Venetoclax Plus RIC Regimen Allo-HSCT for Elderly Patients With High-risk Myeloid Malignancies

Study of Venetoclax and Reduced-intensity Conditioning Regimen(RIC) for Allogeneic Stem Cell Transplantation(Allo-HSCT) in Elderly Patients With High-risk Myeloid Malignancies

This study is a single center, single arm, prospective, phase II clinical study to evaluate the efficacy and safety of Venatoclax combined with reduced intensity conditioning regimen allo-HSCT in the treatment of high-risk myeloid malignancies in the elderly patients.

Study Overview

• Status: Recruiting
• Conditions: Leukemia, Myeloid, Acute; Myeloid Malignancy; MDS; Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Venetoclax plus RIC

Detailed Description

Eligible patients will receive Venetoclax plus RIC regimen allogeneic transplantation. The treatment regimen is: Venetoclax 100mg/d - 10d, 200mg/d - 9d (first use and NR or untreated MDS), 400mg/d, - 8d~ - 2d (7d); Fludarabine: 30mg/m2/d, - 6d~-2d (5d), Cytarabine: 1g/m2/d, - 6d~-2d (5d) Busulfan: 3.2mg/m2/d, - 6d~-5d (2d), total body irradiation(TBI): 3 Gray, - 1d.

Primary end point: 1 year and 2 year progression free survival (PFS) after transplantation. Secondary end point: incidence of acute GVHD within 180 days after transplantation; cumulative rate of relapse, overall survival(OS), graft-versus-host disease (GVHD)-free relapse-free survival(GRFS), non-relapse mortality(NRM), and incidence of chronic GVHD at 1 and 2 years after transplantation; The reactivation rate of cytomegalovirus(CMV) and Epstein-Barr virus (EBV) within 1 year after transplantation.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jie Gao; Phone Number: +86177882248225; Email: siberia77@qq.com
• Study Contact Backup: Name: Xianmin Song; Phone Number: +862163240090; Email: shongxm@139.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200080
      • Recruiting
      • Shanghai General Hospital
      • Contact: Xianmin Song, M.D.; Phone Number: 3172 86-21-63240090; Email: shongxm@sjtu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 51 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥ 55 years old;
2. High risk myeloid malignancies： 1）No hematological remission(NR) after induction/re-induction treatment for AML; 2）Morphological remission but with persistent positive minimal resident disease(MRD) (Flow cytometry>0.01% and/or fusion gene positive and/or digital polymerase chain reaction(PCR) positive）; 3）High risk acute myeloid leukemia(AML) according to 2022 European Leukemia Net(ELN) risk stratification； 4）High risk myelodysplastic syndrome(MDS): IPSS-R score ≥ middle risk-2; therapy-related MDS; MDS with mutation of ASXL1, EZH2, RUNX1, SRSF2, U2AF1, STAG2, NRAS, ZRSR2, or TP53； 5）High risk chronic myelomonocytic leukemia(CMML), MDS/MPN.
3. Patients must have appropriate donor:

1）Related donor must be HLA-A, - B, - C, - DQB1 and - DRB1 matched at least 5/10; 2）Unrelated donor must be HLA-A, - B, - C, - DQB1 and - DRB1 matched at least 8/10; 4. Hematopoietic cell transplantation-comorbidity Index(HCT-CI) score ≤ 4。 5. Eastern Cooperative Oncology Group(ECOG) score 0-2。 6. Liver, kidney and cardiopulmonary functions meet the following requirements:

1. Creatinine≤1.5×ULN;
2. Left ventricular ejection fraction >50%;
3. Baseline oxygen saturation>92%;
4. Total bilirubin≤1.5×ULN；ALT and AST≤2.0×ULN；
5. DLCO≥ 40% and FEV1 ≥ 50%。 7. Able to understand and sign the Informed Consent Document.

Exclusion Criteria:

1. Patients with Venetoclax ineffectiveness;
2. Malignant tumors other than acute myeloid leukemia within 5 years prior to screening, in addition to adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical resection, and ductal carcinoma in situ after radical resection；
3. ECOG socre>2;
4. HCT-CI score> 4。
5. Any instability of systemic disease, including but not limited to unstable angina, cerebrovascular accident, or transient cerebral ischemic (within 3 months prior to screening), myocardial infarction (within 3 months prior to screening), congestive heart failure (New York heart association (NYHA) classification ≥ III), need drug therapy of severe arrhythmia, liver, kidney, or metabolic disease; patients with pulmonary hypertension
6. Uncontrolled infection during screening period; Hemodynamic instability associated with infection,a new infection or aggravation of the original infection;new lesions on imaging;fever of unknown cause;
7. Patients with symptoms of central nervous system;greater than grade 2 requiring treatment,paralysis,aphasia,acute cerebral infarction,severe traumatic brain injury,schizophrenia;
8. HIV infection;
9. Patients with active hepatitis B virus (HBV) and active hepatitis C virus (HCV) need antiviral treatment; Patients at risk of HBV activation refer to patients with positive HBsAg or HBeAb but not receiving anti-HBV treatment;
10. History of autoimmune disease；
11. Pregnant or lactating women；
12. Fertile men and women who are unwilling to use contraceptive technology during the treatment period and within 12 months after treatment.

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: Venetoclax plus RIC; Administration with oral Venetoclax plus RIC regimen for allo-HSCT in the elderly patients with myeloid malignancies.	Drug: Venetoclax plus RIC; Eligible patients will receive Venetoclax plus RIC regimen allogeneic transplantation. The treatment regimen is: Venetoclax 100mg/d - 10d, 200mg/d - 9d (first use and NR or untreated MDS), 400mg/d, - 8d~ - 2d (7d); Fludarabine: 30mg/m2/d, - 6d~-2d (5d), Cytarabine: 1g/m2/d, - 6d~-2d (5d) Busulfan: 3.2mg/m2/d, - 6d~-5d (2d), TBI: 3 Gray, - 1d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progression free survival for all patients enrolled	1- year PFS
PFS	Progression free survival for all patients enrolled	2- year PFS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Overall survival for all patients enrolled	1- year OS
OS	Overall survival for all patients enrolled	2- year OS
aGVHD rate	The incidence rate of acute GVHD after transplantation	180 days after transplantation
cGVHD rate	The incidence rate of chronic GVHD after transplantation	1 year after transplantation
cGVHD rate	The incidence rate of chronic GVHD after transplantation	2 years after transplantation
Relapse rate	Cumulative relapse rate after transplantation	1 year after transplantation
NRM	Non relapse mortality after transplantation	2 years after transplantation
GVHD-free relapse-free survival(GRFS)	Time from transplantation to the diagnosis of chronic GVHD or relapse	2 years after transplantation
Reactivation rate of EBV and CMV	Reactivation rate of Epstein-Barr virus and cytomegalovirus after transplantation	1 year after transplantation
Reactivation rate of EBV and CMV	Reactivation rate of Epstein-Barr virus and cytomegalovirus after transplantation	2 years after transplantation

Collaborators and Investigators

• Sponsor: Xianmin Song, MD
• Investigators: Principal Investigator: Xianmin Song, Shanghai General HospitalShanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Publications and helpful links

General Publications

• Garcia JS, Kim HT, Murdock HM, Cutler CS, Brock J, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro R, Loschi F, Ryan J, Fell G, Karp HQ, Lucas F, Kim AS, Potter D, Mashaka T, Stone RM, DeAngelo DJ, Letai A, Lindsley RC, Soiffer RJ, Antin JH. Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active. Blood Adv. 2021 Dec 28;5(24):5536-5545. doi: 10.1182/bloodadvances.2021005566.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: October 9, 2022
• First Submitted That Met QC Criteria: October 12, 2022
• First Posted (Actual): October 17, 2022

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 26, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: SHSYXY-202202-VEN-RIC

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