Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

1. 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 undergoing allogeneic hematopoietic stem cell transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate with or without sirolimus.

Secondary

1. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in these patients.
2. 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.
3. 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.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL)* in second complete remission (CR2) (M1 bone marrow, < 5% blasts by morphology) meeting the following criteria:
  • Eligible for matched sibling transplantation AND intermediate-risk disease 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**
  • Eligible for other related donor, unrelated donor, or matched sibling transplantation AND high-risk disease 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**

   [Note: *ALL defined as bone marrow with > 25% L1 or L2 lymphoblasts (i.e., M3 marrow). Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc translocation are considered to have Burkitt's lymphoma or mature B-cell leukemia and are not eligible.]

   [Note: **Less than 18 months after initiation of primary chemotherapy]

• Enrolled on an appropriate COG relapsed ALL clinical trial meeting 1 of the following criteria:
  • Must proceed directly to transplantation after completing the required study therapy (i.e., 1 induction course and 2 consolidation courses)
  • 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)

Prior/Concurrent Therapy:

• See Disease Characteristics
• 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
• Other concurrent immunosuppressants allowed

Patient Characteristics:

• 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
• FEV₁ ≥ 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

Expected Enrollment

A total of 236 patients will be accrued for this study.

Outcomes

Two-year event-free survival after transplantation as measured by the O'Brien-Fleming spending function

Rate of relapse
Rate of treatment-related mortality
Rate of acute graft-versus-host-disease (GVHD)
Rate of chronic GVHD
Relative contribution of resistance by acute lymphoblastic leukemia (ALL) blasts to cytolytic therapy (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation
Relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post-transplantation

Outline

This is a randomized, open-label, multicenter study. Patients are stratified according to risk (intermediate CR2 vs high CR2 vs very high CR1), donor type (matched sibling vs unrelated or mismatched vs mismatched 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 10 years.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Michael Pulsipher, MD, Protocol chair		Ph: 801-585-3229
Donna Wall, MD, Protocol co-chair		Ph: 204-787-7095

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Clinical Trials Office - UAB Comprehensive Cancer Center	Ph:  205-934-0309
Arizona
	Phoenix
	Phoenix Children's Hospital
		Jessica Boklan	Ph:  602-546-0920
California
	Duarte
	City of Hope Comprehensive Cancer Center
		Clinical Trials Office - City of Hope Comprehensive Cancer Center	Ph:  800-826-4673
			Email: becomingapatient@coh.org
	Oakland
	Children's Hospital and Research Center Oakland
		Clinical Trial Office - Children's Hospital and Research Center Oakland	Ph:  510-450-7600
	Orange
	Children's Hospital of Orange County
		Violet Shen	Ph:  714-532-8636
	San Diego
	Rady Children's Hospital - San Diego
		Clinical Trials Office - Rady Children's Hospital - San Diego	Ph:  858-966-5934
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Clinical Trials Office - UCSF Helen Diller Family Comprehensive Cancer Center	Ph:  877-827-3222
Colorado
	Aurora
	Children's Hospital Colorado Center for Cancer and Blood Disorders
		Kelly Maloney	Ph:  720-777-6673
District of Columbia
	Washington
	Children's National Medical Center
		Clinical Trials Office - Children's National Medical Center	Ph:  202-884-2549
Florida
	Fort Myers
	Lee Cancer Care of Lee Memorial Health System
		Clinical Trials Office - Lee Cancer Care of Lee Memorial Health System	Ph:  877-680-0008
	Jacksonville
	Nemours Children's Clinic
		Eric Sandler	Ph:  904-697-3793
	Miami
	University of Miami Sylvester Comprehensive Cancer Center - Miami
		University of Miami Sylvester Comprehensive Cancer Center Clinical Trial Matching Service	Ph:  866-574-5124
			Email: Sylvester@emergingmed.com
	Saint Petersburg
	All Children's Hospital
		Gregory Hale	Ph:  727-767-4176
Georgia
	Atlanta
	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
		Howard Katzenstein	Ph:  404-785-0853
Illinois
	Chicago
	Children's Memorial Hospital - Chicago
		Stewart Goldman	Ph:  773-880-3270
Indiana
	Indianapolis
	Indiana University Melvin and Bren Simon Cancer Center
		Clinical Trials Office - Indiana University Cancer Center	Ph:  317-274-2552
Iowa
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Cancer Information Service	Ph:  800-237-1225
Kentucky
	Louisville
	Kosair Children's Hospital
		Clinical Trials Office - Kosair Children's Hospital	Ph:  502-629-5500
			Email: CancerResource@nortonhealthcare.org
Louisiana
	New Orleans
	Children's Hospital of New Orleans
		Clinical Trials Office - Children's Hospital of New Orleans	Ph:  504-894-5377
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
		Suzanne Shusterman	Ph:  617-632-4901
Michigan
	Ann Arbor
	C.S. Mott Children's Hospital at University of Michigan Medical Center
		Clinical Trials Office - C.S. Mott Children's Hospital	Ph:  1-800-865-1125
	Detroit
	Barbara Ann Karmanos Cancer Institute
		Clinical Trials Office - Barbara Ann Karmanos Cancer Institute	Ph:  313-576-9363
Mississippi
	Jackson
	University of Mississippi Cancer Clinic
		Gail Megason	Ph:  601-984-5220
Missouri
	Kansas City
	Children's Mercy Hospital
		Maxine Hetherington	Ph:  816-234-3265
	St. Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Robert Hayashi	Ph:  314-454-4118
Nebraska
	Omaha
	UNMC Eppley Cancer Center at the University of Nebraska Medical Center
		Clinical Trials Office - UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Ph:  800-999-5465
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Clinical Trials Office - Hackensack University Medical Center Cancer Center	Ph:  201-996-2879
New York
	Buffalo
	Roswell Park Cancer Institute
		Clinical Trials Office - Roswell Park Cancer Institute	Ph:  877-275-7724
	New Hyde Park
	Schneider Children's Hospital
		Arlene Redner	Ph:  718-470-3460
	New York
	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
		Clinical Trials Office - Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	Ph:  212-305-8615
	Mount Sinai Medical Center
		Birte Wistinghausen	Ph:  212-241-7022
	Rochester
	James P. Wilmot Cancer Center at University of Rochester Medical Center
		Lisa Hackney	Ph:  585-275-2981
	Valhalla
	New York Medical College
		Mehmet Ozkaynak	Ph:  914-493-7997
North Carolina
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Clinical Trials Office - Lineberger Comprehensive Cancer Center	Ph:  877-668-0683; 919-966-4432
	Charlotte
	Blumenthal Cancer Center at Carolinas Medical Center
		Clinical Trials Office - Blumenthal Cancer Center at Carolinas Medical Center	Ph:  704-355-2884
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		Clinical Trials Office - Cincinnati Children's Hospital Medical Center	Ph:  513-636-2799
	Cleveland
	Cleveland Clinic Taussig Cancer Center
		Clinical Trials Office - Cleveland Clinic Taussig Cancer Center	Ph:  866-223-8100
	Rainbow Babies and Children's Hospital
		Yousif (Joe) Matloub	Ph:  216-844-3345
	Columbus
	Nationwide Children's Hospital
		Laura Martin	Ph:  614-722-3582
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Rene McNall-Knapp	Ph:  405-271-5311
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Clinical Trials Office - Knight Cancer Institute at Oregon Health and Science University	Ph:  503-494-1080
			Email: trials@ohsu.edu
Pennsylvania
	Hershey
	Penn State Children's Hospital
		John Kuttesch	Ph:  717-531-6012
	Philadelphia
	Children's Hospital of Philadelphia
		Elizabeth Fox	Ph:  267-425-3010
	Pittsburgh
	Children's Hospital of Pittsburgh of UPMC
		Clinical Trials Office - Children's Hospital of Pittsburgh	Ph:  412-692-7056
South Carolina
	Charleston
	Hollings Cancer Center at Medical University of South Carolina
		Clinical Trials Office - Hollings Cancer Center at Medical University of South Carolina	Ph:  843-792-9321
Tennessee
	Nashville
	Vanderbilt-Ingram Cancer Center
		Clinical Trials Office - Vanderbilt-Ingram Cancer Center	Ph:  800-811-8480
Texas
	Dallas
	Medical City Dallas Hospital
		Carl Lenarsky	Ph:  972-566-6647x4439
	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
		Clinical Trials Office - Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Ph:  866-460-4673; 214-648-7097
	Fort Worth
	Cook Children's Medical Center - Fort Worth
		Clinical Trials Office - Cook's Children's Medical Center	Ph:  682-885-2103
	San Antonio
	Methodist Children's Hospital of South Texas
		Jaime Estrada	Ph:  210-575-7268
Utah
	Salt Lake City
	Primary Children's Medical Center
		Phillip Barnette	Ph:  801-662-4700
Virginia
	Richmond
	Virginia Commonwealth University Massey Cancer Center
		Clinical Trials Office -Virginia Commonwealth University Massey Cancer Center	Ph:  804-628-1939
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Julie Park	Ph:  206-987-2106
Wisconsin
	Madison
	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
		Clinical Trials Office - University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Ph:  608-262-5223
	Milwaukee
	Midwest Children's Cancer Center at Children's Hospital of Wisconsin
		Michael Kelly	Ph:  414-456-4170
Australia
Queensland
	Brisbane
	Royal Children's Hospital
		Helen Irving	Ph:  617-3636-8671
Western Australia
	Perth
	Princess Margaret Hospital for Children
		Catherine Cole	Ph:  011-6189340-8238
Canada
British Columbia
	Vancouver
	Children's and Women's Hospital of British Columbia
		Caron Strahlendorf	Ph:  604-875-3576
Manitoba
	Winnipeg
	CancerCare Manitoba
		Rochelle Yanofsky	Ph:  204-787-4163
Ontario
	Toronto
	Hospital for Sick Children
		Sylvain Baruchel	Ph:  416-813-7795
Quebec
	Montreal
	Hopital Sainte Justine
		Yvan Samson	Ph:  514-345-4969
	Montreal Children's Hospital at McGill University Health Center
		Sharon Abish	Ph:  514-412-4400x22219

Registry Information
Official Title		A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia
Trial Start Date		2007-03-19
Trial Completion Date		2011-02-02 (estimated)
Registered in ClinicalTrials.gov		NCT00382109
Date Submitted to PDQ		2006-07-28
Information Last Verified		2011-04-07
NCI Grant/Contract Number		CA98543

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