Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT00406393
First received: November 30, 2006
Last updated: February 8, 2016
Last verified: February 2016
  Purpose
The study is designed as a phase III, randomized, open label, multicenter, prospective, comparative trial of sirolimus and tacrolimus versus tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis after human leukocyte antigen (HLA)-matched, related, peripheral blood stem cell transplantation in individuals with hematologic cancer. Participants will be stratified by transplant center and will be randomly assigned to the sirolimus/tacrolimus or tacrolimus/methotrexate arms at a 1:1 ratio.

Condition Intervention Phase
Leukemia, Myelocytic, Acute
Leukemia, Lymphocytic, Acute
Leukemia, Myeloid, Chronic
Myelodysplastic Syndromes
Drug: Tacrolimus
Drug: Methotrexate
Drug: Sirolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease (GVHD) Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (BMT CTN #0402)

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Rate of Grades II-IV Acute GVHD-free Survival [ Time Frame: Day 114 ] [ Designated as safety issue: No ]
    The primary objective is to compare rates of 114-day Grades II-IV acute GVHD-free survival post randomization for HLA-matched, related donor allogeneic peripheral blood stem cell transplantation using two different GVHD prophylaxis regimens. Participants are graded on a scale of 1 to 4 according to their symptoms and organs involved, where 4 represents a worse grade.


Secondary Outcome Measures:
  • Incidence of Acute GVHD [ Time Frame: Measured at Day 100 ] [ Designated as safety issue: No ]
    Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation.

  • Time to Neutrophil and Platelet Engraftment [ Time Frame: Measured through Day 100 ] [ Designated as safety issue: No ]
    Neutrophil engraftment is defined as achieving an Absolute Neutrophil Count (ANC) > 500/mcL for three consecutive measurements on different days. Platelet engraftment is defined as a platelet count > 20,000/mcL for three consecutive measurements over three or more days.

  • Mucositis Severity [ Time Frame: Measured at Day 21 ] [ Designated as safety issue: No ]
    Mucositis severity will be scored per the modified Oral Mucositis Assessment Scale (OMAS) scoring system on a scale of 0 - 4, where 0 equals normal mucosa and 4 represents severe mucosa.

  • Rate of Veno-occlusive Disease (VOD) [ Time Frame: Measured through Day 100 ] [ Designated as safety issue: Yes ]
    VOD will be defined as the occurrence of VOD (based on the Baltimore Criteria for the diagnosis of VOD) in conjunction with other end-organ dysfunction.

  • Thrombotic Microangiopathy (TMA) Infection [ Time Frame: Measured through Day 100 ] [ Designated as safety issue: Yes ]
    The occurrence of TMA within the first 100 days after stem cell transplantation will be recorded. The first day of onset will be used for reporting purposes.

  • Reactivation of Cytomegalovirus (CMV) Infection [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
  • Treatment-related Mortality [ Time Frame: Measured at Day 100 and Year 2 ] [ Designated as safety issue: Yes ]
  • Malignant Disease Relapse [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: Yes ]
    Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, MDS or CMML consistent with pre-transplant features.

  • Overall Survival [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: Yes ]
  • Infections [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
  • Time to Discharge After Transplant [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]

Enrollment: 304
Study Start Date: November 2006
Study Completion Date: October 2015
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tacrolimus/Methotrexate
Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Drug: Tacrolimus

Adults and Children: Tacrolimus will be given at a dose of 0.02 mg/kg every 24 hours as a continuous intravenous infusion beginning on Day -3. An effort will be made to convert the tacrolimus to oral dosing at 2-3 times the total 24-hour intravenous dose, split into 2 doses given every 12 hours as soon as clinically feasible.

The target serum level for tacrolimus is 5-10 ng/mL.

Other Names:
  • Prograf®
  • FK506
Drug: Methotrexate
Methotrexate will be given at a dose of 15 mg/m2 on Day 1 after transplantation, and at a dose of 10 mg/m2 on Days 3, 6 and 11 after transplantation.
Other Name: MTX
Experimental: Tacrolimus/Sirolimus
Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.
Drug: Tacrolimus

Adults and Children: Tacrolimus will be given at a dose of 0.02 mg/kg every 24 hours as a continuous intravenous infusion beginning on Day -3. An effort will be made to convert the tacrolimus to oral dosing at 2-3 times the total 24-hour intravenous dose, split into 2 doses given every 12 hours as soon as clinically feasible.

The target serum level for tacrolimus is 5-10 ng/mL.

Other Names:
  • Prograf®
  • FK506
Drug: Sirolimus

Adults: Sirolimus will be given in a loading dose of 12 mg on Day -3 followed by a daily oral dose of 4 mg per day. Doses may be repeated if the subject vomits within 15 minutes of an oral dose.

Children: Children aged < 12.0 years OR weighing < 40.0 kg will be given an oral loading dose of sirolimus of 3 mg/m2 followed by a daily oral dose of 1 mg/m2, rounded to the nearest full milligram.

The target serum level for sirolimus is 3-12 ng/mL.

Other Names:
  • Rapamycin
  • Rapamune

Detailed Description:

BACKGROUND:

Stem cell transplantation is a standard therapy for acute and chronic leukemias and myelodysplastic disorders. A common problem that may occur after a stem cell transplant is a condition known as GVHD. The purpose of this study is to compare two combinations of medications to see which is better at preventing GVHD. The combinations of medications in this study are:

  • Sirolimus and tacrolimus
  • Methotrexate and tacrolimus

Doctors want to know if one combination is better than the other or if they both have the same result.

DESIGN NARRATIVE:

Participants will receive one of the two conditioning regimens described in the protocol, at the discretion of the transplant physician. The transplant physician must choose among these regimens prior to the participant's assignment to the GVHD prophylaxis treatment. Conditioning regimens will vary by center, but will be the same for all participants at each center. Stem cell donors will donate peripheral blood stem cells according to local institutional practices. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration. Standard post-transplant care will be administered. Participants will be randomly assigned to one of two GVHD prophylaxis regimens and will be followed for the endpoints of interest.

Participants will be followed for 114 days post-randomization for evaluation of the primary endpoint, with additional follow-up for 2 years after transplantation for evaluation of secondary endpoints.

  Eligibility

Ages Eligible for Study:   2 Years to 60 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 6/6 HLA-matched sibling, defined by Class I (HLA-A and B) serologic typing (or higher resolution) and Class II (HLA-DRBI) molecular typing, who is willing to donate peripheral blood stem cells, and meets institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells, according to individual transplant center criteria. Pediatric patients for whom a pediatric sibling donor is not anticipated to be a suitable leukapheresis candidate are not eligible.
  • Karnofsky performance status of at least 70% or Lansky performance status of at least 70% for participants less than 16 years old
  • For participants less than 18 years old, willing and able to take oral medications, per the treating physician's recommendations

Exclusion Criteria:

  • Prior allogeneic or autologous transplant using any hematopoietic stem cell source
  • Seropositive for the human immunodeficiency virus (HIV)
  • Uncontrolled bacterial, viral, or fungal infection (currently taking medication and progression of clinical symptoms)
  • Pregnant (positive serum human chorionic gonadotropin [β-HCG] test) or breastfeeding within 4 weeks of study entry
  • Kidney function: serum creatinine outside the normal range for age, or measured creatinine clearance less than 50 mL/min/1.72m^2 within 4 weeks of study entry
  • Liver function: most recent direct bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) greater than two times the upper limit of normal within 4 weeks of study entry
  • Lung disease: in adults, forced vital capacity (FVC) or forced expiratory volume in one second (FEV1) less than 60% of predicted value (corrected for hemoglobin); in children, overt hypoxemia, as measured by an oxygen saturation of less than 92% within 4 weeks of study entry
  • Cardiac ejection fraction of less than 45% in adults and children, or less than 26% shortening fraction in children within 4 weeks of study entry
  • Cholesterol level greater than 500 mg/dL or triglyceride level greater than 500 mg/dL while being treated, or not on appropriate lipid-lowering therapy within 4 weeks of study entry
  • Prior history of allergy to sirolimus
  • Requires voriconazole at time of study entry
  • Currently receiving another investigational drug unless cleared by the protocol officer or protocol chair
  • Participants with a history of cancer, other than resected basal cell carcinoma or treated carcinoma in-situ. Cancer treated with curative intent for more than 5 years previously will be allowed. Cancer treated with curative intent for less than 5 years previously will not be allowed unless approved by the protocol officer or protocol chair.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00406393

  Show 24 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Investigators
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
  More Information

Additional Information:
Publications:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT00406393     History of Changes
Other Study ID Numbers: BMTCTN0402  U01HL069294  BMT CTN 0402  U01HL069294-05 
Study First Received: November 30, 2006
Results First Received: January 6, 2016
Last Updated: February 8, 2016
Health Authority: United States: Federal Government
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript.

Keywords provided by Medical College of Wisconsin:
Acute Myelogenous Leukemia
Acute Lymphoblastic Leukemia
Chronic Myelogenous Leukemia

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Preleukemia
Graft vs Host Disease
Leukemia, Myeloid
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Immune System Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Myeloproliferative Disorders
Methotrexate
Tacrolimus
Sirolimus
Everolimus
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 28, 2016