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
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 128
- Locations
- 2
- Primary Endpoint
- Incidence of acute GVHD grade II-IV
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
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
Intervention: Tacrolimus (Drug)
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
Intervention: Mycophenolate Mofetil (Drug)
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
Intervention: Ruxolitinib (Drug)
Outcomes
Primary Outcomes
Incidence of acute GVHD grade II-IV
Time Frame: 125 days
Proportion of patients with acute GVHD II-IV grade
Secondary Outcomes
- Overall survival(2 years)
- Primary or secondary graft failure(2 years)
- Incidence of moderate and severe chronic GVHD(2 years)
- Event-free survival(2 years)
- Non-relapse mortality(2 years)
- Incidence of HSCT-associated adverse events (safety and toxicity)(125 days)
- Incidence of infections(6 months)
- Relapse incidence(2 years)
Investigators
Ivan S Moiseev
RM Gorbacheva Research institute scientific director
St. Petersburg State Pavlov Medical University