Benadamustine, Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation (FluBuBe)

Sponsor

St. Petersburg State Pavlov Medical University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04942730

Collaborator

(none)

Enrollment

Location

Arm

47.3

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Haploidentical hematopoietic stem cell transplantation irrespective of the conditioning 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 10-20% of graft failures. Fludarabine and busulfan conditioning is the most commonly used approach for a variety of disease. Furthermore combination of fludarabine and bendamustine was sufficient to facilitate engraftment in patients with chronic lymphocytic leukemia and lymphomas. The aim of the study is to evaluate whether addition of bendamustine to fladarabine and busulfan conditioning reduces the risk of primary graft failure after haploidentical allograft.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Acute Lymphoblastic Myeloid Leukemia, Acute Biphenotypic Acute Leukemia Lymphoblastic Lymphoma Myelodysplastic Syndromes Myeloproliferative Neoplasm	Drug: Fludarabine Drug: Bendamustine Hydrochloride Drug: Busulfan Drug: Cyclophosphamide Drug: Mycophenolate Mofetil Drug: Tacrolimus 5Mg Cap	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Benadamustine, Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation (FluBuBe)

Actual Study Start Date :

Jan 21, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FluBuBe Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days; Days -7 through -6: Bendamustine 130 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 +35: Mycophenolate mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration	Drug: Fludarabine 30 mg/m2/day iv x 6 days, days -7 through -2 of HSCT Drug: Bendamustine Hydrochloride 130 mg/m2 iv x 2 days, Days -7 through -6 of HSCT Drug: Busulfan 1 mg/kg po qid x 3 days, Days -5 through -3 Drug: Cyclophosphamide 50 mg/kg iv x 2 days, Days +3 through +4 Drug: Mycophenolate Mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days, Days +5 through +35 Drug: Tacrolimus 5Mg Cap 0.03 mg/kg/day iv or po, Days +5 through +100 with with further correction by concentration. Target concentration 5-15 ng/ml.

Arm

Intervention/Treatment

Experimental: FluBuBe

Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days; Days -7 through -6: Bendamustine 130 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 +35: Mycophenolate mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Drug: Fludarabine

30 mg/m2/day iv x 6 days, days -7 through -2 of HSCT

Drug: Bendamustine Hydrochloride

130 mg/m2 iv x 2 days, Days -7 through -6 of HSCT

Drug: Busulfan

1 mg/kg po qid x 3 days, Days -5 through -3

Drug: Cyclophosphamide

50 mg/kg iv x 2 days, Days +3 through +4

Drug: Mycophenolate Mofetil

45 mg/kg/day, maximum 3 g/day, iv or po x 30 days, Days +5 through +35

Drug: Tacrolimus 5Mg Cap

0.03 mg/kg/day iv or po, Days +5 through +100 with with further correction by concentration. Target concentration 5-15 ng/ml.

Outcome Measures

Primary Outcome Measures

- Incidence of primary and secondary graft failure [100 days]
Proportion of patients with primary and secondary graft failure defined by the absence of donor chimerism

Secondary Outcome Measures

- Incidence of HSCT-associated adverse events (safety and toxicity) [125 days]
Toxicity assessment is based on NCI CTC AE 5.0 grades. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2016. Transplant-associated microangiopathy incidence assessment is based on Cho et al. criteria. All toxicity measurements will be aggregated as severity scores.
- Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence [[ Time Frame: 100 days ] [ Designated as safety issue: Yes ]]
Proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease
- Incidence of acute GVHD grade II-IV [125 days]
Cumulative incidence of patients with acute GVHD II-IV grade
- Incidence of moderate and severe chronic GVHD [365 days]
Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria.
- Non-relapse mortality analysis [2 years]
Cumulative incidence of patients with mortality without hematological relapse of malignancy
- Overall survival analysis [2 years]
Kaplan-Meier estimate of death from all causes
- Event-free survival analysis [2 years]
Kaplan-Meier estimate of death or relapse
- Relapse rate analysis [2 years]
Cumulative incidence of patients with relapse

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have an indication for allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for malignant disease
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
No second malignancies requiring treatment
No severe concurrent illness

Exclusion Criteria:

Titer of anti-HLA antibodies ≥ 5000 at the time of inclusion
Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%
Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted
Respiratory distress >grade I
Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits
Creatinine clearance < 60 mL/min
Uncontrolled bacterial or fungal infection at the time of enrollment
Requirement for vasopressor support at the time of enrollment
Karnofsky index <30%
Pregnancy
Somatic or psychiatric disorder making the patient unable to sign informed consent