PTCy and Ruxolitinib vs PTCy, Tacrolimus and MMF in MUD and Haploidentical HSCT

Study Overview
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Brief Summary
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This is multicenter investigator-initiated randomized open-label phase II clinical trial to compare prophylaxis of graft versus host disease treated with tacrolimus and mycophenolate mofetil versus ruxolitinib after post-transplant cyclophosphamide. In total 128 patients will be included in the study. After inclusion into the study and performing of transplantation patients will be randomized in 1:1 proportion in two arms (64 patients per arm): arm A will include patients who will be treated with cyclophosphamide and ruxolitinib for GVHD prophylaxis; arm B will include patients who will be treated with cyclophosphamide, tacrolimus and MMF for GVHD prophylaxis. After the end of the treatment patients will be followed-up during two years.

Official Title
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A Randomized, Multicenter, Open-label Phase II Trial to Compare Prophylaxis of Graft Versus Host Disease With Tacrolimus and Mycophenolate Mofetil Versus Ruxolitinib After Post-transplant Cyclophosphamide

Conditions
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Graft-versus-host-disease, Stem Cell Transplant Complications, Acute Myeloid Leukemia, Acute Lymphoid Leukemia

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent to participate in the study, signed by the patient; Diagnosis: acute lymphoblastic or acute myeloblastic leukemia; Morphological remission, defined as less than 5% of blasts by microscopy or flow cytometry with a peripheral leukocyte level of more than 1.500 μL. It is acceptable to include patients without restored platelets or erythrocytes; Indications for performing allogeneic hematopoietic stem cell transplantation, determined by the participating center in accordance with local medical practice; Unrelated or haploidentical donor; Age 18-70 years; Functional status according to ECOG scale 0-2 score. Exclusion Criteria: Repeated allogeneic transplantation, regardless of the indications for its implementation; Source of graft - umbilical cord stem cells; Any ex vivo modification of the graft with the exception of separation or washing of red blood cells; The presence of more than 5% of clonal tumor cells according to flow cytometry in the presence of morphological remission; Diagnosis: acute promyelocytic leukemia; Severe organ failure: creatinine more than 2 ULN; ALT, AST more than 5 ULN; bilirubin more than 1.5 ULN; respiratory failure more than 1 grade; Unstable hemodynamics, requiring the introduction of vasopressors; Uncontrolled bacterial or fungal infection at the time of randomization, determined by the level of CRP> 70 mg/l with adequate antibacterial or antifungal therapy; Rhythm disturbances that persist despite adequate antiarrhythmic therapy: a tachysystolic form of atrial fibrillation, ventricular arrhythmias V gradation according to Laun, AV block of III degree; Decrease in ejection fraction according to echocardiography less than 40%; Angina of more than II functional class or unstable angina; Another severe concomitant pathology, which according to the attending physician does not allow the patient to be included in the study; Pulmonary pathology with a decrease in FEV1 of less than 60% or pulmonary diffusion capacity of less than 60%; Inability to quit smoking for up to 6 months after transplantation; Pregnancy or refusal to perform highly effective contraception for 6 months after transplantation. Highly effective contraceptive methods include: Total abstinence: if it corresponds to the preferred and customary way of life of the patient. Periodic abstinence (for example, calendar, ovulation, symptothermal, postovulation methods) and interrupted sexual intercourse are not considered acceptable methods of contraception; Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before the start of the therapy being studied. In the case of ovariectomy only, the reproductive status of the woman must be confirmed using a subsequent analysis of hormones; Sterilization of the male partner (at least 6 months before screening). For women participating in the study, the sexual partner after a vasectomy should be the only partner; Use of oral, injectable or implanted hormonal contraceptive drugs, intrauterine devices or contraceptive systems, or other forms of hormonal contraception with similar efficacy (failure rate less than 1%), for example, hormonal vaginal rings or transdermal hormonal contraceptives. Somatic or mental pathology not allowing to sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PTCY tacrolimus MMF<br>Conditioning: fludarabine 180 mg/m2 busulfan 8-14 mg/kg per os GVHD prophylaxis: cyclophosphamide 50 mg/kg day+3, +4 tacrolimus 0.03 mg/kg from day+5 to 100 mycophenolate mofetil 30 mg/kg from day+5 to 35 | Drug: Tacrolimus<br>* Tacrolimus 0.03 mg/kg adjusted to concentrations 5-15 ng/ml from day+5 to +100<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil 30 mg/kg from day +5 to +35<br>* Other names: CellCept;|
| Experimental: PTCY ruxolitinib<br>Conditioning: fludarabine 180 mg/m2 busulfan 8-14 mg/kg per os ruxolitinib 5 mg tid days -7 to -2 GVHD prophylaxis: cyclophosphamide 50 mg/kg day+3, +4 ruxolitinib 5 mg tid days +5 to +21 ruxolitinib 5 mg bid days +22 to +150 | Drug: Ruxolitinib<br>* Ruxolitinib administered during conditioning 5 mg tid before allogeneic hematopoietic stem cell transplantation, 5 mg tid days 5-21 and 5 mg bid days 22-150 after transplantation instead of tacrolimus and MMF.<br>* Other names: Jakavi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute GVHD grade II-IV | Proportion of patients with acute GVHD II-IV grade | 125 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-relapse mortality | Cumulative incidence of patients with mortality without hematological relapse of malignancy | 2 years | 
| Relapse incidence | Cumulative incidence of patients with relapse | 2 years | 
| Incidence of moderate and severe chronic GVHD | Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria | 2 years | 
| Overall survival | Kaplan-Meier estimate of death from all causes | 2 years | 
| Event-free survival | Kaplan-Meier estimate of death or relapse | 2 years | 
| Incidence of HSCT-associated adverse events (safety and toxicity) | 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. | 125 days | 
| Primary or secondary graft failure | Cumulative incidence of patients with primary or secondary graft failure defined by the absence of donor chimerism. | 2 years | 
| Incidence of infections | Number of patients with bacteremia before engraftment, bacteremia after engraftment, severe sepsis (presence of multiple organ failure), pneumonia, soft tissue infection, invasive mycosis (probable or proven invasive aspergillosis, candidaemia, zygomycosis), reactivation of cytomegalovirus, other opportunistic viral infections | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft-versus-host-disease, Prophylaxis, ruxolitinib, tacrolimus, MMF, PTCY, cyclophosphamide, unrelated donor, haploidentical donor, randomized trial