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

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

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 Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Acute Lymphoid Leukemia; Stem Cell Transplant Complications; Graft-versus-host-disease
• Intervention / Treatment: Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 125167
    • National Hematology Research Center
  • Saint Petersburg, Russian Federation, 197022
    • RM Gorbacheva Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed consent to participate in the study, signed by the patient;
2. Diagnosis: acute lymphoblastic or acute myeloblastic leukemia;
3. 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;
4. Indications for performing allogeneic hematopoietic stem cell transplantation, determined by the participating center in accordance with local medical practice;
5. Unrelated or haploidentical donor;
6. Age 18-70 years;
7. Functional status according to ECOG scale 0-2 score.

Exclusion Criteria:

1. Repeated allogeneic transplantation, regardless of the indications for its implementation;
2. Source of graft - umbilical cord stem cells;
3. Any ex vivo modification of the graft with the exception of separation or washing of red blood cells;
4. The presence of more than 5% of clonal tumor cells according to flow cytometry in the presence of morphological remission;
5. Diagnosis: acute promyelocytic leukemia;
6. 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;
7. Unstable hemodynamics, requiring the introduction of vasopressors;
8. 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;
9. 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;
10. Decrease in ejection fraction according to echocardiography less than 40%;
11. Angina of more than II functional class or unstable angina;
12. Another severe concomitant pathology, which according to the attending physician does not allow the patient to be included in the study;
13. Pulmonary pathology with a decrease in FEV1 of less than 60% or pulmonary diffusion capacity of less than 60%;
14. Inability to quit smoking for up to 6 months after transplantation;

15. 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.
16. Somatic or mental pathology not allowing to sign informed consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2020
• Primary Completion (Actual): February 27, 2023
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: November 26, 2020
• First Submitted That Met QC Criteria: December 12, 2020
• First Posted (Actual): December 16, 2020

Study Record Updates

• Last Update Posted (Actual): April 10, 2023
• Last Update Submitted That Met QC Criteria: April 7, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: randomized trial; cyclophosphamide; haploidentical donor; MMF; Prophylaxis; tacrolimus; ruxolitinib; Graft-versus-host-disease; unrelated donor; PTCY
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: CINC424ARU01T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Access Criteria: Per request to the Ethical Committee of Pavlov University with the study plan and rationale for the use of the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

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