Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission
NCT ID: NCT00382109
Last Updated: 2019-08-07
Study Results
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
COMPLETED
PHASE3
146 participants
INTERVENTIONAL
2007-03-31
2017-06-30
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
Related Clinical Trials
Explore similar clinical trials based on study characteristics and research focus.
Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)
NCT00406393
Sirolimus, Tacrolimus, and Methotrexate in Preventing Acute Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplantation
NCT00089037
Sirolimus With Tacrolimus for Graft-vs-Host Disease Prophylaxis After Un-Related Stem Cell Transplantation
NCT00144677
Tacrolimus/Sirolimus/Methotrexate vs Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma
NCT00928018
Sirolimus With Tacrolimus for Graft-vs-Host Disease Prophylaxis After Related Stem Cell Transplantation
NCT00144703
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
I. Compare the post-transplant 2-year event-free survival of pediatric patients with intermediate-risk or high-risk acute lymphoblastic leukemia (ALL) in second complete remission or high risk ALL in first remission undergoing allogeneic hematopoietic stem cell transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate with or without sirolimus.
SECONDARY OBJECTIVES:
I. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in these patients.
II. Evaluate the relative contribution of resistance by ALL blasts to cytolytic therapy (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation by correlating ALL in vivo blast resistance with in vivo sirolimus, inhibition levels of the mTOR pathway in patients treated with sirolimus, and altered resistance pathways in ALL blasts measured by microarray analysis.
III. Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post-transplantation by correlating the development of donor anti-ALL T-cell response, the development of acute and/or chronic GVHD, and the detection of altered ALL blast immunogenicity after transplant with increased minimal residual disease, persistent recipient chimerism, and relapse.
OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor type (matched sibling vs unrelated or other related), and stem cell source (filgrastim \[G-CSF\]-primed bone marrow vs unprimed bone marrow vs bone marrow vs peripheral blood vs umbilical cord blood).
PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily on days -8 to -6 and receive thiotepa IV on days -5 and -4 and cyclophosphamide IV on days -3 and -2.
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients are randomized to 1 of 2 treatment arms.
ARM I: (experimental) Patients receive tacrolimus IV continuously or orally (when able) daily beginning on day -2 followed by a taper beginning on day 42 and continuing until day 98 (for patients undergoing matched sibling donor transplantation) OR tacrolimus IV continuously or orally daily beginning on day -2 followed by a taper beginning on day 100 and continuing until day 180 (for patients undergoing related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, and 6 (for patients with matched sibling and umbilical cord blood donors) OR days 1, 3, 6, and 11 (for patients with unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus daily beginning on day 0 followed by a taper beginning on day 180 and continuing until day 207.
ARM II: (control) Patients receive tacrolimus and methotrexate as in arm I.
After completion of study treatment, patients are followed periodically for approximately 5 years.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.
thiotepa
Given IV
cyclophosphamide
Given IV
tacrolimus
Given IV or orally
methotrexate
Given IV
sirolimus
Given orally
total body irradiation
Part of the transplant preparatory regimen
Tacro-MTX GVHD Prophylaxis
Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
thiotepa
Given IV
cyclophosphamide
Given IV
tacrolimus
Given IV or orally
methotrexate
Given IV
total body irradiation
Part of the transplant preparatory regimen
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
thiotepa
Given IV
cyclophosphamide
Given IV
tacrolimus
Given IV or orally
methotrexate
Given IV
sirolimus
Given orally
total body irradiation
Part of the transplant preparatory regimen
Other Intervention Names
Discover alternative or legacy names that may be used to describe the listed interventions across different sources.
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* Intermediate risk relapsed ALL in CR2 (may receive matched sibling transplantation only) meeting 1 of the following criteria:
* B-lineage ALL in CR2 after a late first bone marrow (BM) relapse (≥ 36 months after the initiation of primary chemotherapy) with or without associated extramedullary disease
* B-lineage ALL in CR2 after a very early isolated extramedullary relapse (\<18 months from the initiation of primary chemotherapy)
* High risk relapsed ALL in CR2 (may receive other related donor, unrelated donor, or matched sibling transplantation) meeting 1 of the following criteria:
* In CR2 after an early first BM relapse (\< 36 months from initiation of primary chemotherapy)
* T-lineage ALL in CR2 after a first BM relapse occurring at any time after initiation of primary chemotherapy
* Philadelphia chromosome-positive ALL in CR2 after a first BM relapse occurring at any time after the initiation of primary chemotherapy
* T-lineage ALL in CR2 after a very early isolated extramedullary relapse (\<18 months from the initiation of primary chemotherapy)
* High risk de novo ALL in CR1 (may receive matched sibling, other related/unrelated BM/PBSC or unrelated CB transplantation) meeting 1 of the following criteria:
* Patients with the presence of t(9;22) translocation (Ph+) detected by cytogenetic or PCR analysis at initial diagnosis. For patients on AALL0622, the criteria for transplant are 1) any patient with Ph+ ALL with an available matched sibling donor or 2) any patient with Ph+ ALL that is defined as high risk (MRD \> 1% Day 29 or MRD \> 0.01% end-Consolidation Block 2) with any available donor, related or unrelated. Patients enrolled on AALL0622 are only eligible if they follow this algorithm.
* Patients with the presence of extreme hypodiploidy (\< 44 chromosomes or DNA index of \< 0.81) detected by cytogenetic/ploidy analysis at initial diagnosis.
* Patients with the presence of 11q23 (MLL) rearrangements detected by cytogenetic or PCR analysis at initial diagnosis who are slow early responders (M2/M3 at Day 14 or MRD \> 0.1% at Day 29).
* Enrolled on an appropriate COG relapsed ALL clinical trial after completing the required study therapy (i.e., minimum 1 re-induction course (4-6 weeks) and 1 round of intensive consolidation chemotherapy (3-6 weeks). Patients with high risk ALL in CR1 are eligible as soon as they have achieved a CR.
* Patients not on a COG relapsed ALL clinical trial are eligible provided they have received ≥ 1 round of re-induction lasting 4-6 weeks and 1 round of intensive consolidation chemotherapy lasting 3-6 weeks
* No B-cell ALL L3 morphology with evidence of myc translocation by molecular or cytogenetic technique
* No Down syndrome
* No evidence of active CNS or other extramedullary disease (i.e., no CNS2)
* Karnofsky performance status (PS) 60-100% (for patients \> 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)
* Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
* ALT or AST \< 5 times upper limit of normal
* Bilirubin \< 2.5 mg/dL (unless an increase is attributable to Gilbert's syndrome)
* Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min
* FEV\_1 ≥ 60% by pulmonary function tests (PFTs)
* FVC ≥ 60% by PFTs
* DLCO ≥ 60% by PFTs
* For children who are unable to cooperate for PFTs all of the following criteria must be met:
* No evidence of dyspnea at rest
* No exercise intolerance
* No requirement for supplemental oxygen therapy
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No HIV or uncontrolled fungal, bacterial, or viral infection
* Fungal infection acquired during induction therapy allowed provided there is a significant response to antifungal therapy with minimal or no evidence of disease by CT scan
* Other concurrent immunosuppressants allowed
* No prior allogeneic or autologous stem cell transplantation
* No prior or concurrent voriconazole unless prior voriconazole therapy is completed or a different agent is substituted for voriconazole prior to study entry
* No concurrent grapefruit juice during sirolimus administration
1 Year
21 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
National Cancer Institute (NCI)
NIH
Children's Oncology Group
NETWORK
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Michael Pulsipher, MD
Role: PRINCIPAL_INVESTIGATOR
Children's Oncology Group
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Phoenix Childrens Hospital
Phoenix, Arizona, United States
City of Hope Medical Center
Duarte, California, United States
Children's Hospital and Research Center at Oakland
Oakland, California, United States
Childrens Hospital of Orange County
Orange, California, United States
Rady Children's Hospital - San Diego
San Diego, California, United States
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
All Children's Hospital
St. Petersburg, Florida, United States
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States
Childrens Memorial Hospital
Chicago, Illinois, United States
Indiana University Medical Center
Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
Kosair Children's Hospital
Louisville, Kentucky, United States
Children's Hospital-Main Campus
New Orleans, Louisiana, United States
Johns Hopkins University
Baltimore, Maryland, United States
C S Mott Children's Hospital
Ann Arbor, Michigan, United States
Wayne State University
Detroit, Michigan, United States
The Childrens Mercy Hospital
Kansas City, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Columbia University Medical Center
New York, New York, United States
University of Rochester
Rochester, New York, United States
New York Medical College
Valhalla, New York, United States
University of North Carolina
Chapel Hill, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Oregon Health and Science University
Portland, Oregon, United States
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Cook Children's Medical Center
Fort Worth, Texas, United States
Methodist Children's Hospital of South Texas
San Antonio, Texas, United States
Primary Children's Medical Center
Salt Lake City, Utah, United States
Virginia Commonwealth University
Richmond, Virginia, United States
Seattle Children's Hospital
Seattle, Washington, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
Midwest Children's Cancer Center
Milwaukee, Wisconsin, United States
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia
Princess Margaret Hospital for Children
Perth, Western Australia, Australia
British Columbia Children's Hospital
Vancouver, British Columbia, Canada
CancerCare Manitoba
Winnipeg, Manitoba, Canada
Hospital for Sick Children
Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
Montreal, Quebec, Canada
Countries
Review the countries where the study has at least one active or historical site.
References
Explore related publications, articles, or registry entries linked to this study.
Pulsipher MA, Carlson C, Langholz B, Wall DA, Schultz KR, Bunin N, Kirsch I, Gastier-Foster JM, Borowitz M, Desmarais C, Williamson D, Kalos M, Grupp SA. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015 May 28;125(22):3501-8. doi: 10.1182/blood-2014-12-615757. Epub 2015 Apr 10.
Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. doi: 10.1182/blood-2013-10-534297. Epub 2014 Feb 4.
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
NCI-2009-01068
Identifier Type: REGISTRY
Identifier Source: secondary_id
CDR0000500131
Identifier Type: OTHER
Identifier Source: secondary_id
COG-PBMTC-ONCO51
Identifier Type: OTHER
Identifier Source: secondary_id
COG-ASCT0431
Identifier Type: OTHER
Identifier Source: secondary_id
ASCT0431
Identifier Type: -
Identifier Source: org_study_id
More Related Trials
Additional clinical trials that may be relevant based on similarity analysis.