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Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease

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ClinicalTrials.gov Identifier: NCT00448201
Recruitment Status : Completed
First Posted : March 16, 2007
Results First Posted : May 30, 2017
Last Update Posted : May 30, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Interventions Biological: anti-thymocyte globulin
Biological: sargramostim
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: fludarabine phosphate
Drug: methotrexate
Drug: tacrolimus
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Enrollment 71
Recruitment Details Patients with histologically confirmed hematologic malignancies, who were over the age of 55, or otherwise ineligible for more intensive busulfan-based therapy were enrolled on protocol Lineberger Comprehensive Cancer Center (LCCC) 0306 at the University of North Carolina.
Pre-assignment Details  
Arm/Group Title All Trial Participants
Hide Arm/Group Description All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
Period Title: Overall Study
Started 71
Completed 71
Not Completed 0
Arm/Group Title All Trial Participants
Hide Arm/Group Description All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
Overall Number of Baseline Participants 71
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 71 participants
58
(28 to 69)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants
Female
31
  43.7%
Male
40
  56.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   1.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
9
  12.7%
White
60
  84.5%
More than one race
0
   0.0%
Unknown or Not Reported
1
   1.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 71 participants
71
Donor Types   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants
HLA-matched related donor (MRD)
37
  52.1%
MUD or HLA-mismatched grafts
34
  47.9%
[1]
Measure Description: Human leukocyte antigen (HLA) typing is used to match a recipient with a donor for bone marrow or cord blood transplant. Donor types are either HLA-matched related donor (MRD) or matched unrelated donor (MUD) or HLA-mismatched grafts.
Comorbidity Index (CI)   [1] 
Median (Full Range)
Unit of measure:  Units on a scale
Number Analyzed 71 participants
3
(0 to 8)
[1]
Measure Description: The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed to identify relevant comorbidities in the allogeneic stem cell transplantation population and to enable risk assessment before allogeneic transplant. Comorbidities are given a a weighted score of 1 to 3 if present. The total score can range from 0 to 29, with higher numbers indicating more/worse comorbidities. The HCT-CI scores were further collapsed into 3 risk groups: 0 (low risk), 1 to 2 (intermediate risk), and 3 or more (high risk).
Disease Risk Index (DRI)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants
Low
9
  12.7%
Intermediate
40
  56.3%
High
19
  26.8%
Very High
1
   1.4%
Undetermined
2
   2.8%
[1]
Measure Description: The DRI uses a combination of a ternary breakdown for disease type and a binary breakdown for remission status to assign patients to 1 of 4 risk categories that differ very significantly (statistically and clinically) with respect to overall survival (OS) and Progression free survival (PFS).
1.Primary Outcome
Title Treatment-related Mortality
Hide Description Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title All Trial Participants
Hide Arm/Group Description:
All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
Overall Number of Participants Analyzed 71
Measure Type: Number
Unit of Measure: percentage of participants
8.4
2.Secondary Outcome
Title Complete Response at 6 and 12 Months Post-transplant
Hide Description [Not Specified]
Time Frame 6 and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Complete response was not calculated at 6 and 12 months because the majority of patients had complete response at the time of transplant.
Arm/Group Title All Trial Participants
Hide Arm/Group Description:
All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
3.Secondary Outcome
Title Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant
Hide Description

Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC).

Chimerism was not tabulated on day 30.

Time Frame Days 30, 60, and 90
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Day 60 Day 90
Hide Arm/Group Description:
60 days post-transplant
90 days post-transplant
Overall Number of Participants Analyzed 71 71
Measure Type: Number
Unit of Measure: percentage of patients
Complete Donor 82 87
Mixed Donor 18 13
4.Secondary Outcome
Title 5-year Disease-free Survival
Hide Description The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.
Time Frame Year 5
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title All Trial Participants
Hide Arm/Group Description:
All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
Overall Number of Participants Analyzed 71
Measure Type: Number
Unit of Measure: percentage of participants
31
5.Secondary Outcome
Title Graft-vs-host Disease at 6 Months Post-transplant
Hide Description

Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include:

  • Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body
  • Blistering, causing the exposed skin surface to flake off in severe cases
  • Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected
  • Jaundice, or a yellowing of the skin, which can indicate liver damage
  • Excessive dryness of the mouth and throat, leading to ulcers
  • Dryness of the lungs, vagina and other surfaces

Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled.

Extensive chronic GVHD - Usually occurs at about three months post-transplant.

Time Frame 6 Months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title All Trial Participants
Hide Arm/Group Description:
All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
Overall Number of Participants Analyzed 71
Measure Type: Number
Unit of Measure: percentage of participants
Acute GVHD 13
Extensive Chronic GVHD 30
Time Frame 1 year
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title All Trial Participants
Hide Arm/Group Description All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg).
All-Cause Mortality
All Trial Participants
Affected / at Risk (%)
Total   44/71 (61.97%) 
Show Serious Adverse Events Hide Serious Adverse Events
All Trial Participants
Affected / at Risk (%)
Total   7/71 (9.86%) 
Blood and lymphatic system disorders   
hypoxemia * 1  1/71 (1.41%) 
graft failure * 1  1/71 (1.41%) 
Gastrointestinal disorders   
Graft vs host disease grade 4 * 1  3/71 (4.23%) 
elevated lipase * 1  1/71 (1.41%) 
General disorders   
Failure to thrive * 1  1/71 (1.41%) 
toxic epidermal nectrolysis * 1  1/71 (1.41%) 
Hepatobiliary disorders   
liver toxicity/hyperbilirubinemia * 1  1/71 (1.41%) 
Infections and infestations   
CMV viremia * 1  1/71 (1.41%) 
Fever * 1  2/71 (2.82%) 
CMV pneumonia * 1  1/71 (1.41%) 
BK viruria * 1  1/71 (1.41%) 
fungal pneumonia * 1  1/71 (1.41%) 
bronchiolitis obliterans organizing pneumonia * 1  1/71 (1.41%) 
EBV viremia * 1  1/71 (1.41%) 
nocardia pneumonia * 1  1/71 (1.41%) 
Vascular disorders   
subdural hematoma * 1  1/71 (1.41%) 
1
Term from vocabulary, CTCAE (2.0)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
All Trial Participants
Affected / at Risk (%)
Total   0/0 
Per the protocol, non-serious adverse events were not captured as this was a high-dose transplant study and grades 1,2, and 3 adverse events were expected. No unexpected toxicities were seen beyond those reported in the Serious Adverse Event section.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Thomas Shea
Organization: UNC Lineberger Comprehensive Cancer Center
Phone: 919-966-7746
Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00448201     History of Changes
Other Study ID Numbers: LCCC 0306
P30CA016086 ( U.S. NIH Grant/Contract )
First Submitted: March 14, 2007
First Posted: March 16, 2007
Results First Submitted: April 17, 2017
Results First Posted: May 30, 2017
Last Update Posted: May 30, 2017