Efficacy and Safety of Low-dose Decitabine in Refractory Aplastic Anemia

Study Overview
=================
Brief Summary
-----------------
This is a phase 2, single-center, single-arm, open-label trial. Simon's two-stage design is performed to evaluate the efficacy of low-dose Decitabine in refractory aplastic anemia.

Official Title
-----------------
Efficacy and Safety of Low-dose Decitabine in Refractory Aplastic Anemia (LODACA): a Phase 2, Single-arm, Open-label Study

Conditions
-----------------
Refractory Aplastic Anemia

Intervention / Treatment
-----------------
* Drug: Decitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Subjects eligible for enrollment in the study should meet all of following criteria: Diagnosis of acquired aplastic confirmed by peripheral blood and bone-marrow examinations. Refractory to standard first-line immunosuppressive therapy for at least 6 months, including the combination of rabbit anti-thymocyte globulin (rATG) or porcine anti-lymphocyte globulin (pALG) and cyclosporine (CsA); or ineligible for rATG/ pALG and refractory to CsA alone. Persistent decrease of blood cell count, including platelet <30×10^9/L, and/or hemoglobin <90g/L, and/or absolute neutrophil count <0.5×10^9/L. Age ≥12 years old. An Eastern Cooperative Oncology Group performance status score of 0 to 2 at screening. Patients or their legally authorized representatives who have provided written informed consent of their free will to participate in this study. Exclusion criteria: Subjects must be excluded from participating in this study if they meet any of the following criteria: Diagnosis of inherited bone marrow failure disorders. Bone marrow reticulin grade of ≥2. Having a plan to take thrombopoietin (TPO) receptor agonists. Having a plan to undergo hematopoietic stem cell transplantation within 1 year. Subjects with hemolytic paroxysmal nocturnal hemoglobinuria clone. Having abnormalities of cytogenetic abnormalities related to myelodysplastic syndrome except for +8 or 20q- or -Y. Previous or concurrent active malignancies with chemoradiotherapy, except localized tumors diagnosed more than one year previously and treated surgically with curative intent. Cytopenias secondary to any other non-hematological disorders (e.g., liver cirrhosis, active connective tissue disease, or chronic persistent infectious diseases). Active infection not adequately responding to appropriate therapy. Positive for anti-human immunodeficiency virus antibodies, or current infection of hepatitis B virus or hepatitis C virus at screening. Concurrent condition of acute hemorrhage in gastrointestinal tract or respiratory tract, or central nervous system. Dysfunction of liver: Alanine aminotransferase or aspartate aminotransferase or total bilirubin is more than 2.0 times the upper limit of laboratory normal range. Dysfunction of renal: creatinine clear rate is less than 30ml/min. Clinically significant dysfunction of heart: class Ⅲ or Ⅳ of the New York Heart Association classification. Uncontrolled diabetes mellitus. History of congestive heart failure, unstable angina pectoris, myocardial infarction, arterial or venous thrombosis within one year before enrollment. Lactating or pregnant women or patients who have no intention of using oral contraceptives or birth control. Subjects with psychiatric history or severe cerebrovascular disease with cognitive disorder. Participating in other clinical trials within 4 weeks before enrollment. Hypersensitivity to decitabine or its components. A history of decitabine, azacitidine, or other demethylation agents. Receiving TPO-receptor agonists within 1 month before enrollment (other than patients who are treated with TPO-receptor agonists and have no response after at least 4 months treatment). Patients who are considered to be ineligible for the study by the investigator for reasons other than above.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decitabine<br>Subjects will receive low-dose decitabine for 4 cycles and for another 6 cycles in extension study for patients achieving response during the first 4 cycles. | Drug: Decitabine<br>* Demethylating agents<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving a hematological response (any of the platelet response, erythroid response, and neutrophil response) after 4 cycles of low-dose decitabine |  | At 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of drug-related adverse events |  | Within 52 weeks | 
| Proportion of subjects achieving a hematological response (any of the platelet response, erythroid response, and neutrophil response) |  | Within 52 weeks | 
| Proportion of subjects with transfusion independence or decreased transfusion requirement |  | Within 52 weeks | 
| Absolute changes in blood cell count |  | Within 52 weeks | 
| The utility score of EQ-5D-5L questionnaire | Health-related quality of life is measure by the EQ-5D-5L questionnaire. | Baseline, 20 weeks, 52 weeks | 
| Time from the first decitabine to hematologic response |  | Within 20 weeks | 
| Duration of hematologic response |  | Within 52 weeks | 
| Proportion of relapse |  | Within 52 weeks | 
| Proportion of clonal evolution |  | Within 52 weeks |