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

Chidamide Plus Post-transplantation Cyclophosphamide and Cyclosporine to Prevent Graft-versus-host Disease After Myeloablative Conditioning, Matched Peripheral-blood Stem-cell Transplantation

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

Study Overview

• Status: Unknown
• Conditions: MDS; Leukemia, Acute
• Intervention / Treatment: Drug: Chidamide; Drug: Cyclophosphamide; Drug: cyclosporine A

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 Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jie Ji, MD; Phone Number: 86-28-85422373; Email: jieji@scu.edu.cn
• Study Contact Backup: Name: Ting Liu, MD PHD; Phone Number: 86-28-85422370; Email: liuting@scu.edu.cn

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610044
      • West China Hospital of Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Chidamide; 20 mg orally, twice weekly from D-7 to D+14; Other Names: HBI-8000; Drug: Cyclophosphamide; 50 mg/Kg intravenously D+3, +4; Drug: cyclosporine A; 3 mg/Kg intravenously then orally from D+5 to D+100 if no acute graft-versus-host disease; Other Names: cyclosporine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
aGVHD	accumulated incidence of aGVHD	100 day after infusion of PBSCs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GRFS	GVHD free, relapse free survival	3 years after recruitment
DFS	Disease free survival	3 years after recruitment
OS	Overall survival	3 years after recruitment
cGVHD	accumulated incidence of cGVHD	2 yeas after infusion of PBSCs

Collaborators and Investigators

• Sponsor: Sichuan University
• Investigators: Study Chair: Ting Liu, MD, West China Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2019
• Primary Completion (Anticipated): December 30, 2020
• Study Completion (Anticipated): March 30, 2021

Study Registration Dates

• First Submitted: November 6, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): July 18, 2018
• Last Update Submitted That Met QC Criteria: July 17, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: chidamide; PBSCT; HDACi; myeloablative conditioning
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclophosphamide; Cyclosporine; Cyclosporins
• Other Study ID Numbers: HX-GVHD-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No