Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)
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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/methotrexate Drug: Tacrolimus/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) |
- Rate of Grades II-IV acute GVHD-free survival [ Time Frame: Day 114 ] [ Designated as safety issue: No ]
- Time to neutrophil engraftment [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
- Incidence of acute GVHD [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
- Mucositis severity [ 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 ]
- Infections [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
- Cytomegalovirus (CMV) reactivation and thrombotic microangiopathy [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
- Malignant disease relapse [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 312 |
| Study Start Date: | November 2006 |
| Estimated Study Completion Date: | October 2014 |
| Estimated Primary Completion Date: | October 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: 1
Tacrolimus/methotrexate
|
Drug: Tacrolimus/methotrexate
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. 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 Names:
|
|
Experimental: 2
Tacrolimus/sirolimus
|
Drug: Tacrolimus/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. 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 sirolimus is 3-12 ng/mL. The target serum level for tacrolimus is 5-10 ng/mL. Other Names:
|
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 |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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, ALT, or AST greater than two times the upper limit of normal within 4 weeks of study entry
- Lung disease: in adults, FVC or 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
Show 24 Study Locations| Principal Investigator: | Ryotaro Nakamura, MD | City of Hope National Medical Center |
| Principal Investigator: | Edward Ball, MD | UCSD Medical Center |
| Principal Investigator: | Laura Johnston, MD | Stanford Hospital and Clinics |
| Principal Investigator: | John Wingard, MD | University of Florida College of Medicine (Shands) |
| Principal Investigator: | Edmund Waller, MD, PhD | Emory University |
| Principal Investigator: | Jennifer E. Schwartz, MD | Indiana University School of Medicine |
| Study Chair: | Cory Cutler, MD | DFCI/Brigham & Women's Hospital |
| Principal Investigator: | Sung Choi, MD | University of Michigan |
| Principal Investigator: | William Hogan, MD | Mayo Clinic |
| Principal Investigator: | John DiPersio, MD | Washington University/Barnes Jewish Hospital |
| Principal Investigator: | Philip McCarthy, MD | Roswell Park Cancer Institute |
| Principal Investigator: | Hillard Lazarus, MD | University Hospitals of Cleveland/Case Western |
| Principal Investigator: | George Selby, MD | University of Oklahoma Medical Center |
| Principal Investigator: | David Porter, MD | University of Pennsylvania |
| Principal Investigator: | Paul Shaughnessy, MD | Texas Transplant Institute |
| Principal Investigator: | John McCarty, MD | Virginia Commonwealth University/MCV Hospital |
| Principal Investigator: | Walter Longo, MD | University of Wisconsin Hospital and Clinics |
| Principal Investigator: | Gwynn Long, MD | Duke University |
| Principal Investigator: | Nalini Janakiraman, MD | Henry Ford Health System |
| Principal Investigator: | Gerald Socie, MD | Hopital Saint-Louis |
| Principal Investigator: | Margarida Silverman, MD | University of Iowa |
| Principal Investigator: | Margaret MacMillan, MD | University of Minnesota - Clinical and Translational Science Institute |
| Principal Investigator: | Markus Mapara, MD, PHD | University of Pittsburgh |
More Information
Additional Information:
No publications provided
| Responsible Party: | Medical College of Wisconsin |
| ClinicalTrials.gov Identifier: | NCT00406393 History of Changes |
| Other Study ID Numbers: | 385, U01HL069294, BMT CTN 0402, U01 HL069294-05 |
| Study First Received: | November 30, 2006 |
| Last Updated: | April 2, 2013 |
| Health Authority: | United States: Federal Government |
Keywords provided by Medical College of Wisconsin:
|
Acute Myelogenous Leukemia Acute Lymphoblastic Leukemia Chronic Myelogenous Leukemia |
Additional relevant MeSH terms:
|
Graft vs Host Disease Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myeloid, Acute Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Myelodysplastic Syndromes Preleukemia Immune System Diseases Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders |
Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Methotrexate Sirolimus Everolimus Tacrolimus Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Physiological Effects of Drugs Pharmacologic Actions Therapeutic Uses Antimetabolites, Antineoplastic |
ClinicalTrials.gov processed this record on May 22, 2013