Safety and Clinical Activity of Itolizumab in aGVHD

Study Overview
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Brief Summary
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To evaluate the safety, tolerability, PK, PD, and clinical activity of Itolizumab in subjects with Newly diagnosed Acute Graft Versus Host Disease(aGVHD).

Detailed Description
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The study will enroll approximately 44 subjects in three parts: Part 1 is an open label 3+3 single dose escalation phase and will enroll approximately 30 subjects with aGVHD across 4 cohorts, where subjects will receive Itolizumab administered intravenously for 1 dose. Part 2 is an open label phase and subjects from part 1 will receive Itolizumab administered intravenously every two weeks for a total of 4 doses. Part 3 is a randomized phase and will enroll approximately 14 additional subjects, randomized in a 1:1 ratio to one of the 2 recommended doses provided by Part 1 and Part 2. Subjects will receive Itolizumab administered intravenously every two weeks for a total of 5 doses.

Official Title
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A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Itolizumab in Subjects With Newly Diagnosed Acute Graft Versus Host Disease

Conditions
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Acute Graft Versus Host Disease

Intervention / Treatment
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* Drug: Itolizumab
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject at least 18 years of age. Has received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Clinical diagnosis of Grade II-IV aGVHD per MAGIC guideline requiring systemic immune suppressive therapy. Initiation of systemic steroids therapy ≤ 72 hours. Negative result of serum HCG within 72 hours before enrollment for female with potential fertility. Have a life expectancy of 10 weeks or more. Able to understand and comply with the planned procedure as required by the protocol, and sign a written informed consent form (ICF). Exclusion Criteria: Has received more than 1 allo-HSCT. Presence of morphologic relapsed primary malignancy, treatment for relapse after alloHSCT was performed, or requirement for rapid immunosuppressive treatment withdrawal for early malignancy relapse. Evidence of graft failure based on cytopenia(s), and as determined by the investigator. Evidence of post-transplant lymphoproliferative disease. Any prior therapy for acute GVHD, except for alloHSCT prophylaxis regimens or systemically administered corticosteroids. aGVHD induced by donor lymphocyte infusion(DLI). Clinically or suspected diagnosed of cGVHD or overlap syndrome. Unresolved toxicity or complications due to allo-HSCT,other than aGVHD. Any clinical or laboratory abnormalities that is likely to negatively affect the reliability of the study safety data, as determined by the investigator. Presence of any uncontrolled active infections, which was defined as hemodynamic instability due to sepsis or worsening of new symptoms, signs, or imaging findings due to infection. Presence of any uncontrolled and active infections. Presence of active and uncontrolled viral infections at screening. History of active tuberculosis within 6 months prior to screening or negative result of interferon-gamma release assay at screening. History of class III or IV congestive heart failure per New York Heart Association, clinically significant or uncontrolled unstable angina or myocardial infarction, cerebrovascular accident, or pulmonary embolism within 6 months prior to screening. Severe impaired renal function at screening (serum creatinine > 1.5 ULN or creatinine clearance < 30mL/min). Presence of persistent bilirubin abnormalities induced by hepatic sinusoidal obstruction, hepatic veno-occlusive disease, non-GVHD or progressive organ dysfunction at screening. Serum ALT and AST > 4 ULN at screening. Absolute lymphocyte count < 0.5×109/L at screening. Any major surgical procedures performed within 4 weeks prior to screening, that is likely to negatively affect the evaluation of the study safety data, as determined by the investigator. Any malignant tumor other than the transplanted tumor within 5 years before screening. Suspected allergic to the experimental drug product or any of its excipients. Currently pregnant, breastfeeding,or planning to become pregnant or not using reliable method to avoid pregnancy during study and within 3 months after the last study treatment. As determined by the investigator, any medical, psychiatric, or other condition or circumstance that is likely to negatively affect the reliability of the study data.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itolizumab Dose Level 1<br>Itolizumab of 25 mg administered by intravenous infusion every 2 weeks for a total of 5 doses. | Drug: Itolizumab<br>* Subjects will receive Itolizumab concomitant within 72 hours of systematic Corticosteroids.<br>* Other names: T1h;Drug: Methylprednisolone<br>* Methylprednisolone will be taperred as required<br>* Other names: Methylprednisolone Sodium Succinate;|
| Experimental: Itolizumab Dose Level 2<br>Itolizumab of 50 mg administered by intravenous infusion every 2 weeks for a total of 5 doses. | Drug: Itolizumab<br>* Subjects will receive Itolizumab concomitant within 72 hours of systematic Corticosteroids.<br>* Other names: T1h;Drug: Methylprednisolone<br>* Methylprednisolone will be taperred as required<br>* Other names: Methylprednisolone Sodium Succinate;|
| Experimental: Itolizumab Dose Level 3<br>Itolizumab of 100 mg administered by intravenous infusion every 2 weeks for a total of 5 doses. | Drug: Itolizumab<br>* Subjects will receive Itolizumab concomitant within 72 hours of systematic Corticosteroids.<br>* Other names: T1h;Drug: Methylprednisolone<br>* Methylprednisolone will be taperred as required<br>* Other names: Methylprednisolone Sodium Succinate;|
| Experimental: Itolizumab Dose Level 4<br>Itolizumab of 150 mg administered by intravenous infusion every 2 weeks for a total of 5 doses. | Drug: Itolizumab<br>* Subjects will receive Itolizumab concomitant within 72 hours of systematic Corticosteroids.<br>* Other names: T1h;Drug: Methylprednisolone<br>* Methylprednisolone will be taperred as required<br>* Other names: Methylprednisolone Sodium Succinate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events | Number of subjects with treatment-related adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | Study Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to maximum Itolizumab serum concentration, Tmax | Time to maximum Itolizumab serum concentration | Study Day 85 | 
| Maximum Itolizumab serum drug concentration, Cmax | Maximum Itolizumab serum drug concentration | Study Day 85 | 
| Minimum Itolizumab serum drug concentration, Cmin | Minimum Itolizumab serum drug concentration | Study Day 85 | 
| Total Itolizumab exposure across time, AUC | Total Itolizumab exposure across time, AUC | Study Day 85 | 
| Half life of Itolizumab, t1/2 | Half life of Itolizumab | Study Day 85 | 
| Volume of distribution of Itolizumab, Vd | Volume of distribution of Itolizumab | Study Day 85 | 
| Clearance, Cl | Clearance | Study Day 85 | 
| CD6 receptor expression levels on T cells | CD6 receptor expression levels | Study Day 85 | 
| T cell subsets | T cell subsets | Study Day 85 | 
| Inflammatory Markers | Including but not limited to:IL-2, IL-6, IL-8, IL-17, IFN-γ, TNF-α, CRP, TNFR1, ST2, REG3α, Elafin | Study Day 85 | 
| Overall Response Rate (ORR) | Percentage of subjects demonstrating a CR or PR. | Study Day 337 | 
| Nonrelapse Mortality(NRM) Rate | Proportion of subjects who died due to causes other than malignancy relapse | Study Day 337 | 
| cGVHD rate | Percentage of subjects demonstrating of cGVHD | Study Day 337 | 
| Dose Reduction in Systemic Steroid Use | Change from Baselinein Dose of Systemic Steroid Use | Study Day 337 | 
| Incidence of ADA | Precentage of subjects presenting anti-drug antibody | Study Day 85 |