Efficacy and Safety of Sirolimus With or Without Cyclosporin A in Chinese Patients With Aplastic Anemia Refractory/Intolerant to Cyclosporin A

This is a single center, randomized, open-label, phase II study to compare the efficacy of sirolimus combined with cyclosporin A (CsA) to sirolimus alone in Chinese subjects with aplastic anemia refractory/intolerant to CsA. The safety would also be evaluated. Patients would be randomized to receive sirolimus alone or sirolimus combined with CsA at a 1:3 ratio. Treatment with sirolimus will be started at 1-3 mg once daily orally, with a target trough blood concentration of 4-12 ng/ml. CsA will be given at 25-150 mg orally every 12 hours, with the dose adjusted based on renal function and trough concentration. For patients with normal renal function, the target trough concentration is approximately 150 ng/ml. For patients with impaired renal function, the cyclosporine A dose is reduced to 25-50 mg every 12 hours, aiming for recovery or stabilization of renal function. The hematological response rate and safety will be recorded and compared at 3 and 6 months after starting the study treatment (Week 13 and 25).

Study Overview

• Status: Recruiting
• Conditions: Aplastic Anaemia
• Intervention / Treatment: Drug: Sirolimus (Rapamune®); Drug: Cyclosporin A (CsA)

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ziwei Liu; Phone Number: +8613811615392; Email: liuzw10@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100730
      • Recruiting
      • Peking Union Medical College Hospital
      • Contact: Ziwei Liu; Phone Number: +8613811615392; Email: liuzw10@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years;
2. Diagnosed with acquired aplastic anemia (AA), excluding congenital AA;
3. At least one of the following criteria met at enrollment: hemoglobin < 100 g/L, platelets < 50 × 10⁹/L, or neutrophils < 1.0 × 10⁹/L;

4. At enrollment, meeting at least one of the following conditions:

   ① Cyclosporine A (CsA) ineffective: (CsA) used for at least 3 months without achieving partial response (PR), or disease relapse occurred;

   ② CsA intolerant: Unsuitable for standard dose CsA treatment due to adverse events or underlying conditions.

5. No active infections;
6. Not pregnant or breastfeeding;
7. Willing to sign the consent form;
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.

Exclusion Criteria:

1. Pancytopenia caused by other reasons, such as myelodysplastic syndrome (MDS);
2. Evidence of clonal hematopoietic system bone marrow diseases (e.g., MDS or acute myeloid leukemia, AML);
3. Paroxysmal nocturnal hemoglobinuria (PNH) clone ≥ 50%;
4. History of hematopoietic stem cell transplantation (HSCT) before enrollment;
5. Previous use of sirolimus or allergy to sirolimus;
6. Severe adverse events to CsA in the past, making it unsuitable for reuse;
7. Uncontrolled infection or bleeding with standard treatment;
8. Active infections with HIV, HCV, or HBV, liver cirrhosis, portal hypertension;
9. Any concurrent malignancy within the past 5 years, except for localized basal cell carcinoma of the skin;
10. History of thromboembolic events, myocardial infarction, or stroke (including antiphospholipid antibody syndrome), or current use of anticoagulants;
11. Pregnant or breastfeeding women;
12. Participation in other clinical trials within the past 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sirolimus + cyclosporin A	Drug: Sirolimus (Rapamune®); Sirolimus 1-3 mg once daily orally, with a target trough blood concentration of 4-12 ng/ml.; Drug: Cyclosporin A (CsA); Cyclosporine A 25-150 mg orally every 12 hours, with the dose adjusted based on renal function and trough concentration. For patients with normal renal function, the target trough concentration is approximately 150 ng/ml. For patients with impaired renal function, the cyclosporine A dose is reduced to 25-50 mg every 12 hours, aiming for recovery or stabilization of renal function.
Placebo Comparator: Sirolimus	Drug: Sirolimus (Rapamune®); Sirolimus 1-3 mg once daily orally, with a target trough blood concentration of 4-12 ng/ml.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR) at 3 months	Overall Response Rate (ORR) is defined as the number of participants who meet the criteria of either complete response (CR) or partial response (PR)	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of hematologic response	Time from the date of the start of the first response to the date of first relapse defined as again meeting criteria for aplastic anemia	by 6 months (all patients), at 12 months (responders only)
Percentage of patients with clonal evolution to myelodysplasia, PNH, and acute leukemia	Clonal evolution to myelodysplasia is defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Evolution to leukemia is defined as greater than 20% peripheral blood and/or marrow blasts. Evolution to paroxysmal nocturnal hemoglobinuria (PNH) is defined as a clone at baseline < 10% that rose to greater than 50% on study.	12 months
Overall response rate (ORR) at 6 months	ORR will be evaluated after 6 months of treatment by measuring platelet, reticulocyte, hemoglobin, neutrophil and transfusion independence.	Week 24
Changes in Hemoglobin in the Absence of Red Blood Cells Transfusion	The change in hematology values (hemoglobin) were evaluated	Week 12
Changes in Platelet in the Absence of Platelet Transfusion	The change in hematology values (platelet) were evaluated	Week 12

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2025
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: January 25, 2025
• First Submitted That Met QC Criteria: January 25, 2025
• First Posted (Actual): January 30, 2025

Study Record Updates

• Last Update Posted (Actual): June 4, 2025
• Last Update Submitted That Met QC Criteria: May 29, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Sirolimus; Relapsed/refractory aplastic anemia
• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Hematologic Diseases; Bone Marrow Diseases; Myelodysplastic Syndromes; Anemia; Anemia, Aplastic; Anemia, Refractory; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Dermatologic Agents; Calcineurin Inhibitors; Sirolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: I-25PJ0215

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data would be accepted upon request
• IPD Sharing Time Frame: 10 years
• IPD Sharing Access Criteria: Email request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No