Trial Outcomes & Findings for A Study to Evaluate Steroid-free Treatment for Standard-Risk aGVHD (BMT CTN 1501) (NCT NCT02806947)

NCT ID: NCT02806947

Last Updated: 2021-11-01

Results Overview

Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below: Skin stage: 0: No rash 1. Rash \<25% of body surface area (BSA) 2. Rash on 25-50% of BSA 3. Rash on \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 127 participants
• Primary outcome timeframe: Days 28 and 56 Post-randomization
• Results posted on: 2021-11-01

Participant Flow

The primary analysis population includes only participants with an AA score of 1 or 2 (n=64 on the prednisone arm, n=58 on the sirolimus arm). Three participants on the prednisone arm and two on the sirolimus arm were excluded because they had an AA score of 3 or missing.

Participant milestones

Measure	Sirolimus Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Overall Study STARTED	58	64
Overall Study COMPLETED	53	63
Overall Study NOT COMPLETED	5	1

Reasons for withdrawal

Measure	Sirolimus Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Overall Study Withdrawal by Subject	5	1

Baseline Characteristics

A Study to Evaluate Steroid-free Treatment for Standard-Risk aGVHD (BMT CTN 1501)

Baseline characteristics by cohort

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.	Total n=122 Participants Total of all reporting groups
Age, Continuous	58.0 years n=5 Participants	52.4 years n=7 Participants	54.6 years n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	31 Participants n=7 Participants	52 Participants n=5 Participants
Sex: Female, Male Male	37 Participants n=5 Participants	33 Participants n=7 Participants	70 Participants n=5 Participants
Race/Ethnicity, Customized American Indian / Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Hawaiian/Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized White	55 Participants n=5 Participants	59 Participants n=7 Participants	114 Participants n=5 Participants
Race/Ethnicity, Customized Multiracial	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ann Arbor Biomarker Risk Score 1	38 Participants n=5 Participants	45 Participants n=7 Participants	83 Participants n=5 Participants
Ann Arbor Biomarker Risk Score 2	20 Participants n=5 Participants	19 Participants n=7 Participants	39 Participants n=5 Participants
Skin Abnormalities at Enrollment No active GVHD rash	20 Participants n=5 Participants	19 Participants n=7 Participants	39 Participants n=5 Participants
Skin Abnormalities at Enrollment Maculopapular Rash <25% body surface area	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Skin Abnormalities at Enrollment Maculopapular Rash 25-50% body surface area	14 Participants n=5 Participants	13 Participants n=7 Participants	27 Participants n=5 Participants
Skin Abnormalities at Enrollment Maculopapular Rash >50% body surface area	16 Participants n=5 Participants	21 Participants n=7 Participants	37 Participants n=5 Participants
Upper GI Abnormalities at Enrollment No or Intermittent Nausea, Vomiting, or Anorexia	32 Participants n=5 Participants	36 Participants n=7 Participants	68 Participants n=5 Participants
Upper GI Abnormalities at Enrollment Persistent Nausea, Vomiting, or Anorexia	26 Participants n=5 Participants	28 Participants n=7 Participants	54 Participants n=5 Participants
Lower GI Abnormalities at Enrollment No Diarrhea	53 Participants n=5 Participants	46 Participants n=7 Participants	99 Participants n=5 Participants
Lower GI Abnormalities at Enrollment Adult: <500 mL/day, Child: <10mL/kg/day	3 Participants n=5 Participants	10 Participants n=7 Participants	13 Participants n=5 Participants
Lower GI Abnormalities at Enrollment Adult: 500-999mL/day, Child: 10-19.9mL/kg/day	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Lower GI Abnormalities at Enrollment Adult: 1000-1500mL/day, Child: 20-30mL/kg/day	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Liver Abnormalities at Enrollment Bilirubin <2.0mg/dL	58 Participants n=5 Participants	63 Participants n=7 Participants	121 Participants n=5 Participants
Liver Abnormalities at Enrollment Bilirubin 2.0-3.0mg/dL	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Days 28 and 56 Post-randomization

Population: CR/PR was evaluated in participants remaining on study until the assessment time point. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.

Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below:

Skin stage:

0: No rash

1. Rash <25% of body surface area (BSA)

2. Rash on 25-50% of BSA

3. Rash on >50% of BSA

4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level):

0: <2 mg/dL

1. 2-3 mg/dL

2. 3.01-6 mg/dL

3. 6.01-15.0 mg/dL

4. >15 mg/dL

GI stage:

0: No diarrhea or diarrhea <500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD

2. Diarrhea 1000-1499 mL/day

3. Diarrhea >1500 mL/day

4. Severe abdominal pain with or without ileus

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment CR/PR at Day 28 · Yes	35 Participants	46 Participants
Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment CR/PR at Day 28 · No	19 Participants	17 Participants
Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment CR/PR at Day 56 · Yes	34 Participants	50 Participants
Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment CR/PR at Day 56 · No	19 Participants	13 Participants

SECONDARY outcome

Timeframe: Day 28 Post-randomization

Population: The endpoint was evaluated only in participants that remained on study until Day 28. One participant on the prednisone arm and four on the sirolimus arm were deemed unevaluable at Day 28 due to prior study withdrawal.

The proportion of patients with CR/PR and on a prednisone-equivalent steroid dose of 0.25 mg/kg/day or less is evaluated. CR/PR scoring is in comparison to acute GVHD status at randomization. CR is defined as staging of 0 in all target organs. PR is defined as improvement in some organ(s) without worsening in others. Death and initiation of steroid-free, systemic acute GVHD treatment beyond randomized therapy are considered failures for this endpoint. Organ staging is defined as:

Skin stage:

0: No rash

1. Rash <25% of body surface area (BSA)

2. Rash 25-50% of BSA

3. Rash >50% of BSA

4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level in mg/dL):

0: <2

1. 2-3

2. 3.01-6

3. 6.01-15.0

4. >15 mg/dL

GI stage:

0: No diarrhea or diarrhea <500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD

2. Diarrhea 1000-1499 mL/day

3. Diarrhea >1500 mL/day

4. Severe abdominal pain with or without ileus

Outcome measures

Measure	Sirolimus n=54 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=63 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day Yes	36 Participants	20 Participants
Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day No	18 Participants	43 Participants

SECONDARY outcome

Timeframe: Days 28 and 56 Post-randomization

Population: Acute GVHD response was evaluated in participants remaining on study until the assessment day. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.

Acute GVHD response is classified as CR, PR, mixed response (MR), no response (NR), and progression and scored by comparison to acute GVHD status at randomization. MR is defined as improvement in some organ(s) with worsening in another, progression as worsening in some organ(s) without improvement in others, and NR as absence of any improvement or worsening. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as:

Skin stage:

0: No rash

1. Rash <25% of body surface area (BSA)

2. Rash 25-50% of BSA

3. Rash >50% of BSA

4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level in mg/dL):

0: <2

1. 2-3

2. 3.01-6

3. 6.01-15.0

4. >15

GI stage:

0: No diarrhea or diarrhea <500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD

2. Diarrhea 1000-1499 mL/day

3. Diarrhea >1500 mL/day

4. Severe abdominal pain with or without ileus

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Acute GVHD Response Acute GVHD Response at Day 28 · Complete Response (CR)	30 Participants	39 Participants
Acute GVHD Response Acute GVHD Response at Day 28 · Partial Response (PR)	5 Participants	7 Participants
Acute GVHD Response Acute GVHD Response at Day 28 · Mixed Response (MR)	1 Participants	5 Participants
Acute GVHD Response Acute GVHD Response at Day 28 · No Response (NR)	16 Participants	11 Participants
Acute GVHD Response Acute GVHD Response at Day 28 · Progression	2 Participants	1 Participants
Acute GVHD Response Acute GVHD Response at Day 56 · Complete Response (CR)	30 Participants	48 Participants
Acute GVHD Response Acute GVHD Response at Day 56 · Partial Response (PR)	4 Participants	2 Participants
Acute GVHD Response Acute GVHD Response at Day 56 · Mixed Response (MR)	0 Participants	0 Participants
Acute GVHD Response Acute GVHD Response at Day 56 · No Response (NR)	19 Participants	10 Participants
Acute GVHD Response Acute GVHD Response at Day 56 · Progression	0 Participants	3 Participants

SECONDARY outcome

Timeframe: Days 28 and 56 Post-randomization

Population: Treatment failure was evaluated in participants remaining on study until the assessment day. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.

Treatment failure is defined as either no response (NR) or progression and scored by comparison to acute GVHD status at randomization. Progression is defined as worsening in some target organ(s) without improvement in others and NR is defined as absence of any improvement or worsening in target organs. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as:

Skin stage:

0: No rash

1. Rash <25% of body surface area (BSA)

2. Rash 25-50% of BSA

3. Rash >50% of BSA

4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level in mg/dL):

0: <2

1. 2-3

2. 3.01-6

3. 6.01-15.0

4. >15

GI stage:

0: No diarrhea or diarrhea <500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD

2. Diarrhea 1000-1499 mL/day

3. Diarrhea >1500 mL/day

4. Severe abdominal pain with or without ileus

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Treatment Failure Treatment Failure at Day 28 · Yes	18 Participants	12 Participants
Percentage of Participants With Treatment Failure Treatment Failure at Day 28 · No	36 Participants	51 Participants
Percentage of Participants With Treatment Failure Treatment Failure at Day 56 · Yes	19 Participants	13 Participants
Percentage of Participants With Treatment Failure Treatment Failure at Day 56 · No	34 Participants	50 Participants

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

Overall survival is defined as survival of death from any cause.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Overall Survival Overall Survival at 6 Months	81.9 percentage of participants Interval 68.9 to 89.8	82.7 percentage of participants Interval 71.0 to 90.0
Percentage of Participants With Overall Survival Overall Survival at 12 Months	76.3 percentage of participants Interval 62.7 to 85.5	73.2 percentage of participants Interval 60.4 to 82.4

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Disease-free Survival Disease-free Survival at 6 Months	72.8 percentage of participants Interval 58.9 to 82.6	78.1 percentage of participants Interval 65.9 to 86.4
Percentage of Participants With Disease-free Survival Disease-free Survival at 12 Months	61.6 percentage of participants Interval 47.4 to 73.0	70.2 percentage of participants Interval 57.3 to 79.8

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Proportion of Participants With Event-free Survival Event-free Survival at 6 Months	47.3 percentage of participants Interval 33.6 to 59.7	43.7 percentage of participants Interval 31.4 to 55.4
Proportion of Participants With Event-free Survival Event-free Survival at 12 Months	35.9 percentage of participants Interval 23.4 to 48.5	31.2 percentage of participants Interval 20.4 to 42.7

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

Non-relapse mortality is defined as death due to any cause other than relapse of the underlying malignancy. The cumulative incidence of non-relapse mortality is described, with malignancy relapse treated as a competing risk.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Non-relapse Mortality Non-relapse Mortality at 6 Months	12.7 percentage of participants Interval 5.5 to 23.0	9.4 percentage of participants Interval 3.8 to 18.1
Percentage of Participants With Non-relapse Mortality Non-relapse Mortality at 12 Months	16.5 percentage of participants Interval 8.1 to 27.6	14.2 percentage of participants Interval 6.9 to 24.0

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Malignancy Relapse Malignancy Relapse at 6 Months	14.5 percentage of participants Interval 6.7 to 25.1	12.5 percentage of participants Interval 5.8 to 21.9
Percentage of Participants With Malignancy Relapse Malignancy Relapse at 12 Months	21.9 percentage of participants Interval 12.0 to 33.7	15.7 percentage of participants Interval 8.0 to 25.7

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. The cumulative incidence of chronic GVHD is described, with death and malignancy relapse treated as competing risks.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Chronic GVHD Chronic GVHD at 6 Months	25.7 percentage of participants Interval 14.9 to 37.9	31.2 percentage of participants Interval 20.2 to 42.8
Percentage of Participants With Chronic GVHD Chronic GVHD at 12 Months	31.4 percentage of participants Interval 19.5 to 44.0	40.6 percentage of participants Interval 28.4 to 52.4

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

Population: GVHD-free survival was evaluated only in participants that remained on study until the assessment time point. One participant on the prednisone arm and five on the sirolimus arm were excluded from the analysis at 6 and 12 months due to prior study withdrawal.

GVHD-free survival is defined as freedom from acute GVHD, chronic GVHD, and death. The proportion of participants alive and free of both acute and chronic GVHD are described at 6 and 12 months post-randomization.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With GVHD-free Survival GVHD-free Survival at 6 Months	45.3 percentage of participants Interval 31.9 to 58.8	46.0 percentage of participants Interval 33.7 to 58.3
Percentage of Participants With GVHD-free Survival GVHD-free Survival at 12 Months	50.9 percentage of participants Interval 37.5 to 64.4	46.0 percentage of participants Interval 33.7 to 58.3

SECONDARY outcome

Timeframe: 6 and 12 Months Post-randomization

The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk.

Outcome measures

Measure	Sirolimus n=58 Participants Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 Participants Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Percentage of Participants With Serious Infections Seirious Infections at 6 Months	30.4 percentage of participants Interval 18.9 to 42.7	43.8 percentage of participants Interval 31.3 to 55.6
Percentage of Participants With Serious Infections Seirious Infections at 12 Months	39.6 percentage of participants Interval 26.7 to 52.2	51.8 percentage of participants Interval 38.8 to 63.4

Adverse Events

Sirolimus

Serious events: 8 serious events

Other events: 0 other events

Deaths: 12 deaths

Prednisone

Serious events: 3 serious events

Other events: 0 other events

Deaths: 17 deaths

Serious adverse events

Measure	Sirolimus n=58 participants at risk Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone n=64 participants at risk Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Gastrointestinal disorders Small intestinal obstruction	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Hepatobiliary disorders Hepatic cirrhosis	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Infections and infestations Appendicitis	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Infections and infestations Diverticulitis	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Infections and infestations Pneumonia	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Metabolism and nutrition disorders Failure to thrive	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Psychiatric disorders Delirium	0.00% 0/58 • 1 Year Post-randomization	1.6% 1/64 • Number of events 1 • 1 Year Post-randomization
Psychiatric disorders Mental status changes	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization
Renal and urinary disorders Cystitis noninfective	0.00% 0/58 • 1 Year Post-randomization	1.6% 1/64 • Number of events 1 • 1 Year Post-randomization
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/58 • 1 Year Post-randomization	1.6% 1/64 • Number of events 1 • 1 Year Post-randomization
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.7% 1/58 • Number of events 1 • 1 Year Post-randomization	0.00% 0/64 • 1 Year Post-randomization

Other adverse events

Adverse event data not reported

Additional Information

Adam Mendizabal, PhD

The Emmes Corporation

Phone: 301-251-1161

Email: amendizabal@emmes.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place