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 - Full Text View

Purpose

RATIONALE: 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.

PURPOSE: 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.

Condition	Intervention	Phase
Graft Versus Host Disease Leukemia	Drug: methotrexate Drug: sirolimus Drug: tacrolimus	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Masking: Open Label Primary Purpose: Supportive Care
Official Title:	A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia

Resource links provided by NLM:

MedlinePlus related topics: Cancer Chronic Lymphocytic Leukemia Leukemia

Drug Information available for: Methotrexate Methotrexate sodium Sirolimus Tacrolimus Everolimus Temsirolimus

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Two-year event-free survival after transplantation as measured by the O'Brien-Fleming spending function [ Designated as safety issue: No ]

Secondary Outcome Measures:

Rate of relapse [ Designated as safety issue: No ]
Rate of treatment-related mortality [ Designated as safety issue: Yes ]
Rate of acute graft-versus-host-disease (GVHD) [ Designated as safety issue: Yes ]
Rate of chronic GVHD [ Designated as safety issue: Yes ]
Relative contribution of resistance by acute lymphoblastic leukemia (ALL) blasts to cytolytic therapy (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation [ Designated as safety issue: No ]
Relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post-transplantation [ Designated as safety issue: No ]

Estimated Enrollment:	236
Study Start Date:	March 2007
Estimated Primary Completion Date:	October 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 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.	Drug: methotrexate Given IV Drug: sirolimus Given orally Drug: tacrolimus Given IV
Active Comparator: Arm II (control) Patients receive tacrolimus and methotrexate as in arm I.	Drug: methotrexate Given IV Drug: tacrolimus Given IV

Arms

Assigned Interventions

Experimental: 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.

Drug: methotrexate

Given IV

Drug: sirolimus

Given orally

Drug: tacrolimus

Given IV

Active Comparator: Arm II (control)

Patients receive tacrolimus and methotrexate as in arm I.

Drug: methotrexate

Given IV

Drug: tacrolimus

Given IV

Detailed Description:

OBJECTIVES:

Primary

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

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

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

Eligibility

Ages Eligible for Study:	1 Year to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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)

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
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

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00382109

Show 63 Study Locations

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Michael A. Pulsipher, MD	Primary Children's Medical Center
Investigator:	Donna A. Wall, MD	CancerCare Manitoba

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Gregory H. Reaman, Children's Oncology Group - Group Chair Office
ClinicalTrials.gov Identifier:	NCT00382109 History of Changes
Other Study ID Numbers:	CDR0000500131, COG-ASCT0431, COG-PBMTC-ONCO51
Study First Received:	September 26, 2006
Last Updated:	August 3, 2012
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

graft versus host disease
childhood acute lymphoblastic leukemia in remission
L1 childhood acute lymphoblastic leukemia

L2 childhood acute lymphoblastic leukemia
T-cell childhood acute lymphoblastic leukemia
B-cell childhood acute lymphoblastic leukemia

Additional relevant MeSH terms:

Graft vs Host Disease
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Methotrexate
Sirolimus
Everolimus
Tacrolimus
Abortifacient Agents, Nonsteroidal

Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents

ClinicalTrials.gov processed this record on May 19, 2013