Chidamide Plus PTCy/Cyclosporine to Prevent GVHD After Myeloablative Conditioning, Matched PBSCT

Phase 2

• Conditions: MDS; Leukemia, Acute
• Interventions: Drug: Chidamide; Drug: Cyclophosphamide; Drug: cyclosporine A

• Registration Number: NCT03336632
• Lead Sponsor: Sichuan University

Brief Summary

This study is to explore the efficacy and safety of introduction of chidamide in PTCy based GVHD prophylaxis in patients undergoing allogeneic PBSCT.

Detailed Description

Eligible patients were aged 16 to 65 years, diagnosed with hematologic malignancy, and had a Karnofsky performance score of ≥70% and were candidates for myeloablative HCT. A 8/8 HLA allelic match between the donor and the recipient at HLA-A, HLA-B, HLA-C, and HLA-DRB1 by high-resolution typing was required. The graft source was PBSC.

Patients received a myeloablative conditioning regimen consisting of oral chidamide given twice weekly at a dose of 20 mg from day -7 to 2 weeks post transplantation, intravenous busulfan 3.2 mg/kg from day -6 to -3, intravenous fludarabine 30 mg/m2 and cytarabine 1g/m2 respectively from day -6 to -2. PBSCs were infused on day 0. GVHD prophylaxis was post-transplantation cyclophosphamide (50 mg/kg on day +3, +4) and cyclosporine (started from day +5). In the absence of GVHD, cyclosporine tapering started on day +100 and discontinued on day +180. Minimal residual disease (MRD) was determined by multi-parameter flow cytometry.

Study Timeline

• Study First Submitted: 2017-11-06
• Study First Submitted QC: 2017-11-06
• Study First Posted: 2017-11-08
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-17
• Last Update Posted: 2018-07-18
• Study Start: 2019-01-01
• Primary Completion: 2020-12-30
• Study Completion: 2021-03-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Age ≥ 16 years or older, and ≤ 65 years at time of enrollment
2. Signed informed consent
3. Hematologic disorder requiring allogeneic hematopoietic cell transplantation
4. Left ventricular ejection fraction (LVEF) ≥ 45% by multiple uptake gated acquisition (MUGA) scan or echocardiogram
5. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusing lung capacity oxygenation (DLCO) adjusted ≥ 50% of predicted values on pulmonary function tests
6. Transaminases (AST, ALT) < 3 times upper limit of normal (ULN) values
7. Creatinine clearance calculated ≥ 50 mL/min
8. Karnofsky Performance Status Score ≥ 60%.
9. Human leukocyte antigen (HLA) matched 8/ (A, B, C, DRB1) related or unrelated donor

Exclusion Criteria

1. Active infection not controlled with appropriate antimicrobial therapy HIV, hepatitis B (HBcAb positive but HBsAg negative with undetectable viral load are eligible), or hepatitis C infection
2. Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) ≥4
3. Anti-thymocyte globulin (ATG) as part of the conditioning regimen
4. Pregnancy
5. Histone deacetylase (HDAC), DAC, HSP90 inhibitors or valproic acid for the treatment of cancer within 30 days
6. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first chidamide treatment
7. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: Any history of ventricular fibrillation or torsade de pointes; Bradycardia defined as heart rate (HR)< 45 bpm (Patients with pacemakers are eligible if HR ≥ 45 bpm); Screening electrocardiogram (ECG) with a QTcF > 480 msec; Right bundle branch block + left anterior hemiblock (bifascicular block); Patients with myocardial infarction or unstable angina ≤ 12 months prior to starting study drug; Other clinically significant heart disease (e.g., New York Heart Association (NYHA) class III or IV , uncontrolled hypertension) as per discretion of principal investigator and/or treating physician; Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug with the exception of drugs listed on Appendix B of study documents that are required for hematopoietic cell transplantation (HCT) patients.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Chidamide	Chidamide	Chidamide, tablets, 5 mg/tablet, 20 mg orally twice weekly from D-7\~+14 Cyclophosphamide: 50 mg/Kg intravenously D+3, +4 Cyclosporine A: intravenously then orally 3 mg/Kg D+5\~D+100
Chidamide	Cyclophosphamide	Chidamide, tablets, 5 mg/tablet, 20 mg orally twice weekly from D-7\~+14 Cyclophosphamide: 50 mg/Kg intravenously D+3, +4 Cyclosporine A: intravenously then orally 3 mg/Kg D+5\~D+100
Chidamide	cyclosporine A	Chidamide, tablets, 5 mg/tablet, 20 mg orally twice weekly from D-7\~+14 Cyclophosphamide: 50 mg/Kg intravenously D+3, +4 Cyclosporine A: intravenously then orally 3 mg/Kg D+5\~D+100

Primary Outcome Measures

Name	Time	Method
aGVHD	100 day after infusion of PBSCs	accumulated incidence of aGVHD

Secondary Outcome Measures

Name	Time	Method
GRFS	3 years after recruitment	GVHD free, relapse free survival
DFS	3 years after recruitment	Disease free survival
OS	3 years after recruitment	Overall survival
cGVHD	2 yeas after infusion of PBSCs	accumulated incidence of cGVHD

Trial Locations

Locations (1)

West China Hospital of Sichuan University; 🇨🇳 Chengdu, Sichuan, China