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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00382109




Registration number
NCT00382109
Ethics application status
Date submitted
26/09/2006
Date registered
28/09/2006
Date last updated
9/02/2017

Titles & IDs
Public 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
Scientific title
A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia
Secondary ID [1] 0 0
NCI-2009-01068
Secondary ID [2] 0 0
ASCT0431
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
B-cell Childhood Acute Lymphoblastic Leukemia 0 0
Childhood Acute Lymphoblastic Leukemia in Remission 0 0
Graft Versus Host Disease 0 0
L1 Childhood Acute Lymphoblastic Leukemia 0 0
L2 Childhood Acute Lymphoblastic Leukemia 0 0
T-cell Childhood Acute Lymphoblastic Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - thiotepa
Treatment: Drugs - cyclophosphamide
Treatment: Drugs - tacrolimus
Treatment: Drugs - methotrexate
Treatment: Drugs - sirolimus
Treatment: Other - total body irradiation

Experimental: 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.

Active Comparator: 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).


Treatment: Drugs: thiotepa
Given IV

Treatment: Drugs: cyclophosphamide
Given IV

Treatment: Drugs: tacrolimus
Given IV or orally

Treatment: Drugs: methotrexate
Given IV

Treatment: Drugs: sirolimus
Given orally

Treatment: Other: total body irradiation
Part of the transplant preparatory regimen

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
at 2 years
Secondary outcome [1] 0 0
Rate of Relapses - An event is defined as relapse.
Timepoint [1] 0 0
At 2 years
Secondary outcome [2] 0 0
Estimated Transplant Related Mortality Percentage - Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.
Timepoint [2] 0 0
100 days
Secondary outcome [3] 0 0
Estimated Rate of Acute Graft VS Host Disease (GVHD) - Any grade acute graft vs host disease (defined in APPENDIX II study protocol).
Timepoint [3] 0 0
At 200 days
Secondary outcome [4] 0 0
Estimated Rate of Overall Chronic Graft VS Host Disease - Chronic graft vs host disease is defined in APPENDIX III of study protocol.
Timepoint [4] 0 0
At 2 years
Secondary outcome [5] 0 0
Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation - An event is defined as relapse or transplant-related mortality.
Timepoint [5] 0 0
Up to 1 year
Secondary outcome [6] 0 0
Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) - An event is defined as relapse; estimated probability of relapse.
Timepoint [6] 0 0
At 1 year
Secondary outcome [7] 0 0
Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD) - An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.
Timepoint [7] 0 0
At 2 months
Secondary outcome [8] 0 0
Chimerism - Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.
Timepoint [8] 0 0
Up to 12 months

Eligibility
Key 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:

- 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
Minimum age
1 Year
Maximum age
21 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Unknown status
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,WA
Recruitment hospital [1] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [2] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
4029 - Herston
Recruitment postcode(s) [2] 0 0
6008 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
District of Columbia
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Illinois
Country [8] 0 0
United States of America
State/province [8] 0 0
Indiana
Country [9] 0 0
United States of America
State/province [9] 0 0
Iowa
Country [10] 0 0
United States of America
State/province [10] 0 0
Kentucky
Country [11] 0 0
United States of America
State/province [11] 0 0
Louisiana
Country [12] 0 0
United States of America
State/province [12] 0 0
Maryland
Country [13] 0 0
United States of America
State/province [13] 0 0
Michigan
Country [14] 0 0
United States of America
State/province [14] 0 0
Missouri
Country [15] 0 0
United States of America
State/province [15] 0 0
New Jersey
Country [16] 0 0
United States of America
State/province [16] 0 0
New York
Country [17] 0 0
United States of America
State/province [17] 0 0
North Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Ohio
Country [19] 0 0
United States of America
State/province [19] 0 0
Oregon
Country [20] 0 0
United States of America
State/province [20] 0 0
Pennsylvania
Country [21] 0 0
United States of America
State/province [21] 0 0
South Carolina
Country [22] 0 0
United States of America
State/province [22] 0 0
Tennessee
Country [23] 0 0
United States of America
State/province [23] 0 0
Texas
Country [24] 0 0
United States of America
State/province [24] 0 0
Utah
Country [25] 0 0
United States of America
State/province [25] 0 0
Virginia
Country [26] 0 0
United States of America
State/province [26] 0 0
Washington
Country [27] 0 0
United States of America
State/province [27] 0 0
Wisconsin
Country [28] 0 0
Canada
State/province [28] 0 0
British Columbia
Country [29] 0 0
Canada
State/province [29] 0 0
Manitoba
Country [30] 0 0
Canada
State/province [30] 0 0
Ontario
Country [31] 0 0
Canada
State/province [31] 0 0
Quebec

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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 website
https://clinicaltrials.gov/show/NCT00382109
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Michael Pulsipher, MD
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT00382109