Trial Outcomes & Findings for Allogeneic Hematopoietic Cell Transplantation for Patients With Busulfex-based Regimen (NCT NCT00448357)
NCT ID: NCT00448357
Last Updated: 2017-07-17
Results Overview
Relapse is defined as new or increased sites of disease or positive one marrow after a complete response (CR). The RFS was calculated as the percentage of patients who were alive and without relapse at 3 years
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
54 participants
Primary outcome timeframe
Three years post-transplant
Results posted on
2017-07-17
Participant Flow
Patients with advanced, refractory, or high-risk hematologic cancers who were deemed suitable for myeloablative conditioning were recruited from one institution.
A total of 55 subjects were consented, but one subject was not enrolled due to disease progression or death prior to protocol therapy.
Participant milestones
| Measure |
Experimental: GVHD Prophylaxis
Experimental: GVHD prophylaxis
Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine .
Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
|
|---|---|
|
Overall Study
STARTED
|
54
|
|
Overall Study
COMPLETED
|
54
|
|
Overall Study
NOT COMPLETED
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Allogeneic Hematopoietic Cell Transplantation for Patients With Busulfex-based Regimen
Baseline characteristics by cohort
| Measure |
Experimental: GVHD Prophylaxis
n=54 Participants
Experimental: GVHD prophylaxis
Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine .
Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
|
|---|---|
|
Age, Continuous
|
50 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
20 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
34 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
3 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
48 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
2 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
54 participants
n=5 Participants
|
|
Donor-recipient sex
Male-Female
|
6 Participants
n=5 Participants
|
|
Donor-recipient sex
Female-Male
|
12 Participants
n=5 Participants
|
|
Donor-recipient sex
Male-Male
|
22 Participants
n=5 Participants
|
|
Donor-recipient sex
Female-Female
|
14 Participants
n=5 Participants
|
|
Host cytomegalovirus (CMV) status
Negative
|
18 Participants
n=5 Participants
|
|
Host cytomegalovirus (CMV) status
Positive
|
36 Participants
n=5 Participants
|
|
Disease histology
Myelogenous leukemia
|
26 Participants
n=5 Participants
|
|
Disease histology
Myelodysplasia
|
8 Participants
n=5 Participants
|
|
Disease histology
Chronic myelogenous leukemia
|
1 Participants
n=5 Participants
|
|
Disease histology
Acute lymphoblastic leukemia
|
7 Participants
n=5 Participants
|
|
Disease histology
Non-Hodgkin Lymphoma
|
5 Participants
n=5 Participants
|
|
Disease histology
Hodgkin lymphoma
|
2 Participants
n=5 Participants
|
|
Disease histology
Myelofibrosis
|
1 Participants
n=5 Participants
|
|
Disease histology
Chronic lymphoblastic leukemia
|
1 Participants
n=5 Participants
|
|
Disease histology
Chronic myelomonocytic leukemia
|
1 Participants
n=5 Participants
|
|
Disease histology
Plastic cell leukemia
|
2 Participants
n=5 Participants
|
|
Type of transplant
Matched unrelated donor (MUD)
|
34 Participants
n=5 Participants
|
|
Type of transplant
Matched unrelated donor (MRD)
|
20 Participants
n=5 Participants
|
|
Disease risk
Low
|
16 Participants
n=5 Participants
|
|
Disease risk
Intermediate
|
20 Participants
n=5 Participants
|
|
Disease risk
High
|
18 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Three years post-transplantPopulation: Because AUC levels varied between the groups and the goal was to identify an actual achieved AUC-based dose, additional outcome analyses were undertaken by dividing patients into thirds according to the actual AUCs delivered rather than the original planned AUCs.
Relapse is defined as new or increased sites of disease or positive one marrow after a complete response (CR). The RFS was calculated as the percentage of patients who were alive and without relapse at 3 years
Outcome measures
| Measure |
Low Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 5078 (full range 3933-5615) microM/min
|
Intermediate Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 6372 (full range 5639-6965) microM/min
|
High Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 7605 (full range 7054-8863) microM/min
|
Dose Level 4
Target AUC/24 hrs of 7603 uM-min+/- 15%
|
Dose Level 5
Target AUC/24 hrs of 8363 uM-min+/- 15%
|
|---|---|---|---|---|---|
|
Three-year Relapse-free Survival (RFS) Rate at the Maximum Tolerated Dose Identified During Phase I of the Trial (Target AUC 6912)
|
22 percentage of participants
|
39 percentage of participants
|
43 percentage of participants
|
—
|
—
|
PRIMARY outcome
Timeframe: first 6 weeks or 42 days following stem cell infusionDose limiting toxicity will be defined as any irreversible grade 3 or any grade 4 non-hematologic toxicity that is related to busulfan infusion and not graft vs host disease or late infection after recovery from the initial period of myelosuppression. The maximum tolerated dose (MTD) is defined as the dose with probability of dose limiting toxicity (DLT) of 0.25. The dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine and alemtuzumab plus tacrolimus for GVHD prophylaxis.
Outcome measures
| Measure |
Low Busulfan AUC Tertile
n=14 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 5078 (full range 3933-5615) microM/min
|
Intermediate Busulfan AUC Tertile
n=7 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 6372 (full range 5639-6965) microM/min
|
High Busulfan AUC Tertile
n=24 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 7605 (full range 7054-8863) microM/min
|
Dose Level 4
n=7 Participants
Target AUC/24 hrs of 7603 uM-min+/- 15%
|
Dose Level 5
n=2 Participants
Target AUC/24 hrs of 8363 uM-min+/- 15%
|
|---|---|---|---|---|---|
|
Number of Participants With Dose Limiting Toxicities (DLTs)
|
1 DLTs
|
1 DLTs
|
1 DLTs
|
2 DLTs
|
2 DLTs
|
SECONDARY outcome
Timeframe: Day -15 to Day -11Test doses of busulfan were administered and plasma levels were measured to determine a targeted AUC dosing estimate. The capacity is reported as the precision with which these test dose goals predicted the actual 90-hour mean AUC levels.Dose targeting precision was estimated by root mean squared error.
Outcome measures
| Measure |
Low Busulfan AUC Tertile
n=14 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 5078 (full range 3933-5615) microM/min
|
Intermediate Busulfan AUC Tertile
n=7 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 6372 (full range 5639-6965) microM/min
|
High Busulfan AUC Tertile
n=24 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 7605 (full range 7054-8863) microM/min
|
Dose Level 4
n=7 Participants
Target AUC/24 hrs of 7603 uM-min+/- 15%
|
Dose Level 5
n=2 Participants
Target AUC/24 hrs of 8363 uM-min+/- 15%
|
|---|---|---|---|---|---|
|
Capacity of Test Dosing of Busulfan That Would Result in the Desired Area Under the Curve Concentration Exposure of Patients Receiving a Full-dose Busulfan Regimen
|
11.7 percentage of error
|
4.9 percentage of error
|
10.2 percentage of error
|
11.1 percentage of error
|
15.9 percentage of error
|
SECONDARY outcome
Timeframe: 100 days post transplantPopulation: Because AUC levels varied between the groups and the goal was to identify an actual achieved AUC-based dose, additional outcome analyses were undertaken by dividing patients into thirds according to the actual AUCs delivered rather than the original planned AUCs.
GVHD can be mild, moderate or severe depending on the differences in tissue type between patient and donor. GVHD can be acute or chronic. 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
Outcome measures
| Measure |
Low Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 5078 (full range 3933-5615) microM/min
|
Intermediate Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 6372 (full range 5639-6965) microM/min
|
High Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 7605 (full range 7054-8863) microM/min
|
Dose Level 4
Target AUC/24 hrs of 7603 uM-min+/- 15%
|
Dose Level 5
Target AUC/24 hrs of 8363 uM-min+/- 15%
|
|---|---|---|---|---|---|
|
Incidence of Graft vs Host Disease in Patients Between One Month and Two Years Post Transplant
Acute GVHD grade >=II
|
7 Participants
|
10 Participants
|
11 Participants
|
—
|
—
|
|
Incidence of Graft vs Host Disease in Patients Between One Month and Two Years Post Transplant
Acute GVHD grades III and IV
|
2 Participants
|
4 Participants
|
3 Participants
|
—
|
—
|
|
Incidence of Graft vs Host Disease in Patients Between One Month and Two Years Post Transplant
Chronic GVHD; intermediate/severe
|
4 Participants
|
6 Participants
|
2 Participants
|
—
|
—
|
SECONDARY outcome
Timeframe: 30 days post transplantPopulation: Because there were no differences in chimerism results as a function of either the immunosuppression used or busulfan dose received, the results are being reported only for the total population.
Deoxyribonucleic acid (DNA) chimerism is a measure identifying the genetic profiles of the transplant recipient and of the donor and then evaluating the extent of mixture in the recipient's blood, bone marrow, or other tissue.
Outcome measures
| Measure |
Low Busulfan AUC Tertile
n=54 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 5078 (full range 3933-5615) microM/min
|
Intermediate Busulfan AUC Tertile
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 6372 (full range 5639-6965) microM/min
|
High Busulfan AUC Tertile
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 7605 (full range 7054-8863) microM/min
|
Dose Level 4
Target AUC/24 hrs of 7603 uM-min+/- 15%
|
Dose Level 5
Target AUC/24 hrs of 8363 uM-min+/- 15%
|
|---|---|---|---|---|---|
|
Incidence of DNA Chimerism in Patients Between One Month Post Transplant
Whole blood chimerism-Any
|
49 Participants
|
—
|
—
|
—
|
—
|
|
Incidence of DNA Chimerism in Patients Between One Month Post Transplant
Whole blood chimerism->=95% donor
|
47 Participants
|
—
|
—
|
—
|
—
|
|
Incidence of DNA Chimerism in Patients Between One Month Post Transplant
T Cell chimerism-Any
|
46 Participants
|
—
|
—
|
—
|
—
|
|
Incidence of DNA Chimerism in Patients Between One Month Post Transplant
T Cell chimerism>=95% donor
|
30 Participants
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Three years post-transplantPopulation: Because AUC levels varied between the groups and the goal was to identify an actual achieved AUC-based dose, additional outcome analyses were undertaken by dividing patients into thirds according to the actual AUCs delivered rather than the original planned AUCs.
Percentage of participants alive at 3 years post transplant
Outcome measures
| Measure |
Low Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 5078 (full range 3933-5615) microM/min
|
Intermediate Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 6372 (full range 5639-6965) microM/min
|
High Busulfan AUC Tertile
n=18 Participants
Participants with the lowest tertile of measured busulfan Area under the curve (AUC); with a mean value of 7605 (full range 7054-8863) microM/min
|
Dose Level 4
Target AUC/24 hrs of 7603 uM-min+/- 15%
|
Dose Level 5
Target AUC/24 hrs of 8363 uM-min+/- 15%
|
|---|---|---|---|---|---|
|
Overall Survival
|
28 percentage of participants
|
39 percentage of participants
|
55 percentage of participants
|
—
|
—
|
Adverse Events
Experimental: GVHD Prophylaxis
Serious events: 26 serious events
Other events: 54 other events
Deaths: 15 deaths
Serious adverse events
| Measure |
Experimental: GVHD Prophylaxis
n=54 participants at risk
Experimental: GVHD prophylaxis
Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine .
Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
|
|---|---|
|
Infections and infestations
BK cystitis
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Hepatobiliary disorders
Liver Failiure
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Infections and infestations
Sepsis
|
7.4%
4/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Gastrointestinal disorders
Gr 4 GVHD
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Gastrointestinal disorders
Gr 4 mucositis
|
9.3%
5/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Hepatobiliary disorders
Veno-occlusive disease
|
5.6%
3/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Infections and infestations
Aspergillus pneumonia
|
3.7%
2/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Infections and infestations
CMV pneumonitis
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Blood and lymphatic system disorders
Graft Failure
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Respiratory, thoracic and mediastinal disorders
Diffuse alveolar hemorrhage
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Blood and lymphatic system disorders
anemia
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Blood and lymphatic system disorders
thrombocytopenia
|
7.4%
4/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Respiratory, thoracic and mediastinal disorders
acute respiratory failure
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Renal and urinary disorders
renal Failure
|
3.7%
2/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Vascular disorders
left neck hematoma
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Endocrine disorders
Glucose Intolerance
|
1.9%
1/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
Other adverse events
| Measure |
Experimental: GVHD Prophylaxis
n=54 participants at risk
Experimental: GVHD prophylaxis
Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine .
Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
|
|---|---|
|
Blood and lymphatic system disorders
grade 3 or 4 hematologic toxicities (expected)
|
100.0%
54/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Skin and subcutaneous tissue disorders
Alopecia
|
100.0%
54/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
|
Gastrointestinal disorders
grade 3 GI toxicity
|
38.9%
21/54 • Mortality was assessed at one year
Additional toxicities were not captured as this was a high-dose transplant study and grades 1, 2 and 3 AEs were generally expected and no unexpected toxicities were seen beyond those reported as SAEs
|
Additional Information
Dr. Thomas Shea
UNC Lineberger Comprehensive Cancer Center
Phone: 919-966-7746
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place