The Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMPL-523 in Immune Thrombocytopenia Patients

Study Overview
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Brief Summary
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This is a randomized, double blinded, placebo-controlled phase Ib clinical trial in adult patients with immune thrombocytopenia. Cross-over treatment will be allowed during the study.

Detailed Description
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Approximate 51 to 60 patients will be enrolled in dose escalation (3 cohorts, 8-20 subjects each with the ratio of 3:1 vs Placebo) .

Official Title
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The Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMPL-523, a Syk Inhibitor in Adult Patients of Immune Thrombocytopenia: a Randomized, Double Blinded, Placebo Controlled Phase Ib Study

Conditions
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Immune Thrombocytopenia (ITP)

Intervention / Treatment
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* Drug: HMPL-523
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form 18 75 years old male of female Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Diagnosed immune thrombocytopenia before randomization with platelet decrease for more than 6 months. Patients with refractory or relapsed ITP who have been treated with 1st line anti-ITP regimen or have experienced splenectomy. Relative stable disease with World Health Organization (WHO) bleeding score of 0-1 and no rescue treatment needed within 2 weeks based on investigator's judgment. Laboratory tests meet the following conditions： During screening stage, twice PLT<30x10^9/L(exceed 24 hours) Hb≥90g/L(if iron-deficiency anemia,Hb>80g/L),WBC>2.5x10^9/L, NEU>1.8x10^9/L Crea≤1.5xULN and CCR≥50mL/min TBIL、ALT、AST≤1.5xULN Amylase、lipase<ULN INR、APTT<20%xULN Exclusion Criteria: Patients with secondary thrombocytopenia or patients have other auto immune diseases who need long term steroids or immunosuppressants treatment. Patients with Myelofibrosis, Myelodysplastic syndrome, Aplastic anemia, or other hematologic malignancies. Have splenectomy within 12 weeks before randomization Major surgery was performed within 4 weeks before randomization;Or require major elective surgery during the study period. Have malignant tumor(except basal cell carcinoma of skin and carcinoma in situ of cervix) Have previous/significant arterial/venous embolic disease History of serious cardiovascular disease, or QTc≥450 ms. Patients with resistant hypertension (Systolic blood pressure ≥140 mmHg or Diastolic blood pressure ≥90 mmHg) Has a history of severe gastrointestinal diseases, such as dysphagia, active gastric ulcer, and is unable to take oral medication or has absorption disorder HIV infection Uncontrolled, active infections Known history of clinically significant liver disease, such as hepatitis b（HBV DNA ≥2000IU/mL (or ≥1×104 copies)）, hepatitis c, or cirrhosis Prior anti-ITP emergency treatment within 2 weeks before randomization. Prior anti-ITP treatment within 4 weeks before randomization except for stable dose steroids, including but not limited to Thrombopoietin, thrombopoietin receptor agonist, azathioprine, cyclosporine A and mycophenolate mofetil. Any condition requiring anti-coagulant therapy or the regular use of any medication having effluence to Platelet function. Exposure to Rituximab 14 weeks prior to randomization. Treament with Chinese medicine within 1 week before randomization. Use of strong cytochrome P450 isoform 3A inhibitors and inducers and drugs metabolized by cytochrome P450 isoform 3A, cytochrome P450 isoform 2B6, and cytochrome P450 isoform 1A2, and are identified as narrow therapeutic drugs within 14 days or 5 half-lives, whichever is longer, prior to initiation of study treatment. Prior treatment with any spleen tyrosine kinase (SYK) inhibitors (eg, fostamatinib) Allergic to study drug active ingredient or excipient Subjects who have participated in clinical studies of drugs or invasive medical devices within 4 week before randomization Subjects have severe psychological or mental abnormalities Alcoholic or drug abuser Female subjects during pregnancy and lactation The investigator considered that the subjects were not suitable to participate in the study

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: treatment arm<br>Eligible subjects will be treated with planned dose of 100 mg, 200 mg and 300 mg HMPL-523 once daily for 8 weeks and 16 weeks open-label treatment. | Drug: HMPL-523<br>* HMPL-523 will be oral administrated once daily for 8 weeks and 16 weeks open-label treatment.<br>|
| Placebo Comparator: placebo arm<br>Eligible subjects will be treated with HMPL-523 matching placebo once daily for 8 weeks and 16 weeks open-label treatment. | Drug: HMPL-523<br>* HMPL-523 will be oral administrated once daily for 8 weeks and 16 weeks open-label treatment.<br>Drug: Placebo<br>* HMPL-523 matching placebo will be oral administrated once daily for 8 weeks and 16 weeks open-label treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with any Adverse Event | Adverse Events evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | From first dose to within 28 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) | Maximum plasma concentration (Cmax) | Day 15, 16, 29, 43 and 47 | 
| Area under the concentration-time curve in a selected time interval (AUC0-t) | Area under the concentration-time curve in a selected time interval (AUC0-t) | Day 15, 16, 29, 43 and 47 | 
| Rate of Clinical Remission | Rate of Clinical Remission was defined as the proportion of patients with two consecutive visits in the first 8 weeks (including the 8th week) during the medication period, platelet count ≥30×10^9/L, and a 2-fold increase from baseline (no emergency treatment during the period) | Day 1 to 8 weeks treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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syk inhibitor, ITP