Safety and Preliminary Clinical Activity of Itolizumab in Dermatomyositis

Study Overview
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Brief Summary
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To evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of Itolizumab in subjects with Dermatomyositis.

Detailed Description
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The study will enroll approximately 44 subjects in two parts: Part 1 is an open label, 3+3 single dose escalation and then mutiple dose administration phase. 9 30 patients with DM are expected to be enrolled across 3 dose cohorts. Part 2 is a randomized phase and will enroll approximately 14 additional subjects, randomized in a 1:1 ratio to one of the 2 doses based on efficacy data obtained from Part 1. All participants in this study will receive Itolizumab intravenously every two weeks for a total of 7 doses.

Official Title
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A Phase 1 Study to Evaluate the Safety, Tolerability and Preliminary Clinical Activity of Itolizumab in Subjects With Dermatomyositis

Conditions
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Dermatomyositis, Adult Type

Intervention / Treatment
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* Drug: Itolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject aged 18-75 years old (inclusive). Fulfill one of the following criteria for DM:1) Bohan and Peter criteria for definite or probable DM;2) ENMC 2018 Dermatomyositis Classification Criteria Disease activity fulfills at least three of the following criteria:1) MMT-8 score < 142; 2) physician's global disease activity ≥2 cm; 3) patient's global activity ≥2 cm; 4) extra-muscular activity ≥2 cm; 5) Health Assessment Questionnaire [HAQ] ≥0.25; 6) at least one muscle enzyme >1.5 times ULN Under treatment with corticosteroids and/or at least 1 immunesuppressant, and being on stable therapy for at least 4 and 8 weeks for corticosteroids and immunesuppressant respectively (see Section 5.7.1) Fulfill all of the following criteria: 1) % predicted values of FVC≥70%; 2) % predicted values of DLCO≥60%; 3) chest HRCT indicating the extent of disease lesion of DM-ILD < 20% as determined by the investigator Negative result of serum HCG within 72 hours before enrollment for female with potential fertility Able to understand and comply with the planned procedure as required by the protocol, and sign a written informed consent form (ICF) Exclusion Criteria: Subject with other connective tissue diseases (e.g., systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, Sjogren's syndrome, mixed connective tissue disease, etc.) or ANCA associated vasculitis. Diagnosed with polymyositis or IMNM. Diagnosed with systemic, severe musculoskeletal disorder that unrelated to DM and will interfere with the investigator's assessment of the subject's muscle strength. Subject who plans to start a physical therapy program during the trial. Subject who has a medical history of New York Heart Association class III or IV congestive heart failure, clinically significant or uncontrolled unstable angina or myocardial infarction, cerebrovascular accident, or pulmonary embolism within 6 months prior to screening Subject with impaired renal function (serum creatinine > 1.5 x ULN or creatinine clearance < 30 mL/min [Cockcroft-Gault formula]) at screening. Any of following significant abnormalities in liver function at screening: Serum alanine transaminase (ALT) or glutathione transaminase (AST) ≥ 3 x ULN, except when judged by the investigator to be due to DM; Total bilirubin ≥ 1.5 x ULN; Cirrhosis classification of Child-Pugh grade C. Any of the following abnormalities at screening: Hepatitis B-related tests: ① positive hepatitis B surface antigen (HBsAg); ② positive hepatitis B core antibody (HBcAb); ③ positive hepatitis B surface antibody (HBsAb) and no history of hepatitis B vaccination; ④ positive hepatitis B e antigen or hepatitis B e antibody; Positive hepatitis C virus nucleic acid test (HCV-RNA); Positive acquired immunodeficiency syndrome antibody (HIV-Ab); Positive anti-syphilis spiral antibody (TP-Ab); Other acute or chronic infections requiring treatment. Absolute lymphocyte count < 0.5×109/L at screening Subject who has a medical history of tuberculosis or those who deny a history of tuberculosis but has a positive gamma-interferon release test at screening. Any other clinically significant clinical condition or laboratory tests abnormality that, in the judgment of the investigator, may affect the safety evaluation Any malignant tumor other than the cured carcinoma in situ or basal cell carcinoma within 5 years before screening Suspected allergic to the investigational drug or any of its excipients Subject who had participated in other clinical studies (other than those not receiving interventions, such as observational study or questionnaires survey) within 3 months prior to screening, or who are participating in other experimental treatments. Subject who requires to be administrated with higher dose of corticosteroids and/or immunesuppressant than the allowed maximum dose specified in the protocol (section 5.7.1) Subject who had been treated by one or more of the following drugs during the corresponding time window prior to screening: cyclophosphamide, rituximab within 12 months prior to screening; belizumab, tetrasip within 24 weeks prior to screening; intravenous immunoglobulin injections, baliximab, infliximab, adalimumab, tolimumab, JAK inhibitors within 12 weeks prior to screening; Other monoclonal antibodies or other biological agents within 12 weeks or 5 half-lives [whichever is longer] prior to screening. 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
Maximum Age: 75 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 7 doses. | Drug: Itolizumab<br>* Patients to be treated with Itolizumab.<br>* Other names: T1h;|
| Experimental: Itolizumab Dose Level 2<br>Itolizumab of 50 mg administered by intravenous infusion every 2 weeks for a total of 7 doses. | Drug: Itolizumab<br>* Patients to be treated with Itolizumab.<br>* Other names: T1h;|
| Experimental: Itolizumab Dose Level 3<br>Itolizumab of 100 mg administered by intravenous infusion every 2 weeks for a total of 7 doses. | Drug: Itolizumab<br>* Patients to be treated with Itolizumab.<br>* Other names: T1h;|

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 Week 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration of Itolizumab, Cmax | Maximum serum concentration of Itolizumab | Study Week 16 | 
| Minimum serum concentration of Itolizumab, Cmin | Minimum serum concentration of Itolizumab | Study Week 16 | 
| Time to maximum serum concentration of Itolizumab, Tmax | Time to maximum serum concentration of Itolizumab | Study Week 16 | 
| Total Itolizumab exposure across time, AUC0-t | Total Itolizumab exposure across time | Study Week 16 | 
| Half life of Itolizumab, t1/2 | Half life of Itolizumab | Study Week 16 | 
| IL-2 | Inflammatory Markers：IL-2 | Study Week 16 | 
| IL-6 | Inflammatory Markers:IL-6 | Study Week 16 | 
| TNF-α | Inflammatory Markers: TNF-α | Study Week 16 | 
| IFN-γ | Inflammatory Markers:IFN-γ | Study Week 16 | 
| CRP | Inflammatory Markers:CRP | Study Week 16 | 
| Serum ferritin | Inflammatory Markers:Serum ferritin | Study Week 16 | 
| ESR | Inflammatory Markers:ESR | Study Week 16 | 
| IgG | Inflammatory Markers：IgG | Study Week 16 | 
| IgM | Inflammatory Markers：IgM | Study Week 16 | 
| IgA | Inflammatory Markers： IgA | Study Week 16 | 
| CD6 receptor expression levels | Mean change of CD6 receptor expression levels in relative to baseline | Study Week 16 | 
| T cell subsets | Mean change of different proportion of T cell subsets in relative to baseline | Study Week 16 | 
| Proportion of patients achieving a TIS of ≥20 | Defined as patients with an increase of ≥20 points on the Total Improvement Score in relative to baseline. | Study Week 16 | 
| Proportion of patients achieving DOI | DOI defined as ≥ 20% improvement in 3 of any 6 core set measures, with no more than 2 core set measures worsening by ≥ 25% (MMT-8 cannot worsen by ≥ 25%). | Study Week 16 | 
| Mean Change of Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score | Defined as the mean change of activity score of CDASI（Score Range：0 132，The hingher score indcates the worse outcome） relative to baseline. | Study Week 16 | 
| Incidence of ADA | Defined as the precentage of subjects presenting anti-drug antibody | Study Week 16 |