Neihulizumab (ALTB-168) in Patients With Steroid-refractory Acute Graft-versus-host Disease or Treatment-refractory Acute Graft-versus-host Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Steroid-refractory Acute Graft-versus-Host Disease, Treatment-refractory Acute Graft-versus-Host Disease

Intervention / Treatment
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* Biological: Neihulizumab (ALTB-168)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (must meet all of the following criteria): Patients must have clinical aGVHD and pathologic findings consistent with the diagnosis by biopsy of at least 1 involved site, and progressed after 3 days of treatment with methylprednisolone (MP) 2 mg/kg/day equivalent, or did not improve after 7 days of treatment with MP 2 mg/kg/day equivalent, or progressed to involve a new organ after treatment with MP 1 mg/kg/day equivalent for skin and upper gastrointestinal (GI) GVHD, or recurred during or after a steroid taper 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). 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. Patient must give informed consent and sign an approved consent form prior to any study procedures. 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): For single dose phase: Prior administration of anti-lymphocyte globulin or anti- thymocyte globulin for treatment of aGVHD. For multiple dose phase: Has received any systemic treatment in addition to corticosteroids for aGVHD. Stage 4 lower GI GVHD, defined by the presence of ileus, severe abdominal pain, or overt GI bleeding. Uncontrolled infections not responding to antimicrobial therapy or requiring intensive critical care or vasopressors. Evidence of end-organ cytomegalovirus (CMV) or adenovirus infection. 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. HIV infection or a known HIV-related malignancy. Tuberculosis, history of tuberculosis or a known positive Quantiferon test for tuberculosis. Unplanned donor lymphocyte infusion (DLI) for residual or relapsed malignancy or mixed chimerism. DLI as part of the planned HCT protocol is allowed. Known relapsed or progressive malignancy after transplant, posttransplant lymphoproliferative disease or any secondary malignancy diagnosed after HCT. Absolute neutrophil count (ANC) <1000/mm3. Total serum bilirubin concentration >3.0 mg/dL UNLESS attributed to GVHD. Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault equation. Sodium (Na) concentration < 130 mmol/L. Karnofsky Performance Status (KPS) or Lansky Performance Status < 20%. 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. History of allergy or hypersensitivity to any systemically administered antibody agent or its excipients. Pregnancy or nursing. Less than 12 years of age.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neihulizumab (ALTB-168)<br>Intravenous doses of Neihulizumab (ALTB-168) | Biological: Neihulizumab (ALTB-168)<br>* Single dose phase: Patients will receive single dose of Neihulizumab based on the protocol escalation criteria. Multiple dose phase: Parients will receive weekly doses of Neihulizumab for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Neihulizumab - AUC | Including AUC0-t, AUC0-tz, AUC 0-inf | Up to Day 56 | 
| Pharmacokinetics of Neihulizumab - Cmax | Maximum plasma concentration | Up to Day 56 | 
| Pharmacokinetics of Neihulizumab - tmax | Time to reach Cmax | Up to Day 56 | 
| Pharmacokinetics of Neihulizumab - Lambda-z | Terminal phase elimination rate constant | Up to Day 56 | 
| Pharmacokinetics of Neihulizumab - t1/2 | Half life | Up to Day 56 | 
| Pharmacokinetics of Neihulizumab - MRT | Mean Residence Time | Up to Day 56 | 
| Pharmacokinetics of Neihulizumab - Vz and Vss | Volume of distribution and volume of distribution at steady state | Up to Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | AEs graded according to CTCAE v4.03 | Up to Day 180 | 
| To measure the Receptor Occupancy (RO) | Receptor occupancy will be monitored using a flow cytometry based method | Up to Day 56 | 
| To measure regenerating islet-derived 3-alpha (REG3α) and suppression of tumorigenicity 2 (ST2) as Pharmacodynamics (PD) biomarkers. | Receptor occupancy will be monitored using a flow cytometry based method | Up to Day 56 | 
| Complete Response (CR) | To assess the rate of complete response (CR) at Day 28 in patients treated with Neihulizumab | Day 28 | 
| Overall Response Rate (ORR) | To assess the Overall Response Rate (ORR) at Day 28: CR+PR | Day 28 | 
| Duration of Response | For subjects with CR at Day 28, duration of response will be assessed according to the time interval from Day 28 to the first occurrence of (1) resumption of Neihulizumab administration or initiation of new systemic treatment for aGvHD or (for patients who have tapered steroids) an increase in corticosteroids to methylprednisolone 2 mg/kg (+/-10%) equivalent or more, or (2) death. | Up to Day 180 | 
| Non Relapse Mortality (NRM) | Patients will be followed-up for survival for 6 months after the first Neihulizumab treatment | Day 180 | 
| Immunogenicity | Immunogenicity will be monitored by anti-drug antibody (ADA) ELISA | Up to Day 56 |