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

Sponsor

St. Petersburg State Pavlov Medical University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04669210

Collaborator

(none)

128

Enrollment

Locations

Arms

48.9

Anticipated Duration (Months)

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Graft-versus-host-disease Stem Cell Transplant Complications Acute Myeloid Leukemia Acute Lymphoid Leukemia	Drug: Ruxolitinib Drug: Tacrolimus Drug: Mycophenolate Mofetil	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

128 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Nov 3, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: PTCY tacrolimus MMF 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 Tacrolimus 0.03 mg/kg adjusted to concentrations 5-15 ng/ml from day+5 to +100 Other Names: Prograf Drug: Mycophenolate Mofetil Mycophenolate mofetil 30 mg/kg from day +5 to +35 Other Names: CellCept
Experimental: PTCY ruxolitinib 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 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. Other Names: Jakavi

Arm

Intervention/Treatment

Active Comparator: PTCY tacrolimus MMF

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

Tacrolimus 0.03 mg/kg adjusted to concentrations 5-15 ng/ml from day+5 to +100

Other Names:

Prograf

Drug: Mycophenolate Mofetil

Mycophenolate mofetil 30 mg/kg from day +5 to +35

Other Names:

CellCept

Experimental: PTCY ruxolitinib

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

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.

Other Names:

Jakavi

Outcome Measures

Primary Outcome Measures

Incidence of acute GVHD grade II-IV [125 days]
Proportion of patients with acute GVHD II-IV grade

Secondary Outcome Measures

Non-relapse mortality [2 years]
Cumulative incidence of patients with mortality without hematological relapse of malignancy
Relapse incidence [2 years]
Cumulative incidence of patients with relapse
Incidence of moderate and severe chronic GVHD [2 years]
Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria
Overall survival [2 years]
Kaplan-Meier estimate of death from all causes
Event-free survival [2 years]
Kaplan-Meier estimate of death or relapse
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.
Primary or secondary graft failure [2 years]
Cumulative incidence of patients with primary or secondary graft failure defined by the absence of donor chimerism.
Incidence of infections [6 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.