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
A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia
6 other identifiers
interventional
146
3 countries
50
Brief Summary
This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host disease in young patients who are undergoing donor stem cell transplant for intermediate-risk or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It is not yet known whether tacrolimus and methotrexate are more effective with or without sirolimus in preventing graft-versus-host disease.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started Mar 2007
Longer than P75 for phase_3
50 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 26, 2006
CompletedFirst Posted
Study publicly available on registry
September 28, 2006
CompletedStudy Start
First participant enrolled
March 1, 2007
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 1, 2011
CompletedResults Posted
Study results publicly available
February 9, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
June 30, 2017
CompletedAugust 7, 2019
June 1, 2019
4.2 years
September 26, 2006
October 6, 2015
July 24, 2019
Conditions
Outcome Measures
Primary Outcomes (1)
Estimated Percentage of Participants With Event Free Survival
An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.
at 2 years
Secondary Outcomes (8)
Rate of Relapses
At 2 years
Estimated Transplant Related Mortality Percentage
100 days
Estimated Rate of Acute Graft VS Host Disease (GVHD)
At 200 days
Estimated Rate of Overall Chronic Graft VS Host Disease
At 2 years
Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation
Up to 1 year
- +3 more secondary outcomes
Study Arms (2)
Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
EXPERIMENTALPreparative 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.
Tacro-MTX GVHD Prophylaxis
ACTIVE COMPARATORPreparative 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).
Interventions
Given IV
Given IV
Given IV or orally
Given IV
Given orally
Part of the transplant preparatory regimen
Eligibility Criteria
You may qualify if:
- Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL) in second complete remission (CR2) (M1 bone marrow, \< 5% blasts by morphology) meeting the following 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
- +24 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Children's Oncology Grouplead
- National Cancer Institute (NCI)collaborator
Study Sites (50)
Phoenix Childrens Hospital
Phoenix, Arizona, 85016, United States
City of Hope Medical Center
Duarte, California, 91010, United States
Children's Hospital and Research Center at Oakland
Oakland, California, 94609-1809, United States
Childrens Hospital of Orange County
Orange, California, 92868-3874, United States
Rady Children's Hospital - San Diego
San Diego, California, 92123, United States
University of California San Francisco Medical Center-Parnassus
San Francisco, California, 94143, United States
Children's Hospital Colorado
Aurora, Colorado, 80045, United States
Children's National Medical Center
Washington D.C., District of Columbia, 20010, United States
All Children's Hospital
St. Petersburg, Florida, 33701, United States
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, 30322, United States
Childrens Memorial Hospital
Chicago, Illinois, 60614, United States
Indiana University Medical Center
Indianapolis, Indiana, 46202, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242, United States
Kosair Children's Hospital
Louisville, Kentucky, 40202, United States
Children's Hospital-Main Campus
New Orleans, Louisiana, 70118, United States
Johns Hopkins University
Baltimore, Maryland, 21287-8936, United States
C S Mott Children's Hospital
Ann Arbor, Michigan, 48109, United States
Wayne State University
Detroit, Michigan, 48202, United States
The Childrens Mercy Hospital
Kansas City, Missouri, 64108, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
Roswell Park Cancer Institute
Buffalo, New York, 14263, United States
Columbia University Medical Center
New York, New York, 10032, United States
University of Rochester
Rochester, New York, 14642, United States
New York Medical College
Valhalla, New York, 10595, United States
University of North Carolina
Chapel Hill, North Carolina, 27599, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229, United States
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, 44106, United States
Cleveland Clinic Foundation
Cleveland, Ohio, 44195, United States
Nationwide Children's Hospital
Columbus, Ohio, 43205, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, 17033, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232, United States
University of Texas Southwestern Medical Center
Dallas, Texas, 75390, United States
Cook Children's Medical Center
Fort Worth, Texas, 76104, United States
Methodist Children's Hospital of South Texas
San Antonio, Texas, 78229, United States
Primary Children's Medical Center
Salt Lake City, Utah, 84113, United States
Virginia Commonwealth University
Richmond, Virginia, 23298, United States
Seattle Children's Hospital
Seattle, Washington, 98105, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792, United States
Midwest Children's Cancer Center
Milwaukee, Wisconsin, 53226, United States
Royal Brisbane and Women's Hospital
Herston, Queensland, 4029, Australia
Princess Margaret Hospital for Children
Perth, Western Australia, 6008, Australia
British Columbia Children's Hospital
Vancouver, British Columbia, V6H 3V4, Canada
CancerCare Manitoba
Winnipeg, Manitoba, R3E 0V9, Canada
Hospital for Sick Children
Toronto, Ontario, M5G 1X8, Canada
The Montreal Children's Hospital of the MUHC
Montreal, Quebec, H3H 1P3, Canada
Related Publications (2)
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.
PMID: 25862561DERIVEDPulsipher 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.
PMID: 24497539DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
Outcome Measures 6, 7, 8 and 9 are exploring in nature and did not investigate the actual relapse rates of the 2 treatment regiments.
Results Point of Contact
- Title
- Results Reporting Coordinator
- Organization
- Children's Oncology Group
Study Officials
- PRINCIPAL INVESTIGATOR
Michael Pulsipher, MD
Children's Oncology Group
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NETWORK
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 26, 2006
First Posted
September 28, 2006
Study Start
March 1, 2007
Primary Completion
May 1, 2011
Study Completion
June 30, 2017
Last Updated
August 7, 2019
Results First Posted
February 9, 2017
Record last verified: 2019-06