Up to Day 56
measure: Complete Response (CR)
timeFrame: Day 28
measure: Overall Response Rate (ORR)
timeFrame: Day 28
measure: Duration of Response
timeFrame: Up to Day 180
measure: Non Relapse Mortality (NRM)
timeFrame: Day 180
measure: Immunogenicity
timeFrame: Up to Day 56
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: Miami
country: United States
facility: University of Miami - Sylvester Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Westwood
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Cleveland
country: United States
facility: University Hospitals Seidman Cancer Center
state: Ohio
city: Houston
country: United States
facility: Baylor College of Medicine-Houston Methodist & Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: AltruBio, Inc. (formerly AbGenomics International)
name: Shih-Yao Lin, MD, PhD
role: STUDY_DIRECTOR
affiliation: Fred Hutchinson Cancer Center
name: Paul Martin, MD
role: PRINCIPAL_INVESTIGATOR
References: