Trial Outcomes & Findings for Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402) (NCT NCT00406393)

Last Updated: 2023-01-04

Results Overview

The primary objective is to compare rates of 114-day Grades II-IV acute GVHD-free survival post randomization for HLA-matched, related donor allogeneic peripheral blood stem cell transplantation using two different GVHD prophylaxis regimens. Participants are graded on a scale of 1 to 4 according to their symptoms and organs involved, where 4 represents a worse grade.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

304 participants

Primary outcome timeframe

Day 114

Results posted on

2023-01-04

Participant Flow

Participants were enrolled from 2006 to 2011 from 24 different transplant centers.

Participant milestones

Participant milestones
Measure	Tacrolimus/Sirolimus Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Overall Study STARTED	151	153
Overall Study COMPLETED	149	152
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Tacrolimus/Sirolimus Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Overall Study Did not undergo transplantation	2	1

Baseline Characteristics

Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tacrolimus/Sirolimus n=151 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=153 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.	Total n=304 Participants Total of all reporting groups
Age, Continuous	45 years n=5 Participants	43 years n=7 Participants	44 years n=5 Participants
Sex: Female, Male Female	74 Participants n=5 Participants	68 Participants n=7 Participants	142 Participants n=5 Participants
Sex: Female, Male Male	77 Participants n=5 Participants	85 Participants n=7 Participants	162 Participants n=5 Participants
Primary Disease Acute Myelogenous Leukemia (AML)	71 participants n=5 Participants	63 participants n=7 Participants	134 participants n=5 Participants
Primary Disease Acute Lymphoblastic Leukemia (ALL)	51 participants n=5 Participants	68 participants n=7 Participants	119 participants n=5 Participants
Primary Disease Chronic Myelogenous Leukemia (CML)	9 participants n=5 Participants	14 participants n=7 Participants	23 participants n=5 Participants
Primary Disease Myelodysplastic Syndrome (MDS)	19 participants n=5 Participants	7 participants n=7 Participants	26 participants n=5 Participants
Primary Disease Acute Biphenotypic Leukemia (ABL)	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Disease Status at Transplantation AML 1st Complete Remission	60 participants n=5 Participants	56 participants n=7 Participants	116 participants n=5 Participants
Disease Status at Transplantation AML 2nd Complete Remission	11 participants n=5 Participants	7 participants n=7 Participants	18 participants n=5 Participants
Disease Status at Transplantation ALL 1st Complete Remission	41 participants n=5 Participants	55 participants n=7 Participants	96 participants n=5 Participants
Disease Status at Transplantation ALL 2nd Complete Remission	10 participants n=5 Participants	13 participants n=7 Participants	23 participants n=5 Participants
Disease Status at Transplantation CML 1st Complete Remission	7 participants n=5 Participants	10 participants n=7 Participants	17 participants n=5 Participants
Disease Status at Transplantation CML 2nd Complete Remission	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Disease Status at Transplantation ABL 1st Complete Remission	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Disease Status at Transplantation MDS	19 participants n=5 Participants	7 participants n=7 Participants	26 participants n=5 Participants
Karnofsky Score Scores 90 - 100	101 participants n=5 Participants	116 participants n=7 Participants	217 participants n=5 Participants
Karnofsky Score Scores < 90	50 participants n=5 Participants	37 participants n=7 Participants	87 participants n=5 Participants
Recipient-Donor Cytomegalovirus Status +/+	59 participants n=5 Participants	47 participants n=7 Participants	106 participants n=5 Participants
Recipient-Donor Cytomegalovirus Status +/-	14 participants n=5 Participants	24 participants n=7 Participants	38 participants n=5 Participants
Recipient-Donor Cytomegalovirus Status -/+	30 participants n=5 Participants	44 participants n=7 Participants	74 participants n=5 Participants
Recipient-Donor Cytomegalovirus Status -/-	38 participants n=5 Participants	30 participants n=7 Participants	68 participants n=5 Participants
Recipient-Donor Cytomegalovirus Status Missing	10 participants n=5 Participants	8 participants n=7 Participants	18 participants n=5 Participants
Conditioning Regimen Cyclophosphamide/Total Body Irradiation	124 participants n=5 Participants	122 participants n=7 Participants	246 participants n=5 Participants
Conditioning Regimen Etoposide/Total Body Irradiation	27 participants n=5 Participants	31 participants n=7 Participants	58 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 114

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Rate of Grades II-IV Acute GVHD-free Survival	67 percentage of participants Interval 59.0 to 74.0	62 percentage of participants Interval 54.0 to 70.0

SECONDARY outcome

Timeframe: Measured at Day 100

Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation.

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Incidence of Acute GVHD	26 percentage of participants Interval 19.0 to 34.0	34 percentage of participants Interval 26.0 to 41.0

SECONDARY outcome

Timeframe: Measured through Day 100

Neutrophil engraftment is defined as achieving an Absolute Neutrophil Count (ANC) \> 500/mcL for three consecutive measurements on different days. Platelet engraftment is defined as a platelet count \> 20,000/mcL for three consecutive measurements over three or more days.

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Time to Neutrophil and Platelet Engraftment Neutrophil Engraftment	14 days Interval 8.0 to 27.0	16 days Interval 10.0 to 68.0
Time to Neutrophil and Platelet Engraftment Platelet Engraftment	16 days Interval 7.0 to 100.0	19 days Interval 9.0 to 100.0

SECONDARY outcome

Timeframe: Measured at Day 21

Mucositis severity will be scored per the modified Oral Mucositis Assessment Scale (OMAS) scoring system on a scale of 0 - 4, where 0 equals normal mucosa and 4 represents severe mucosa.

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Mucositis Severity	0.31 units on a scale Standard Deviation 0.28	0.47 units on a scale Standard Deviation 0.40

SECONDARY outcome

Timeframe: Measured through Day 100

VOD will be defined as the occurrence of VOD (based on the Baltimore Criteria for the diagnosis of VOD) in conjunction with other end-organ dysfunction.

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Rate of Veno-occlusive Disease (VOD)	11 percentage of participants Interval 6.0 to 16.0	5 percentage of participants Interval 2.0 to 9.0

SECONDARY outcome

Timeframe: Measured through Day 100

The occurrence of TMA within the first 100 days after stem cell transplantation will be recorded. The first day of onset will be used for reporting purposes.

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Thrombotic Microangiopathy (TMA) Infection	5 percentage of participants Interval 3.0 to 10.0	1 percentage of participants Interval 0.0 to 4.0

SECONDARY outcome

Timeframe: Measured at Year 2

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Reactivation of Cytomegalovirus (CMV) Infection	13 percentage of participants Interval 9.0 to 19.0	15 percentage of participants Interval 10.0 to 21.0

SECONDARY outcome

Timeframe: Measured at Day 100 and Year 2

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Treatment-related Mortality Day 100	7 percentage of participants Interval 3.0 to 11.0	7 percentage of participants Interval 4.0 to 12.0
Treatment-related Mortality Year 2	20 percentage of participants Interval 13.0 to 26.0	16 percentage of participants Interval 11.0 to 23.0

SECONDARY outcome

Timeframe: Measured at Year 2

Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, MDS or CMML consistent with pre-transplant features.

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Malignant Disease Relapse	28 percentage of participants Interval 20.0 to 35.0	29 percentage of participants Interval 22.0 to 37.0

SECONDARY outcome

Timeframe: Measured at Year 2

Outcome measures

Outcome measures
Measure	Tacrolimus/Sirolimus n=149 Participants Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 Participants Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Overall Survival	59 percentage of participants Interval 51.0 to 67.0	63 percentage of participants Interval 55.0 to 70.0

SECONDARY outcome

Timeframe: Measured at Year 2

Population: Insufficient data to report on this outcome measure

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Measured at Year 2

Population: Insufficient data to report on this outcome measure

Outcome measures

Outcome data not reported

Adverse Events

Tacrolimus/Sirolimus

Serious events: 9 serious events

Other events: 0 other events

Deaths: 0 deaths

Tacrolimus/Methotrexate

Serious events: 12 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

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

Measure	Tacrolimus/Sirolimus n=149 participants at risk Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.	Tacrolimus/Methotrexate n=152 participants at risk Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Psychiatric disorders Mental status changes	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
General disorders Death	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Vascular disorders Embolism	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Nervous system disorders Aphasia	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Surgical and medical procedures Thoracotomy	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Eye disorders Retinal tear	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
General disorders Chest pain	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Infections and infestations Staphylococcal infection	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.67% 1/149 • Number of events 1 • 2-years post transplant Serious adverse events 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.	0.00% 0/152 • 2-years post transplant Serious adverse events 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.
Nervous system disorders Cerebrovascular accident	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Cardiac disorders Pericardial effusion	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Nervous system disorders VIIth nerve paralysis	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Infections and infestations Septic shock	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Eye disorders Glaucoma	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Hepatobiliary disorders Cholecystitis	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Cardiac disorders Supraventricular tachycardia	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.
Nervous system disorders Neuropathy peripheral	0.00% 0/149 • 2-years post transplant Serious adverse events 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.	0.66% 1/152 • Number of events 1 • 2-years post transplant Serious adverse events 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.