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Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

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ClinicalTrials.gov Identifier: NCT00105001
Recruitment Status : Completed
First Posted : March 4, 2005
Results First Posted : September 15, 2015
Last Update Posted : October 30, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Brenda Sandmaier, Fred Hutchinson Cancer Research Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Previously Treated Myelodysplastic Syndrome
Refractory Chronic Lymphocytic Leukemia
Refractory Plasma Cell Myeloma
Waldenstrom Macroglobulinemia
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Acute Myeloid Leukemia in Remission
Childhood Burkitt Lymphoma
Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Childhood Diffuse Large Cell Lymphoma
Childhood Immunoblastic Lymphoma
Childhood Myelodysplastic Syndrome
Stage II Contiguous Adult Burkitt Lymphoma
Stage II Contiguous Adult Diffuse Large Cell Lymphoma
Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma
Stage II Contiguous Adult Diffuse Small Cleaved Cell Lymphoma
Stage II Adult Contiguous Immunoblastic Lymphoma
Stage II Contiguous Adult Lymphoblastic Lymphoma
Stage II Grade 1 Contiguous Follicular Lymphoma
Stage II Grade 2 Contiguous Follicular Lymphoma
Stage II Grade 3 Contiguous Follicular Lymphoma
Stage II Contiguous Mantle Cell Lymphoma
Stage II Non-Contiguous Adult Burkitt Lymphoma
Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma
Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma
Stage II Non-Contiguous Adult Diffuse Small Cleaved Cell Lymphoma
Stage II Adult Non-Contiguous Immunoblastic Lymphoma
Stage II Non-Contiguous Adult Lymphoblastic Lymphoma
Stage II Grade 1 Non-Contiguous Follicular Lymphoma
Stage II Grade 2 Non-Contiguous Follicular Lymphoma
Stage II Grade 3 Non-Contiguous Follicular Lymphoma
Stage II Non-Contiguous Mantle Cell Lymphoma
Stage II Small Lymphocytic Lymphoma
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Childhood Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Recurrent Childhood Anaplastic Large Cell Lymphoma
Recurrent Childhood Large Cell Lymphoma
Recurrent Childhood Lymphoblastic Lymphoma
Recurrent Childhood Burkitt Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Recurrent Childhood Hodgkin Lymphoma
Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Secondary Myelodysplastic Syndrome
Stage I Adult Burkitt Lymphoma
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Adult Diffuse Mixed Cell Lymphoma
Stage I Adult Immunoblastic Lymphoma
Stage I Adult Lymphoblastic Lymphoma
Stage I Childhood Anaplastic Large Cell Lymphoma
Stage I Childhood Large Cell Lymphoma
Stage I Childhood Lymphoblastic Lymphoma
Stage I Childhood Burkitt Lymphoma
Stage I Grade 1 Follicular Lymphoma
Stage I Grade 2 Follicular Lymphoma
Stage I Grade 3 Follicular Lymphoma
Stage I Mantle Cell Lymphoma
Stage I Marginal Zone Lymphoma
Stage I Small Lymphocytic Lymphoma
Stage II Childhood Anaplastic Large Cell Lymphoma
Stage II Childhood Lymphoblastic Lymphoma
Stage II Childhood Burkitt Lymphoma
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Diffuse Small Cleaved Cell Lymphoma
Stage III Adult Immunoblastic Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Childhood Anaplastic Large Cell Lymphoma
Stage III Childhood Large Cell Lymphoma
Stage III Childhood Lymphoblastic Lymphoma
Stage III Childhood Burkitt Lymphoma
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Marginal Zone Lymphoma
Stage III Small Lymphocytic Lymphoma
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
Stage IV Adult Immunoblastic Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Childhood Anaplastic Large Cell Lymphoma
Stage IV Childhood Large Cell Lymphoma
Stage IV Childhood Lymphoblastic Lymphoma
Stage IV Childhood Burkitt Lymphoma
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Marginal Zone Lymphoma
Stage IV Small Lymphocytic Lymphoma
Interventions Drug: Fludarabine Phosphate
Radiation: Total-Body Irradiation
Procedure: Peripheral Blood Stem Cell Transplantation
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Tacrolimus
Drug: Mycophenolate Mofetil
Drug: Sirolimus
Enrollment 210
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive Mycophenolate Mofetil [MMF] PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive Mycophenolate Mofetil [MMF] PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and Mycophenolate Mofetil [MMF] as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Period Title: Overall Study
Started 70 71 69
Completed 70 71 69
Not Completed 0 0 0
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus) Total
Hide Arm/Group Description

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Total of all reporting groups
Overall Number of Baseline Participants 70 71 69 210
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 70 participants 71 participants 69 participants 210 participants
<=18 years
0
   0.0%
1
   1.4%
1
   1.4%
2
   1.0%
Between 18 and 65 years
57
  81.4%
50
  70.4%
49
  71.0%
156
  74.3%
>=65 years
13
  18.6%
20
  28.2%
19
  27.5%
52
  24.8%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 70 participants 71 participants 69 participants 210 participants
60
(26 to 74)
60
(13 to 72)
60
(15 to 75)
60
(13 to 75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 70 participants 71 participants 69 participants 210 participants
Female
29
  41.4%
30
  42.3%
23
  33.3%
82
  39.0%
Male
41
  58.6%
41
  57.7%
46
  66.7%
128
  61.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 70 participants 71 participants 69 participants 210 participants
United States 59 59 58 176
Denmark 5 5 5 15
Germany 6 7 6 19
1.Primary Outcome
Title Number of Participants With Grades II-IV Acute GVHD
Hide Description

Number of patients with grades II-IV acute GVHD

aGVHD Stages

Skin:

  1. a maculopapular eruption involving < 25% BSA
  2. a maculopapular eruption involving 25 - 50% BSA
  3. generalized erythroderma
  4. generalized erythroderma w/ bullous formation and often w/ desquamation

Liver:

  1. bilirubin 2.0 - 3.0 mg/100 mL
  2. bilirubin 3 - 5.9 mg/100 mL
  3. bilirubin 6 - 14.9 mg/100 mL
  4. bilirubin > 15 mg/100 mL

Gut:

Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall.

aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death

Time Frame 150 days after transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects counted towards accrual but did not proceed to transplant and thus were not evaluable.
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description:

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Overall Number of Participants Analyzed 69 71 68
Measure Type: Count of Participants
Unit of Measure: Participants
44
  63.8%
34
  47.9%
32
  47.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.09
Comments Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
Method Regression, Cox
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.10
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.4 to 1.1
Estimation Comments HR for Arm II relative to Arm I, reflecting events over the entire period of follow-u[
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.6 to 1.0
Estimation Comments HR for Arm III relative to Arm I, reflecting events over the entire period of follow-up
2.Secondary Outcome
Title Number of Non-Relapse Mortalities
Hide Description

Percentage of NRM as estimated by cumulative incidence methods with competing risks.

Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

Time Frame 200 days after transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects counted towards accrual but did not proceed to transplant and thus were not evaluable.
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description:

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Overall Number of Participants Analyzed 69 71 68
Measure Type: Count of Participants
Unit of Measure: Participants
3
   4.3%
6
   8.5%
2
   2.9%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.55
Comments Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
Method Regression, Cox
Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants Utilizing High-Dose Corticosteroids
Hide Description

Number of patients utilizing high-dose corticosteroids (as a surrogate marker for reduction of acute GVHD), estimated by cumulative incidence methods.

Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

Time Frame 150 days after transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects counted towards accrual but did not proceed to transplant and thus were not evaluable.
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description:

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Overall Number of Participants Analyzed 69 71 68
Measure Type: Count of Participants
Unit of Measure: Participants
38
  55.1%
35
  49.3%
22
  32.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.009
Comments Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
Method Regression, Cox
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.51
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.5 to 1.4
Estimation Comments HR for Arm II relative to Arm I, reflecting events over the entire period of follow-up
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
0.3 to 0.8
Estimation Comments HR for Arm III relative to Arm I, reflecting events over the entire period of follow-up
4.Secondary Outcome
Title Number of Participants Surviving Overall
Hide Description

Number of patients surviving, estimated by cumulative incidence methods

Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

Time Frame 1 Year post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects counted towards accrual but did not proceed to transplant and thus were not evaluable.
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description:

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Overall Number of Participants Analyzed 69 71 68
Measure Type: Count of Participants
Unit of Measure: Participants
48
  69.6%
47
  66.2%
40
  58.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.93
Comments Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
Method Regression, Cox
Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants Surviving Without Progression
Hide Description

Number of patients with progression-free survival, estimated by cumulative incidence methods

Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

Time Frame 2 Years post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects counted towards accrual but did not proceed to transplant and thus were not evaluable.
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description:

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

Overall Number of Participants Analyzed 69 71 68
Measure Type: Count of Participants
Unit of Measure: Participants
28
  40.6%
27
  38.0%
26
  38.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (MMF and Tacrolimus), Arm II (MMF and Tacrolimus Alternate Schedule), Arm III (MMF, Tacrolimus, and Sirolimus)
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.96
Comments Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
Method Regression, Cox
Comments [Not Specified]
Time Frame AEs: From the start of conditioning to 100 Days post-transplant SAEs: From the start of conditioning to 200 Days post-transplant All-Cause Mortality: Conditioning through 1 Year
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Hide Arm/Group Description

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

Fludarabine Phosphate: Given IV

Total-Body Irradiation: Undergo total-body irradiation

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation

Tacrolimus: Given IV or PO

Mycophenolate Mofetil: Given PO

Sirolimus: Given PO

All-Cause Mortality
Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   21/69 (30.43%)      24/71 (33.80%)      28/68 (41.18%)    
Hide Serious Adverse Events
Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   9/69 (13.04%)      8/71 (11.27%)      7/68 (10.29%)    
Cardiac disorders       
Pericardial effusion   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Hypertension   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Gastrointestinal disorders       
Intestinal pneumatosis   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
General disorders       
Toxic leukoencephalopathy, infections w/ pneumonia and pyelonephritis   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Multi-organ failure   0/69 (0.00%)  0 1/71 (1.41%)  1 1/68 (1.47%)  1
Hepatobiliary disorders       
Hepatic   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Immune system disorders       
GvHD w/ infection   1/69 (1.45%)  1 1/71 (1.41%)  1 1/68 (1.47%)  1
GVHD   0/69 (0.00%)  0 0/71 (0.00%)  0 2/68 (2.94%)  2
Infections and infestations       
Respiratory infection   1/69 (1.45%)  1 3/71 (4.23%)  3 0/68 (0.00%)  0
Sepsis   1/69 (1.45%)  1 1/71 (1.41%)  1 1/68 (1.47%)  1
Mucormycosis   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Injury, poisoning and procedural complications       
Severe hemoptysis   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Renal and urinary disorders       
Renal insufficiency   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Vascular disorders       
Thrombosis   2/69 (2.90%)  2 1/71 (1.41%)  1 0/68 (0.00%)  0
CNS cerebrovascular ischemia   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm I (MMF and Tacrolimus) Arm II (MMF and Tacrolimus Alternate Schedule) Arm III (MMF, Tacrolimus, and Sirolimus)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   25/69 (36.23%)      22/71 (30.99%)      25/68 (36.76%)    
Blood and lymphatic system disorders       
Febrile neutropenia   1/69 (1.45%)  1 1/71 (1.41%)  1 0/68 (0.00%)  0
Hemolysis   1/69 (1.45%)  1 1/71 (1.41%)  1 0/68 (0.00%)  0
Thrombotic thrombocytopenic purpura   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Cardiac disorders       
Atrial fibrillation   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Cardiac arrest   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Heart failure   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Pericardial tamponade   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Ventricular arrhythmia   2/69 (2.90%)  2 0/71 (0.00%)  0 0/68 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Colitis   1/69 (1.45%)  1 1/71 (1.41%)  1 0/68 (0.00%)  0
Diarrhea   5/69 (7.25%)  5 1/71 (1.41%)  1 4/68 (5.88%)  4
Enterocolitis   2/69 (2.90%)  2 0/71 (0.00%)  0 0/68 (0.00%)  0
Mucositis oral   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Nausea   1/69 (1.45%)  1 1/71 (1.41%)  1 3/68 (4.41%)  3
Vomiting   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
General disorders       
Fatigue   0/69 (0.00%)  0 1/71 (1.41%)  1 1/68 (1.47%)  1
Fever   0/69 (0.00%)  0 3/71 (4.23%)  3 0/68 (0.00%)  0
Infections and infestations       
Duodenal infection   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Lung infection   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Sepsis   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Skin infection   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Investigations       
Blood bilirubin increased   2/69 (2.90%)  2 2/71 (2.82%)  2 1/68 (1.47%)  1
Creatinine increased   1/69 (1.45%)  1 1/71 (1.41%)  1 4/68 (5.88%)  4
Neutrophil count decreased   1/69 (1.45%)  1 3/71 (4.23%)  3 0/68 (0.00%)  0
Platelet count decreased   0/69 (0.00%)  0 2/71 (2.82%)  2 0/68 (0.00%)  0
White blood cell decreased   0/69 (0.00%)  0 1/71 (1.41%)  1 1/68 (1.47%)  1
Metabolism and nutrition disorders       
Anorexia   1/69 (1.45%)  1 0/71 (0.00%)  0 1/68 (1.47%)  1
Hyperglycemia   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Hypertriglyceridemia   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Hypokalemia   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Hyponatremia   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthritis   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Back pain   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Generalized muscle weakness   1/69 (1.45%)  1 2/71 (2.82%)  2 0/68 (0.00%)  0
Musculoskeletal and connective tissue disorder - Other, specify (Cervical disk herniation)   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Musculoskeletal and connective tissue disorder - Other, specify (Pain, NOS)   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Treatment related secondary malignancy   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Nervous system disorders       
Ataxia   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Headache   0/69 (0.00%)  0 1/71 (1.41%)  1 2/68 (2.94%)  2
Psychosis   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Seizure   1/69 (1.45%)  1 0/71 (0.00%)  0 1/68 (1.47%)  3
Syncope   2/69 (2.90%)  2 0/71 (0.00%)  0 2/68 (2.94%)  3
Tremor   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  2
Psychiatric disorders       
Anxiety   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Renal and urinary disorders       
Acute kidney injury   1/69 (1.45%)  1 1/71 (1.41%)  1 1/68 (1.47%)  1
Respiratory, thoracic and mediastinal disorders       
Bronchopulmonary hemorrhage   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Epistaxis   0/69 (0.00%)  0 1/71 (1.41%)  1 0/68 (0.00%)  0
Hypoxia   5/69 (7.25%)  5 8/71 (11.27%)  9 4/68 (5.88%)  4
Pleural effusion   0/69 (0.00%)  0 1/71 (1.41%)  1 2/68 (2.94%)  2
Pneumonitis   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Respiratory failure   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Respiratory, thoracic and mediastinal disorders - Other, specify (Pulmonary, NOS)   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Skin and subcutaneous tissue disorders       
Rash maculo-papular   0/69 (0.00%)  0 0/71 (0.00%)  0 1/68 (1.47%)  1
Vascular disorders       
Hematoma   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Hypertension   1/69 (1.45%)  1 0/71 (0.00%)  0 0/68 (0.00%)  0
Hypotension   1/69 (1.45%)  2 1/71 (1.41%)  3 1/68 (1.47%)  1
Thromboembolic event   1/69 (1.45%)  1 1/71 (1.41%)  1 2/68 (2.94%)  2
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Brenda M. Sandmaier
Organization: Fred Hutchinson Cancer Research Center
Phone: (206) 667-4961
EMail: bsandmai@fhcrc.org
Layout table for additonal information
Responsible Party: Brenda Sandmaier, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00105001    
Other Study ID Numbers: 1938.00
NCI-2010-00268 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1938.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
P01CA018029 ( U.S. NIH Grant/Contract )
First Submitted: March 3, 2005
First Posted: March 4, 2005
Results First Submitted: August 13, 2015
Results First Posted: September 15, 2015
Last Update Posted: October 30, 2019