Hypomethylating Agent and Venetoclax After Allo-HSCT in Patients With High-risk Myeloid Malignancies.

A Single Arm, Phase 2 Study Evaluating Safety and Efficacy of Maintenance Therapy With Hypomethylating Agent and Venetoclax After Allogeneic Stem Cell Transplantation in Patients With f High-risk Myeloid Malignancies.

The main objective of the study is to evaluate the efficacy and safety of maintenance therapy with hypomethylating agent and Venetoclax to improve leukemia free survival for high-risk myeloid malignancies after allogeneic hematopoietic stem cell transplantation .

Study Overview

• Status: Recruiting
• Conditions: Myeloid Malignancy; Venetoclax; Hypomethylating Agent
• Intervention / Treatment: Drug: Venetoclax; Drug: Azacitidine or decitabine

Detailed Description

This is a prospective single-arm study. Patients with high-risk AML or MDS aged between 18-70 years old will enroll in the study. They will be given hypomethylating agents (azacytidine 32mg/m2 or decitabine 5mg/m2) for 5 days and venetoclax 400mg/d for 7 days after allogeneic hematopoietic stem cell transplantation. The maintenance therapy will start from 60th days posttransplant, repeated every 28 days until up to 1-year posttransplant. The 1-year leukemia-free survival rate，1-year cumulative recurrence rate, and 1-year overall survival will be analyzed.

• Study Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xueying Ding, Ph.D.; Phone Number: 8621-36126060; Email: shiyicss@126.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200080
      • Recruiting
      • Shanghai Jiao Tong University School of Medicine Affilated Shanghai General Hospital
      • Principal Investigator: Liping Wan, M.D., Ph.D.
      • Contact: Xueying Ding, Ph.D; Phone Number: 86-21-36126060; Email: shiyicss@126.com
      • Contact: Yanhong Zhu, M.S; Phone Number: 6213 86-21-63240090; Email: sfph_edu2@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with AML or MDS and have received allogeneic hematopoietic cell transplantation;
• Patients with AML must have one of the following high-risk factors: Cytogenetics and molecular features consistent with adverse risk group by European LeukemiaNet classification for AML； require more than 2 courses of induction chemotherapy to reach complete remission； Extramedullary myeloid malignancy；≥CR2； Presence of measurable residual disease at the time of HSCT. *
• Patients with MDS must have one of the following high-risk factors: IPSS-R scores are high-risk or very high-risk； Presence of TP53 mutation； Presence of measurable residual disease at the time of HSCT. *
• CBC: ANC ≥ 1.0 × 10e9/L, Hb ≥ 80g/L, and PLT ≥ 50 × 10e9/L；

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

  • Presence of measurable residual disease at the time of HSCT is defined as the following: Blast percentage in bone marrow detected by flow cytometry ≥0.01%； Presence of fusion gene or mutated gene by qPCR.

Exclusion Criteria:

• Concurrent use of targeted drugs ;
• Resistant to Venetoclax before transplantation;
• Allergic to decitabine , Azacitidine or venetoclax;
• Active grade II or higher acute GVHD ;
• Active moderate or severe chronic GVHD ;
• Diseases recurrence (abnormal myeloid cells detected by flow cytometry >0.01%, presence of WT1 or other genes, or extramedullary malignancy ), percentage of donor cells in bone marrow <90% or graft rejection:
• CBC: ANC < 1.0 × 10e9/L, or PLT < 50 × 10e9/L；
• Severe organ dysfunction: Elevated Aspartate transaminase (AST) /alanine transaminase (ALT), or direct bilirubin >3 times upper limit of normal; Creatinine clearance (Ccr)<50mL/min or serum creatinine >1.5 times upper limit of normal, whether hemodialysis treatment is performed;
• Active uncontrolled systemic fungal, bacterial, or viral infection
• Pregnant or lactating women;
• Other severe complications and not suitable judged by researchers.

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: AZA-VEN maintenance; hypomethylating agents (azacytidine 32mg/m2 or decitabine 5mg/m2) for 5 days and venetoclax 400mg/d for 7 days, repeated every 28 days until up to 1-year posttransplant.

Drug: Venetoclax; Participants will receive maintenance therapy with venetoclax and azacitidine or decitabine after allogeneic stem cell transplantation. Azacitidine will be administered once daily subcutaneously (32mg/m2/d) on days 1-5, and venetoclax will be administered once daily orally (400mg/day) on days 1-7. If the patient is refractory or allergic to azacitidine, they will receive decitabine. Decitabine will be administered intravenously (5mg/m2/d) on days 1-5. If the patient is treated with CYP450 inhibitors(such as posaconazole or voriconazole), the dose of venetoclax will reduce to 100 mg once daily on days 1-7. Maintenance therapy will start from the 60th to 120th days after allogeneic hematopoietic stem cell transplantation and repeat every 28 days for up to 10 cycles within the first year after transplantation.; Other Names: BCL-2 inhibitor; Drug: Azacitidine or decitabine; azacytidine 32mg/m2 or decitabine 5mg/m2; Other Names: Hypomethylating Agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leukemia-free survival (LFS) time	Summary statistics for LFS time will be computed for all patients.	From the date of transplantation, assessed up to 1 year after transplantation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of relapse	Use the method of Gooley et al to estimate the cumulative incidence of relapse.	From the date of transplantation, assessed up to 1 year after transplantation.
Overall survival	The method of Kaplan and Meier will be used to estimate the distribution of overall survival. Cox proportional hazards regression analysis will be used to model the association between overall survival and covariates of interest.	From the date of transplantation, assessed up to 1 year after transplantation.
Incidence of toxicity of the regimen	Descriptive statistics will be used to summarize adverse events.	From the date of transplantation, assessed up to 1 year after transplantation.

Collaborators and Investigators

• Sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
• Investigators: Principal Investigator: Liping Wan, M.D., Shanghai Jiao Tong University School of Medicine Affiliated Shanghai General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: May 2, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Actual): May 8, 2023
• Last Update Submitted That Met QC Criteria: May 5, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Venetoclax; Azacitidine
• Other Study ID Numbers: SHSYXY-AZA-VEN-202301

Drug and device information, study documents

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