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

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00382109
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 146
• Locations: 50
• Arms: 2
• Duration (Months): 124
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: thiotepa; Drug: cyclophosphamide; Drug: tacrolimus; Drug: methotrexate; Drug: sirolimus; Radiation: total body irradiation	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

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 or high risk ALL in first 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:

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.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor type (matched sibling vs unrelated or other 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 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 146 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Jun 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: thiotepa; Given IV; Other Names: Oncotiotepa STEPA TESPA Tespamin TSPA ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: tacrolimus; Given IV or orally; Other Names: FK 506 Prograf ; Drug: methotrexate; Given IV; Other Names: amethopterin Folex methylaminopterin Mexate MTX ; Drug: sirolimus; Given orally; Other Names: AY 22989 Rapamune rapamycin SLM ; Radiation: total body irradiation; Part of the transplant preparatory regimen; Other Names: TBI
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).	Drug: thiotepa; Given IV; Other Names: Oncotiotepa STEPA TESPA Tespamin TSPA ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: tacrolimus; Given IV or orally; Other Names: FK 506 Prograf ; Drug: methotrexate; Given IV; Other Names: amethopterin Folex methylaminopterin Mexate MTX ; Radiation: total body irradiation; Part of the transplant preparatory regimen; Other Names: TBI

Outcome Measures

Primary Outcome Measures

1. Estimated Percentage of Participants With Event Free Survival [at 2 years]

   An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.

Secondary Outcome Measures

1. Rate of Relapses [At 2 years]

   An event is defined as relapse.

2. Estimated Transplant Related Mortality Percentage [100 days]

   Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.

3. Estimated Rate of Acute Graft VS Host Disease (GVHD) [At 200 days]

   Any grade acute graft vs host disease (defined in APPENDIX II study protocol).

4. Estimated Rate of Overall Chronic Graft VS Host Disease [At 2 years]

   Chronic graft vs host disease is defined in APPENDIX III of study protocol.

5. 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]

   An event is defined as relapse or transplant-related mortality.

6. Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) [At 1 year]

   An event is defined as relapse; estimated probability of relapse.

7. Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD) [At 2 months]

   An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.

8. Chimerism [Up to 12 months]

   Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
2	City of Hope Medical Center	Duarte	California	United States	91010
3	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
4	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
5	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
6	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
7	Children's Hospital Colorado	Aurora	Colorado	United States	80045
8	Children's National Medical Center	Washington	District of Columbia	United States	20010
9	All Children's Hospital	Saint Petersburg	Florida	United States	33701
10	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
11	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
12	Indiana University Medical Center	Indianapolis	Indiana	United States	46202
13	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
14	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
15	Children's Hospital-Main Campus	New Orleans	Louisiana	United States	70118
16	Johns Hopkins University	Baltimore	Maryland	United States	21287-8936
17	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
18	Wayne State University	Detroit	Michigan	United States	48202
19	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
20	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
21	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
22	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
23	Columbia University Medical Center	New York	New York	United States	10032
24	University of Rochester	Rochester	New York	United States	14642
25	New York Medical College	Valhalla	New York	United States	10595
26	University of North Carolina	Chapel Hill	North Carolina	United States	27599
27	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
28	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
29	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
30	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
31	Oregon Health and Science University	Portland	Oregon	United States	97239
32	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
33	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
34	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
35	Medical University of South Carolina	Charleston	South Carolina	United States	29425
36	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
37	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
38	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
39	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
40	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
41	Virginia Commonwealth University	Richmond	Virginia	United States	23298
42	Seattle Children's Hospital	Seattle	Washington	United States	98105
43	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
44	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
45	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
46	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
47	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
48	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
49	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
50	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michael Pulsipher, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00382109
• Other Study ID Numbers: ASCT0431; NCI-2009-01068; CDR0000500131; COG-PBMTC-ONCO51; COG-ASCT0431; U10CA098543
• First Posted: Sep 28, 2006
• Last Update Posted: Aug 7, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Graft vs Host Disease; Sirolimus; Cyclophosphamide; Thiotepa; Methotrexate; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen	Tacro-MTX GVHD Prophylaxis
Arm/Group Description	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.	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).
Period Title: Overall Study
STARTED	76	70
COMPLETED	64	66
NOT COMPLETED	12	4

Baseline Characteristics

Arm/Group Title	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen	Tacro-MTX GVHD Prophylaxis	Total
Arm/Group Description	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.	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).	Total of all reporting groups
Overall Participants	76	70	146
Age (Year) [Median (Full Range) ]
Median (Full Range) [Year]	9	10	9
Sex: Female, Male (Count of Participants)
Female	30 39.5%	29 41.4%	59 40.4%
Male	46 60.5%	41 58.6%	87 59.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 2.6%	1 1.4%	3 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 6.6%	6 8.6%	11 7.5%
White	59 77.6%	51 72.9%	110 75.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	10 13.2%	12 17.1%	22 15.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 30.3%	16 22.9%	39 26.7%
Not Hispanic or Latino	51 67.1%	53 75.7%	104 71.2%
Unknown or Not Reported	2 2.6%	1 1.4%	3 2.1%
Region of Enrollment (participants) [Number]
United States	71 93.4%	62 88.6%	133 91.1%
Canada	3 3.9%	2 2.9%	5 3.4%
Australia	2 2.6%	6 8.6%	8 5.5%

Outcome Measures

1. Primary Outcome

Title	Estimated Percentage of Participants With Event Free Survival
Description	An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.
Time Frame	at 2 years

Outcome Measure Data

Analysis Population Description

Two ineligible patients on experimental arm excluded from analysis.

Arm/Group Title	Experimental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	74	70
Number (95% Confidence Interval) [percentage of participants]	45 59.2%	54 77.1%

2. Secondary Outcome

Title	Rate of Relapses
Description	An event is defined as relapse.
Time Frame	At 2 years

Outcome Measure Data

Analysis Population Description

2 ineligible patients on experimental arm excluded from analysis.Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of ALL consistent with pre-transplant features.

Arm/Group Title	Experimental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	74	70
Number (95% Confidence Interval) [percentage of participants]	41 53.9%	33 47.1%

3. Secondary Outcome

Title	Estimated Transplant Related Mortality Percentage
Description	Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

2 ineligible patients on experimental arm excluded from analysis.

Arm/Group Title	Experimental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	74	70
Number (95% Confidence Interval) [percentage of participants]	13 17.1%	6 8.6%

4. Secondary Outcome

Title	Estimated Rate of Acute Graft VS Host Disease (GVHD)
Description	Any grade acute graft vs host disease (defined in APPENDIX II study protocol).
Time Frame	At 200 days

Outcome Measure Data

Analysis Population Description

2 ineligible patients on experimental arm excluded from analysis. Definition of Acute GVHD: APPENDIX II: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS HOST DISEASE (GVHD) page 90-96 protocol.

Arm/Group Title	Experiemental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	74	70
Number (95% Confidence Interval) [percentage of participants]	32 42.1%	49 70%

5. Secondary Outcome

Title	Estimated Rate of Overall Chronic Graft VS Host Disease
Description	Chronic graft vs host disease is defined in APPENDIX III of study protocol.
Time Frame	At 2 years

Outcome Measure Data

Analysis Population Description

2 ineligible patients on experimental arm excluded from analysis. Definition of Chronic GVHD: APPENDIX III: DEFINING CHRONIC GRAFT VS. HOST DISEASE (FROM BMT CTN MOP SEPT. 2005) on page 97 protocol.

Arm/Group Title	Experimental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	74	70
Number (95% Confidence Interval) [percentage of participants]	22 28.9%	27 38.6%

6. Secondary Outcome

Title	Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation
Description	An event is defined as relapse or transplant-related mortality.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

We made a large number of xenograft models but were not able to correlate resistance to rapamycin in mice with outcome on the trial with the numbers that we had. For this reason, no specific publications addressing this aim were put forward.

Arm/Group Title	Experiemental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	0	0

7. Secondary Outcome

Title	Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse)
Description	An event is defined as relapse; estimated probability of relapse.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

Number at risk among no aGVHD and number at risk among aGVHD at 1 year. The two treatment regimens were intended to be analyzed together (combined data), as pre-specified in the study protocol, therefore results are not reported for each Arm of study.

Arm/Group Title	All Patients
Arm/Group Description	Relative contribution of ALL blasts to the donor immune response as a cause of relapse post transplantation (correlating development of aGVHD with relapse).
Measure Participants	67
Experienced aGVHD, later relapsed	5 6.6%
No aGVHD occurence, relapsed	24 31.6%

8. Secondary Outcome

Title	Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD)
Description	An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.
Time Frame	At 2 months

Outcome Measure Data

Analysis Population Description

The two treatment regimens were intended to be analyzed together (combined data), as pre-specified in the study protocol. However, we are not able to perform this analysis given the low numbers of blast samples available.

Arm/Group Title	All Patients
Arm/Group Description	Relative contribution of ALL blasts to the donor immune response as a cause of relapse pre transplantation (MRD)
Measure Participants	0

9. Secondary Outcome

Title	Chimerism
Description	Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

We are not able to perform this analysis given the low numbers of blast samples available.

Arm/Group Title	Experiemental	Control
Arm/Group Description	Tacro-MTX/Sirolimus GVHD Prophylaxis	Tacro-MTX GVHD Prophylaxis
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Arm/Group Title	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen		Tacro-MTX GVHD Prophylaxis
Arm/Group Description	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.		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).
All Cause Mortality
	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen		Tacro-MTX GVHD Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen		Tacro-MTX GVHD Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/72 (12.5%)		5/70 (7.1%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/72 (1.4%)		0/70 (0%)
Cardiac disorders
Cardiac disorders - Other, specify	0/72 (0%)		1/70 (1.4%)
Pericardial effusion	1/72 (1.4%)		0/70 (0%)
Gastrointestinal disorders
Ascites	1/72 (1.4%)		1/70 (1.4%)
General disorders
Death NOS	0/72 (0%)		1/70 (1.4%)
Multi-organ failure	2/72 (2.8%)		1/70 (1.4%)
Hepatobiliary disorders
Hepatic failure	0/72 (0%)		2/70 (2.9%)
Hepatobiliary disorders - Other, specify	1/72 (1.4%)		0/70 (0%)
Investigations
Blood bilirubin increased	1/72 (1.4%)		1/70 (1.4%)
Nervous system disorders
Encephalopathy	0/72 (0%)		1/70 (1.4%)
Seizure	0/72 (0%)		1/70 (1.4%)
Renal and urinary disorders
Acute kidney injury	1/72 (1.4%)		2/70 (2.9%)
Renal and urinary disorders - Other, specify	1/72 (1.4%)		0/70 (0%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/72 (1.4%)		1/70 (1.4%)
Bronchopulmonary hemorrhage	1/72 (1.4%)		0/70 (0%)
Pneumonitis	1/72 (1.4%)		1/70 (1.4%)
Respiratory, thoracic and mediastinal disorders - Other, specify	0/72 (0%)		1/70 (1.4%)
Vascular disorders
Hypotension	0/72 (0%)		1/70 (1.4%)
Thromboembolic event	1/72 (1.4%)		0/70 (0%)
Vascular disorders - Other, specify	1/72 (1.4%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen		Tacro-MTX GVHD Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/72 (52.8%)		30/70 (42.9%)
Blood and lymphatic system disorders
Anemia	5/72 (6.9%)		3/70 (4.3%)
Blood and lymphatic system disorders - Other, specify	0/72 (0%)		1/70 (1.4%)
Cardiac disorders
Pericardial effusion	2/72 (2.8%)		0/70 (0%)
Gastrointestinal disorders
Abdominal pain	1/72 (1.4%)		0/70 (0%)
Anal pain	1/72 (1.4%)		0/70 (0%)
Ascites	2/72 (2.8%)		0/70 (0%)
Diarrhea	1/72 (1.4%)		0/70 (0%)
Gastrointestinal disorders - Other, specify	0/72 (0%)		1/70 (1.4%)
Mucositis oral	1/72 (1.4%)		0/70 (0%)
Vomiting	1/72 (1.4%)		0/70 (0%)
General disorders
Death NOS	0/72 (0%)		1/70 (1.4%)
Localized edema	1/72 (1.4%)		0/70 (0%)
Hepatobiliary disorders
Hepatic failure	0/72 (0%)		1/70 (1.4%)
Immune system disorders
Anaphylaxis	1/72 (1.4%)		0/70 (0%)
Infections and infestations
Bladder infection	0/72 (0%)		1/70 (1.4%)
Infections and infestations - Other, specify	6/72 (8.3%)		1/70 (1.4%)
Sepsis	1/72 (1.4%)		0/70 (0%)
Investigations
Alanine aminotransferase increased	2/72 (2.8%)		0/70 (0%)
Aspartate aminotransferase increased	2/72 (2.8%)		2/70 (2.9%)
Blood bilirubin increased	1/72 (1.4%)		0/70 (0%)
Lymphocyte count decreased	12/72 (16.7%)		8/70 (11.4%)
Neutrophil count decreased	22/72 (30.6%)		21/70 (30%)
Platelet count decreased	22/72 (30.6%)		20/70 (28.6%)
White blood cell decreased	23/72 (31.9%)		21/70 (30%)
Metabolism and nutrition disorders
Hypercalcemia	3/72 (4.2%)		1/70 (1.4%)
Hyperglycemia	1/72 (1.4%)		2/70 (2.9%)
Hyperkalemia	2/72 (2.8%)		2/70 (2.9%)
Hypocalcemia	1/72 (1.4%)		0/70 (0%)
Hypokalemia	8/72 (11.1%)		1/70 (1.4%)
Hyponatremia	0/72 (0%)		1/70 (1.4%)
Nervous system disorders
Ataxia	1/72 (1.4%)		0/70 (0%)
Encephalopathy	1/72 (1.4%)		0/70 (0%)
Peripheral sensory neuropathy	0/72 (0%)		1/70 (1.4%)
Seizure	1/72 (1.4%)		0/70 (0%)
Tremor	1/72 (1.4%)		0/70 (0%)
Psychiatric disorders
Confusion	1/72 (1.4%)		0/70 (0%)
Renal and urinary disorders
Acute kidney injury	2/72 (2.8%)		0/70 (0%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/72 (1.4%)		0/70 (0%)
Atelectasis	1/72 (1.4%)		0/70 (0%)
Dyspnea	1/72 (1.4%)		0/70 (0%)
Hypoxia	3/72 (4.2%)		1/70 (1.4%)
Laryngeal edema	1/72 (1.4%)		0/70 (0%)
Pleural effusion	3/72 (4.2%)		0/70 (0%)
Pneumonitis	2/72 (2.8%)		0/70 (0%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/72 (1.4%)		0/70 (0%)
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome	1/72 (1.4%)		0/70 (0%)
Vascular disorders
Capillary leak syndrome	1/72 (1.4%)		0/70 (0%)
Hypertension	1/72 (1.4%)		0/70 (0%)

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior sponsor approval.