BeFluBu vs FluBuRux Conditioning in Haploidentical HCT

Randomized Trial of Benadamustine Versus Ruxolitinib With Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation irrespective of the conditioning intensity and graft-versus-host disease prophylaxis is associated with high frequency of primary and secondary graft failure. Different technologies of with replete or depleted graft are associated with 7-20% of graft failures in different diseases. Fludarabine and busulfan conditioning is the most commonly used approach for a variety of diseases. In two previously completed trials of addition of either bendamustine and ruxolitinib to conditioning we observed low rates of primary graft failure with both approaches. The study is the direct randomized comparisons of these two approaches with the primary aim of reducing composite events of primary graft failure, relapse and non-relapse mortality. The stratas for the study are Disease Risk Index (DRI) and the age of the haploidentical donor (<35 vs ≥35).

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Acute Lymphoblastic Leukemia; Lymphoblastic Lymphoma; Myeloproliferative Neoplasm; Biphenotypic Acute Leukemia
• Intervention / Treatment: Drug: Bendamustine Hydrochloride; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: IVAN SERGEEVICH MOISEEV; Phone Number: 0079217961951; Email: moisiv@mail.ru
• Study Contact Backup: Name: Yulia Vlasova; Email: jj_vlasova@mail.ru

Study Locations

• Russian Federation
  • Saint Petersburg, Russian Federation, 197022
    • Recruiting
    • RM Gorbacheva Research Institute
    • Contact: Alexandr Kulagin; Phone Number: +78123386265; Email: bmt-director@1spbgmu.ru
    • Contact: Ivan Moiseev; Phone Number: +79217961951; Email: moisiv@mail.ru

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients must have an indication for allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for malignant disease
• Diagnosis: acute myeloid leukemia, acute lymphoblastic leukemia, mixed lineage acute leukemia, lymphoblastic lymphoma, chronic myeloid leukemia, myelodysplastic syndromes, myeloprolipherative neoplasm
• Age ≥18
• Malignant disease in hematologic response: <5% of clonal blasts in the bone marrow and no clonal blasts in peripheral blood.
• Patients with 5-9/10 HLA-matched related donor available. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.
• Peripheral blood stem cells or bone marrow as a graft source

Exclusion Criteria:

• Titer of anti-donor anti-HLA antibodies ≥ 5000 at the time of inclusion
• Moderate or severe cardiac disease: ejection fraction <50%, unstable angina, stable angina NYHA class III or IV, chronic heart failure NYHA class III or IV, Lawn grade V arrhythmia, myocardial infarction within 3 months before inclusion
• Stroke within 3 months of inclusion, unless related to the underlying malignancy
• Severe decrease in pulmonary function: FEV1 <50% or DLCO<50% of predicted or respiratory distress or need for oxygen support;
• Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits
• Creatinine clearance < 40 mL/min
• Uncontrolled bacterial or fungal infection at the time of enrollment defined by CRP> 70 mg/L
• Requirement for vasopressor support at the time of enrollment
• Karnofsky index <70%
• Pregnancy
• Somatic or psychiatric disorder making the patient unable to sign informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FluBeBu conditioning; Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days; Days -7 through -6: Bendamustine 90 mg/m2 iv x 2 days; Days -5 through -3: Busulfan 1 mg/kg po qid x 3 days;Days +3 through +4: Cyclophosphamide 50 mg/kg iv x 2 days; Days +5 through +20: ruxolitinib 5 mg tid per os; Days +21 through 150: ruxolitinib 5 mg bid per os.	Drug: Bendamustine Hydrochloride; Days -7 through -6: Bendamustine 90 mg/m2 iv x 2 days
Active Comparator: FluBeRux conditioning; Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days; Days -7 through -2: ruxolitinib 5 mg tid per os; Days -5 through -3: Busulfan 1 mg/kg po qid x 3 days; Days +3 through +4: Cyclophosphamide 50 mg/kg iv x 2 days; Days +5 through +20: ruxolitinib 5 mg tid per os; Days +21 through 150: ruxolitinib 5 mg bid per os.	Drug: Ruxolitinib; Days -7 through -2: ruxolitinib 5 mg tid per os

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Measure: Kaplan-Meier estimate of either relapse, primary or secondary graft failure or death from all causes	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of primary and secondary graft failure	Cumulative primary and secondary graft failure, competing risk is death and relapse	365 days
Incidence of HSCT-associated adverse events (safety and toxicity)	Toxicity assessment is based on presence of NCI CTC AE 5.0 event grades 3-5. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2020. Transplant-associated microangiopathy incidence assessment is based on Harmonization criteria by Schoettler et al. All toxicity measurements will be aggregated as severity scores	125 days
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence	proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease	100 days
Cumulative incidence of acute GVHD grade II-IV	Cumulative incidence of patients with acute GVHD II-IV grade, competing risk is death, relapse and primary graft failure	125 days
Incidence of moderate and severe chronic GVHD	Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria, competing risk is death, relapse and primary graft failure	2 years
Non-relapse mortality analysis	Cumulative incidence of patients with mortality without hematological relapse of malignancy	2 years
Overall survival analysis	Measure: Kaplan-Meier estimate of death from all causes	2 years
GVHD-relapse-free survival analysis	Measure: Kaplan-Meier estimate of death, acute GVHD grade III-IV, severe chronic GVHD or relapse	2 years
Relapse cumulative incidence analysis	Cumulative incidence of patients with relapse, competing risk is non-relapse mortality	2 years

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: June 21, 2024
• First Submitted That Met QC Criteria: June 21, 2024
• First Posted (Actual): June 27, 2024

Study Record Updates

• Last Update Posted (Actual): June 27, 2024
• Last Update Submitted That Met QC Criteria: June 21, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Myelodysplastic Syndromes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myeloproliferative Disorders; Leukemia, Biphenotypic, Acute; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Bendamustine Hydrochloride
• Other Study ID Numbers: 14/24-n

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Written proposal to the department of scientific affairs of Pavlov University with a subsequent signed contract for research
• IPD Sharing Time Frame: After final study analysis availability for 15 years
• IPD Sharing Access Criteria: Written proposal to the department of scientific affairs of Pavlov University with a subsequent signed contract for research
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Study Data/Documents

1. Study Protocol
   Information identifier: Protocol version 1.0
   Information comments: Study protocol signed

Drug and device information, study documents

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