Trial Outcomes & Findings for Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301) (NCT NCT00326417)

Last Updated: 2021-10-28

Results Overview

DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10\^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

97 participants

Primary outcome timeframe

Day 100

Results posted on

2021-10-28

Participant Flow

Participants were enrolled from February 2006 to August 2007 for Phase I of the trial. Phase II opened in November 2007 and closed to accrual on December 2, 2013.

Participant milestones

Participant milestones
Measure	Cyclophosphamide 150mg Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 100mg Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Fludarabine Fludarabine only (no Cyclophosphamide administered)
Overall Study STARTED	14	41	39	3
Overall Study Phase I	6	6	6	3
Overall Study Phase II	8	35	33	0
Overall Study COMPLETED	0	41	38	0
Overall Study NOT COMPLETED	14	0	1	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Cyclophosphamide 150mg Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Fludarabine Fludarabine only (no Cyclophosphamide administered)
Overall Study Withdrawal by Subject	0	1	0
Overall Study Arm Closed	7	0	3
Overall Study Death	7	0	0

Baseline Characteristics

Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cyclophosphamide 100mg n=41 Participants Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 Participants Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Total n=79 Participants Total of all reporting groups
Age, Continuous	17.6 years n=5 Participants	24.5 years n=7 Participants	20.6 years n=5 Participants
Age, Customized < 18	21 participants n=5 Participants	11 participants n=7 Participants	32 participants n=5 Participants
Age, Customized 18 - 40	14 participants n=5 Participants	18 participants n=7 Participants	32 participants n=5 Participants
Age, Customized > 40	6 participants n=5 Participants	9 participants n=7 Participants	15 participants n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants	19 Participants n=7 Participants	39 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	19 Participants n=7 Participants	40 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	34 participants n=5 Participants	30 participants n=7 Participants	64 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	6 participants n=5 Participants	8 participants n=7 Participants	14 participants n=5 Participants
Race/Ethnicity, Customized Unknown	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Recipient Cytomegalovirus Status Positive	26 participants n=5 Participants	17 participants n=7 Participants	43 participants n=5 Participants
Recipient Cytomegalovirus Status Negative	15 participants n=5 Participants	21 participants n=7 Participants	36 participants n=5 Participants
Karnofsky Score 100	18 participants n=5 Participants	12 participants n=7 Participants	30 participants n=5 Participants
Karnofsky Score 90	15 participants n=5 Participants	17 participants n=7 Participants	32 participants n=5 Participants
Karnofsky Score 80	3 participants n=5 Participants	7 participants n=7 Participants	10 participants n=5 Participants
Karnofsky Score 70	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
Karnofsky Score 60	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Immunosuppressive therapy prior to transplant Yes	41 participants n=5 Participants	35 participants n=7 Participants	76 participants n=5 Participants
Immunosuppressive therapy prior to transplant No	0 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants
Donor-recipient HLA match HLA-A, -B, -C,-DRB1 matched	27 participants n=5 Participants	31 participants n=7 Participants	58 participants n=5 Participants
Donor-recipient HLA match Single HLA-locus mismatch	14 participants n=5 Participants	7 participants n=7 Participants	21 participants n=5 Participants
Type of anti-thymocyte globulin administered Rabbit-derived	33 participants n=5 Participants	29 participants n=7 Participants	62 participants n=5 Participants
Type of anti-thymocyte globulin administered Horse-derived	7 participants n=5 Participants	9 participants n=7 Participants	16 participants n=5 Participants
Type of anti-thymocyte globulin administered None	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 100

Outcome measures

Outcome measures
Measure	Cyclophosphamide 100mg n=41 Participants Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 Participants Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Disease-free Survival (DFS) Graft Failure	6 participants	3 participants
Disease-free Survival (DFS) Major RRT	9 participants	4 participants
Disease-free Survival (DFS) Survival	39 participants	37 participants
Disease-free Survival (DFS) Alive and engrafted	35 participants	35 participants

SECONDARY outcome

Timeframe: Day 365

Primary and secondary graft failure are included, secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in the ANC to less than 0.5 x 10\^9/L for three consecutive measurements on different days, unresponsive to growth factor.

Outcome measures

Outcome measures
Measure	Cyclophosphamide 100mg n=41 Participants Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 Participants Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Cumulative Incidence of Graft Failure	14.6 percentage of participants	11.7 percentage of participants

SECONDARY outcome

Timeframe: Day 100

All GVHD grades 2-4 will be graded according to the BMT CTN Manual of Procedures (MOP)

Outcome measures

Outcome measures
Measure	Cyclophosphamide 100mg n=41 Participants Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 Participants Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Acute Graft vs Host Disease (GVHD)	26.8 percentage of participants Interval 13.0 to 40.6	23.7 percentage of participants Interval 10.0 to 37.4

SECONDARY outcome

Timeframe: Day 365

Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.

Outcome measures

Outcome measures
Measure	Cyclophosphamide 100mg n=41 Participants Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 Participants Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Chronic GVHD	31.7 percentage of participants Interval 18.1 to 46.2	22.5 percentage of participants Interval 10.3 to 37.5

SECONDARY outcome

Timeframe: Day 365

OS is defined as alive at 1 year, the event is death from any cause. Patients alive at the time of last observation, for statistical purposes, will have a survival time which is censored.

Outcome measures

Outcome measures
Measure	Cyclophosphamide 100mg n=41 Participants Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 Participants Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Overall Survival (OS)	80.5 percentage of participants Interval 64.8 to 89.7	97.4 percentage of participants Interval 82.8 to 99.6

Adverse Events

Cyclophosphamide 150mg

Serious events: 8 serious events

Other events: 0 other events

Deaths: 0 deaths

Cyclophosphamide 100mg

Serious events: 4 serious events

Other events: 1 other events

Deaths: 0 deaths

Cyclophosphamide 50mg

Serious events: 4 serious events

Other events: 0 other events

Deaths: 0 deaths

Fludarabine

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cyclophosphamide 150mg n=14 participants at risk Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 100mg n=41 participants at risk Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 participants at risk Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Fludarabine n=3 participants at risk Fludarabine only (no Cyclophosphamide administered)
Eye disorders Papilloedema	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/41 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/38 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	33.3% 1/3 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastasis	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.4% 1/41 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/38 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Cerebral ischaemia	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.4% 1/41 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/38 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Nervous system disorders Somnolence	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/41 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.6% 1/38 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Respiratory, thoracic and mediastinal disorders Pleural effusion	7.1% 1/14 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/41 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/38 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Vascular disorders Deep vein thrombosis	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/41 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.6% 1/38 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/41 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.6% 1/38 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
General disorders Death	50.0% 7/14 • Number of events 7 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	4.9% 2/41 • Number of events 2 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.6% 1/38 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.

Other adverse events

Other adverse events
Measure	Cyclophosphamide 150mg n=14 participants at risk Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 100mg n=41 participants at risk Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Cyclophosphamide 50mg n=38 participants at risk Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Fludarabine n=3 participants at risk Fludarabine only (no Cyclophosphamide administered)
Cardiac disorders Pericardial effusion	0.00% 0/14 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	2.4% 1/41 • Number of events 1 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/38 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.	0.00% 0/3 • 1 year post-transplant Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.

Additional Information

Adam Mendizabal, PhD

The Emmes Corporation

Phone: 301-251-1161

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place