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A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia


Phase 3
1 Year
21 Years
Not Enrolling
Both
B-cell Childhood Acute Lymphoblastic Leukemia, Childhood Acute Lymphoblastic Leukemia in Remission, Graft Versus Host Disease, L1 Childhood Acute Lymphoblastic Leukemia, L2 Childhood Acute Lymphoblastic Leukemia, T-cell Childhood Acute Lymphoblastic Leukemia

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Trial Information

A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia


PRIMARY OBJECTIVES:

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 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 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.


Inclusion Criteria:



- 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**

- 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)

- 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival after transplantation as measured by the O'Brien-Fleming spending function

Outcome Time Frame:

Up to 2 years

Safety Issue:

No

Principal Investigator

Michael Pulsipher

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Institutional Review Board

Study ID:

ASCT0431

NCT ID:

NCT00382109

Start Date:

March 2007

Completion Date:

Related Keywords:

  • B-cell Childhood Acute Lymphoblastic Leukemia
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Graft Versus Host Disease
  • L1 Childhood Acute Lymphoblastic Leukemia
  • L2 Childhood Acute Lymphoblastic Leukemia
  • T-cell Childhood Acute Lymphoblastic Leukemia
  • Graft vs Host Disease
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
New York Medical CollegeValhalla, New York  10595
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's National Medical CenterWashington, District of Columbia  20010-2970
All Children's HospitalSt. Petersburg, Florida  33701
Kosair Children's HospitalLouisville, Kentucky  40202-3830
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
City of Hope Medical CenterDuarte, California  91010
University of North CarolinaChapel Hill, North Carolina  27599
University of RochesterRochester, New York  14642
Wayne State UniversityDetroit, Michigan  48202
Indiana University Medical CenterIndianapolis, Indiana  46202
University of Texas Southwestern Medical CenterDallas, Texas  
Oregon Health and Science UniversityPortland, Oregon  97201
Virginia Commonwealth UniversityRichmond, Virginia  
Seattle Children's HospitalSeattle, Washington  98105
Childrens Memorial HospitalChicago, Illinois  60614
Columbia University Medical CenterNew York, New York  10032
Cook Children's Medical CenterFort Worth, Texas  76104
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Phoenix Childrens HospitalPhoenix, Arizona  85016
Childrens Hospital of Orange CountyOrange, California  92868-3874
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Children's Hospital ColoradoAurora, Colorado  80045
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Children's Hospital-Main CampusNew Orleans, Louisiana  70118