Study of Chidamide for Steroid-resistant/Steroid-dependent Severe cGVHD

Study of Chidamide in the Treatment of Steroid-resistant/Steroid-dependent Severe cGVHD

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is one of the most important and effective methods for the treatment of hematologic malignancies.Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. It is a leading cause of late nonrelapse mortality for transplant patients, also contributing to morbidity and a decrease in quality of life.Corticosteroids, the standard frontline treatment, are typically administered for a median of 2 to 3 years, leading to substantial morbidity. An effort to decrease corticosteroid doses has led to their use in combination with other immunosuppressants, such as cyclosporine, tacrolimus, and sirolimus, in frontlineor second-line settings, despite a lack of clinical evidence supporting additional efficacy after combining these agents with corticosteroids. B and T cells play a rolein the pathophysiology of cGVHD. Previous studies have shown that low-dose histone deacetylase inhibitors (HDACi) have a negative immune regulation in GVHD while maintain the GVL effect. Chidamide is one of new HDACis in China, the previous studies suggested that low dose Chidamide could reduce condition of cGVHD mice by regulating the immune homeostasis of follicular helper T (Tfh) cells. Chidamide also has effects on the regulation of antigen presenting cells, the activation donor T cells, the release of proinflammatory cytokines and the function of Treg cells. Furthermore, low-dose Chidamide has the potential to maintain GVL effects. In preclinical models,Chidamide reduced severity of cGVHD. Based on the biological rationale and preclinical data, a study was designed to evaluate the safety and efficacy of Chidamide in patients with cGVHD who was steroid-resistant/steroid-dependent .

Study Overview

• Status: Recruiting
• Conditions: Safety and Efficacy
• Intervention / Treatment: Drug: Chidamide

Detailed Description

Promoting graft-versus-leukemia (GVL) effect and inhibiting chronic graft-versus-host disease (cGVHD), is the key to improve the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have shown that low-dose histone deacetylase inhibitors (HDACi) have a negative immune regulation in aGVHD while maintain the GVL effect. Chidamide is one of new HDACis in China, its immune regulatory role in cGVHD is unclear. The results suggested that low dose Chidamide could reduce condition of cGVHD mice by regulating the immune homeostasis of follicular helper T (Tfh) cells. Chidamide also has effects on the regulation of antigen presenting cells, the activation donor T cells, the release of proinflammatory cytokines and the function of Treg cells. Furthermore, low-dose Chidamide has the potential to maintain GVL effects.

On this basis,a study was designed to evaluate the safety and efficacy of Chidamide in patients with cGVHD who was steroid-resistant/steroid-dependent.To Evaluate the Safety and Tolerability of Chidamide in Steroid Dependent/Refractory cGVHD.Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of Chidamide.

Inclusion Criteria:

1. The disease progressed after at least 1 week of treatment with ≥ 1 mg/kg/d prednisone based immunosuppressive therapy;
2. The disease did not improve after at least 1 month of immunosuppressive therapy with ≥ 1 mg·kg once every 2 days or ≥ 0.5 mg/kg/d prednisone;
3. Gocorticoid dependence: Prednisone with > 0.25 mg/kg/d or > 0.5 mg·kg every 2 days after at least 8 weeks of glucocorticoid-based immunosuppressant therapy is required to prevent recurrence or progression.
4. Patients with severe glucocorticoid-resistant/dependent cGVHD who have poor response to second-line treatment drugs (mycophoranate, high-dose glucocorticoid, extracorporeal light therapy, sirolimus, imatinib, azathiopurine, thalidomide, rituximab, anti-CD25, etc.).
5. Ages 18-59
6. ECOG score 0-3
7. Expected survival longer than 6 months
8. The patient who signed the informed consent must be able to understand and willing to participate in the study, and must sign the informed consent.

Exclusion Criteria:

1. Basic diseases of important organs: such as myocardial infarction, chronic cardiac insufficiency, decompensated liver insufficiency, renal insufficiency, etc.;Clinically uncontrolled active infections (including bacterial, fungal or viral infections), but not those under effective medication;
2. Malignant tumors with other progression;
3. Cardiac dysfunction patients: ejection fraction (EF) < 30%, NYHA standard, cardiac dysfunction grade Ⅲ or above;
4. Pregnant or lactating women;
5. People undergoing clinical trials of other drugs; After screening according to inclusion and exclusion criteria, patients meeting the criteria were enrolled. Treatment regimen: Chidamide 15mg biw po, lasted for 8 weeks. Pretransplant use of Chidamide for reasons other than cGVHD, such as for the treatment of leukemia or lymphoma, was permitted.All patients received systemic corticosteroid therapy for cGVHD prior to and during the study; concomitant use of other immunosuppressive therapies was also permitted, however, pre-existing corticosteroid and immunosuppressant doses must have been stable for 14 days before initiating Chidamide. Doses of concomitant corticosteroids and immunosuppressants could be tapered during the study as clinically indicated.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: yuejun Liu; Phone Number: 0086-0512-67781856; Email: liuyuejun@suda.edu.cn

Study Locations

• China
  • Jiangsu
    • Suzhou, Jiangsu, China, 215000
      • Recruiting
      • First Affiliated Hospital,Soochow University
      • Contact: Liu yuejun, Phd; Phone Number: 13915535177; Email: liuyuejun@suda.edu.cn
      • Contact: Xu mingzhu; Email: xumingzhu1983213@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 57 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The disease progressed after at least 1 week of treatment with ≥ 1 mg/kg/d prednisone based immunosuppressive therapy;
2. The disease did not improve after at least 1 month of immunosuppressive therapy with ≥ 1 mg·kg once every 2 days or ≥ 0.5 mg/kg/d prednisone;
3. Gocorticoid dependence: Prednisone with > 0.25 mg/kg/d or > 0.5 mg·kg every 2 days after at least 8 weeks of glucocorticoid-based immunosuppressant therapy is required to prevent recurrence or progression.
4. Patients with severe glucocorticoid-resistant/dependent cGVHD who have poor response to second-line treatment drugs (mycophoranate, high-dose glucocorticoid, extracorporeal light therapy, sirolimus, imatinib, azathiopurine, thalidomide, rituximab, anti-CD25, etc.).
5. Ages 18-59
6. ECOG score 0-3
7. Expected survival longer than 6 months
8. The patient who signed the informed consent must be able to understand and willing to participate in the study, and must sign the informed consent.

Exclusion Criteria:

1. Basic diseases of important organs: such as myocardial infarction, chronic cardiac insufficiency, decompensated liver insufficiency, renal insufficiency, etc.;Clinically uncontrolled active infections (including bacterial, fungal or viral infections), but not those under effective medication;
2. Malignant tumors with other progression;
3. Cardiac dysfunction patients: ejection fraction (EF) < 30%, NYHA standard, cardiac dysfunction grade Ⅲ or above;
4. Pregnant or lactating women;
5. People undergoing clinical trials of other drugs;

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: Study of Chidamide in the Treatment of Steroid-resistant/Steroid-dependent Severe cGVHD; Subjects receive twice a week dose of 15mg of Chidamide tablets

Drug: Chidamide; After screening according to inclusion and exclusion criteria, patients meeting the criteria were enrolled. Treatment regimen: Chidamide 15mg biw po, lasted for 8 weeks. Pretransplant use of Chidamide for reasons other than cGVHD, such as for the treatment of leukemia or lymphoma, was permitted.All patients received systemic corticosteroid therapy for cGVHD prior to and during the study; concomitant use of other immunosuppressive therapies was also permitted, however, pre-existing corticosteroid and immunosuppressant doses must have been stable for 14 days before initiating Chidamide. Doses of concomitant corticosteroids and immunosuppressants could be tapered during the study as clinically indicated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate the Safety and Tolerability of Chidamide in Steroid Dependent/Refractory cGVHD.Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of Chidamide.	The primary end point was safety, tolerability and efficacy,which included the number of dose limiting toxicities occurring on Chidamide. The primary efficacy endpoint was the best overall cGVHD response rate on 3 montns and 6 months, which was defined as the proportion of all patients who achieved a complete response (CR) or partial response (PR). It will begin with the evaluation of the safety of the dose (Chidamide 15mg biw po, lasted for 8 weeks) with the potential for subsequent dose reductions if dose limiting toxicities (DLTs) are detected. A dose limiting toxicity (DLT) is defined as any drug-related hematologic or non-hematologic toxicity Grade 3 or higher. Best overall cGVHD response rate is defined as the proportion of subjects who achieve a NIH-defined complete response (CR) or partial response (PR) during the study.	up to 12 months

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Soochow University
• Investigators: Study Chair: depei Wu, the first affiliated hospital of Soochow Uninersity

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2021
• Primary Completion (Anticipated): May 31, 2024
• Study Completion (Anticipated): May 31, 2024

Study Registration Dates

• First Submitted: July 6, 2021
• First Submitted That Met QC Criteria: November 30, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): December 1, 2021
• Last Update Submitted That Met QC Criteria: November 30, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Other Study ID Numbers: cGVHD-01

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