Randomized Study: Standard of Care With or Without Atorvastatin for Prevention of GVHD for Matched Unrelated Donor BMT

Randomized Study of Atorvastatin Prophylaxis as a Supplement to Standard of Care Prophylaxis to Prevent Chronic Graft Versus Host Disease Allogeneic Stem Cell Transplantation From Matched Unrelated Donors

Chronic Graft Versus Host Disease (GVHD) is one of the most challenging complications in long term survivors of allogeneic stem cell transplantation. As the number of allogeneic stem cell transplantations rises annually, the incidence of chronic GVHD rates have also increased due to a variety of factors including but not limited to increasing use of peripheral blood stem cell (PBSC) grafts, increasing age of both donors and recipients, and increased use of matched unrelated donors. One study showed much lower than traditional acute GHVD rate and chronic GHVD which is similar with historical rates when atorvastatin was administered prophylactically to both the donors as well as recipients of matched related allogeneic stem cell transplantation, lead to the interest in further examining the role of Atorvastatin in relation to the development of GVHD. The investigator hypothesize that the administration of atorvastatin in recipients of matched unrelated allogeneic stem cell transplantation, a group with known higher incidence of chronic GHVD, would be a safe and effective method to reduce the incidence of chronic GVHD. Matched related allogeneic stem cell transplantation recipients will not be included in this study due to their significantly lower GVHD rates. The definition and monitoring of our primary endpoint of GVHD is well established in clinical trials in allogeneic stem cell transplantations and the investiagor will utilize the National Institutes of Health (NIH) Staging System for the diagnosis and severity assessment of chronic GVHD as well the recommendations from the NIH Consensus Conference for the conduct of clinical trials in chronic GVHD.

Several secondary endpoints will be examined as defined below and include standard complementary data in the examination of clinical trials in chronic GVHD again as laid out by the NIH Consensus Conference for conduct of clinical trials in chronic GHVD.

Study Overview

• Status: Withdrawn
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia
• Intervention / Treatment: Drug: Atorvastatin; Drug: Methotrexate; Drug: Tacrolimus

Detailed Description

This is a randomized, open label phase III trial in patients with Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, and Myelodysplastic Syndrome undergoing matched unrelated donor transplant.

Patients randomized to the treatment arm (atorvastatin):

The prophylaxis atorvastatin treatment (taken by mouth) for GVHD will start at 14 days prior to transplant and continue until 365 days post-transplant or until development of significant adverse events or desire of the primary treating physician to stop the administration.

The patients will also receive our institution's standard graft versus host disease prophylactic regimen which consists of two drugs. It has been shown that immunosuppression with two drugs is better than a single agent thus our institution utilizes a combination of Methotrexate and Tacrolimus. For all matched unrelated donor allogeneic transplantation patients, the following schedule of Methotrexate will be administered intravenously (IV) post-transplant on Days 1, 3 and 6. Tacrolimus will be administered 2 days prior to transplant and continue approximately 180 days post-transplant. Tacrolimus will be administered IV until patient can take it by mouth.

Patients randomized to standard of care:

Patients will receive our institution's standard graft versus host disease prophylactic regimen which consists of two drugs. It has been shown that immunosuppression with two drugs is better than a single agent thus our institution utilizes a combination of Methotrexate and Tacrolimus. For all matched unrelated donor allogeneic transplantation patients, the following schedule of Methotrexate will be administered intravenously (IV) post-transplant on Days 1, 3 and 6. Tacrolimus will be administered 2 days prior to transplant and continue approximately 180 days post-transplant. Tacrolimus will be administered IV until patient can take it by mouth.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Men or women between 18-65 years of age

• Patients designated to undergo allogeneic peripheral blood or bone marrow stem cell transplantation from matched unrelated donor following the diagnosis of one of the following primary diseases in early or intermediate disease status:

  • AML at the following stages at time of screening: 1st remission, 2nd remission, and 3rd or subsequent remission
  • ALL at the following stages at time of screening: 1st remission, 2nd remission, and 3rd or subsequent remission
  • MDS
• Patients must have Performance Score (PS) greater than 70 percent

Exclusion Criteria

• Cardiac: ejection fraction less than 40 percent or other significant cardiac disease
• Pulmonary: FEV1 or DLCO less than 45 percent
• Renal: creatinine greater than the upper limit of normal
• Hepatic: bilirubin greater than 2.0 times the upper limit of normal
• CNS: documented active CNS disease
• Patients who are known to be positive for Hepatitis B surface antigen or Hepatitis C antibody, or who have tested positive for HIV

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm A: Atorvastatin; The preventative atorvastatin treatment 40mg daily by mouth for GVHD will start at 14 days prior to transplant & continue until 365 days post-transplant or if significant adverse events occur. Patients will also receive our standard of care for graft versus host disease prevention which consists of two drugs, Methotrexate and Tacrolimus. For all matched unrelated donor allogeneic transplantation patients, the following schedule of Methotrexate 5mg/metered square will be administered IV post-transplant on Days 1, 3 & 6. Tacrolimus will be administered 2 days prior to transplant & continue approximately 180 days post-transplant. Tacrolimus 0.03 mg/kg daily will be administered IV until patient can take it by mouth.	Drug: Atorvastatin; Oral medication given to prevent graft versus host disease in bone marrow transplant.; Other Names: Lipitor; Drug: Methotrexate; IV medication given to prevent graft versus host disease in bone marrow transplant.; Other Names: Trexall; Drug: Tacrolimus; IV or Oral medication given to prevent graft versus host disease in bone marrow transplant.; Other Names: Prograft
ACTIVE_COMPARATOR: Arm B: Standard of Care; Patients will receive our standard of care for graft versus host disease prevention which consists of two drugs, Methotrexate and Tacrolimus. For all matched unrelated donor allogeneic transplantation patients, the following schedule of Methotrexate 5mg/metered square will be administered IV post-transplant on Days 1, 3 & 6. Tacrolimus will be administered 2 days prior to transplant & continue approximately 180 days post-transplant. Tacrolimus 0.03 mg/kg daily will be administered IV until patient can take it by mouth.	Drug: Methotrexate; IV medication given to prevent graft versus host disease in bone marrow transplant.; Other Names: Trexall; Drug: Tacrolimus; IV or Oral medication given to prevent graft versus host disease in bone marrow transplant.; Other Names: Prograft

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective is to determine the cumulative incidence of chronic GVHD at one year after stem cell transplantation and treatment with atorvastatin	National Institutes of Health Chronic Graft-Versus-Host Disease Grading and Form	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the cumulative incidence of grade 3 to 4 acute GVHD	National Institutes of Health Acute Graft-Versus-Host Disease Grading and Form	100 days
To determine rate of disease relapse	Blood work and/or bone marrow biopsy will be used	2 years
To determine non-relapse mortality (NRM)	Blood work and/or bone marrow biopsy will be used	2 years
To determine progression-free survival (PFS)	Blood work and/or bone marrow biopsy will be used	2 years
To determine overall survival (OS)	Blood work and/or bone marrow biopsy will be used	2 years
Number of participants with Grade 4 through 5 Adverse Events that are related to study treatment, grading according to NCI CTCAE Version 4	Toxicities that are possibly, probably, and definitely related	30 days of the last dose of protocol treatment
Determine the frequency and severity of chronic GVHD	National Institutes of Health Chronic Graft-Versus-Host Disease Grading and Form	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the effect of atorvastatin on immune reconstitution	Blood work will be used to evaluate recovery of white blood cells, red blood cells and platelets plus T and B cell count subset.	2 years

Collaborators and Investigators

• Sponsor: Loyola University
• Investigators: Study Director: Patrick Stiff, MD, Cardinal Bernardin Cancer Center, Loyola University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): December 10, 2019
• Primary Completion (ANTICIPATED): February 28, 2020
• Study Completion (ANTICIPATED): February 28, 2021

Study Registration Dates

• First Submitted: February 23, 2017
• First Submitted That Met QC Criteria: February 23, 2017
• First Posted (ACTUAL): February 28, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 27, 2021
• Last Update Submitted That Met QC Criteria: April 23, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Myelodysplastic Syndrome; BMT; GVHD; Graft versus Host Disease; Matched unrelated donor transplant
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Atorvastatin; Methotrexate; Tacrolimus
• Other Study ID Numbers: 208106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No