NCT01951885

Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention

Completed Phase 3 Results posted Last updated 11 September 2023

What this trial tests

Phase 3 trial testing tacrolimus in Chronic Myelogenous Leukemia in 101 participants. Completed in 11 August 2021.

Timeline

7 July 2014

Primary endpoint
9 October 2020

11 August 2021

Quick facts

Lead sponsor	Case Comprehensive Cancer Center
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	supportive care
Enrollment	101
Start date	7 July 2014
Primary completion	9 October 2020
Estimated completion	11 August 2021
Sites	1 location across United States

Drugs / interventions tested

• tacrolimus (TACROLIMUS) — full drug profile →
• methotrexate — full drug profile →
• Mycophenolate mofetil (MYCOPHENOLATE MOFETIL) — full drug profile →
• Methotrexate (low dose) — full drug profile →

Conditions studied

• Chronic Myelogenous Leukemia — all drugs for Chronic Myelogenous Leukemia →
• Acute Lymphoblastic Leukemia — all drugs for Acute Lymphoblastic Leukemia →
• Acute Myeloid Leukemia — all drugs for Acute Myeloid Leukemia →
• Acute Biphenotypic Leukemia — all drugs for Acute Biphenotypic Leukemia →

Sponsor

Case Comprehensive Cancer Center — full company profile →

Who can join

Under 70, any sex, with Chronic Myelogenous Leukemia or Acute Lymphoblastic Leukemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale Primary · Up to day 28

Participants (percentage of) will be graded three times per week through day 28 of the study. Incidence will be compared through Wilcoxon rank sum tests. The WHO grading scale for mucositis is scaled depending on the severity of mucositis symptoms, with a lower stage associated with a better outcome and greater stages associated with worse outcomes. The staging is as follows: Stage 0: None Stage 1 (mild): Oral soreness, erythema Stage 2 (moderate): Oral erythema, ulcers, solid diet tolerated Stage 3 (severe): Oral ulcers, liquid diet only Stage 4 (life-threatening): Oral alimentation impossi

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	81.6
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	57.4

Time to Neutrophil Engraftment Primary · Up to 28 days

The number of days to reach a neutrophil count of greater than or equal to 500/ul for three consecutive laboratory values obtained on different days. The day of engraftment will be the first day of the three consecutive laboratory values.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	17	11 – 27
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	15	11 – 23

Time to Platelet Engraftment Primary · The date the participant engrafts, up to 28 days

The number of days to reach a platelet count of greater than or equal to 20,000/ul for three consecutive laboratory values obtained on different days, independent of platelet transfusions the prior 7 days. The day of engraftment will be the first day of the three consecutive laboratory values. For cases of delayed engraftment beyond 28 days, results will be recorded once the participant engrafts.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	27	16 – 131
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	23	10 – 112

Cumulative Incidence of Participants With Acute GVHD Primary · Day 7- Day 100

Acute GVHD by grade will be estimated using cumulative incidence methods and compared using the Gray test. A lower clinical grade and/or stage of GVHD corresponds to a better participant outcome and a higher grade corresponds to a worse participant outcome. Grading is as follows: Grade 0: No stage 1-4 of any organ Grade 1: Stage 1-2 skin without liver, upper GI, or lower GI involvement. Grade 2: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. Grade 3: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. Grade 4: Stage

Grade 1-4

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	37	23 – 50
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	47	32 – 60

Grade 2-4

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	27	15 – 39
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	28	16 – 41

Grade 3-4

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	4	1 – 12
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	13	5 – 24

Length of Hospitalization Secondary · Date of transplant to date of discharge, assessed up to 1 year

Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	31	22 – 89
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	27	20 – 55

Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days Secondary · Up to day 100

TPN use will be compared using the Chi-square test.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	41
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	38

Overall Survival Secondary · Up to 1 year

Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	71	56 – 82
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	72	57 – 83

Progression-free Survival Secondary · Up to 1 year

Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	59	44 – 71
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	68	53 – 79

Incidence of Chronic GVHD Secondary · at 6 months

Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of

any chronic GVHD

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	16	8 – 28
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	15	6 – 27

moderate-severe chronic GVHD

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	12	5 – 23
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	11	4 – 21

Incidence of Chronic GVHD Secondary · at 12 months

Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of

any chronic GVHD

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	25	13 – 37
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	36	23 – 50

moderate-severe chronic GVHD

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	20	10 – 33
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	23	12 – 36

Length of Time on Continuous Infusion Narcotics Secondary · up to +28 day

Start and stop dates for the need of continuous IV infusion of narcotics for severe mucositis pain will be recorded. Time on IV infusion will be compared between patients in groups A and B using the Wilcoxon rank sum test.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	10	1 – 19
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	9	2 – 25

Incidence of Infection Secondary · Up to day +100

100-day incidence of infection will be compared using a the Gray test.

Group	Value	95% CI
Group A (Tacrolimus, Methotrexate)	63	48 – 75
Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)	53	38 – 66

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse event data were collected through one year post transplant. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Group A (Tacrolimus, Methotrexate)

Serious: 13/50 (26%)

Deaths: 25/50

Group B (Tacrolimus, Methotrexate, Mycophenolate Mofetil)

Serious: 3/51 (6%)

Deaths: 15/51

Serious adverse events (14 terms)

Reaction	System	Group A (Tacrolimus, Metho…	Group B (Tacrolimus, Metho…
Hepatic failure	Hepatobiliary disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Adult respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	—	—
Encephalopathy	Hepatobiliary disorders	—	—
Escherichia Coli (E-Coli)	Infections and infestations	—	—
Pulmonary hypertension	Respiratory, thoracic and mediastinal disorders	—	—
Idiopathic pneumonia syndrome	Respiratory, thoracic and mediastinal disorders	—	—
Seizure	Nervous system disorders	—	—
Sepsis	Infections and infestations	—	—
Upper respiratory infection	Respiratory, thoracic and mediastinal disorders	—	—
Lung infection	Respiratory, thoracic and mediastinal disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Acidosis	Metabolism and nutrition disorders	—	—

Other adverse events (324 terms — click to expand)

Reaction	System	Group A (Tacrolimus, Metho…	Group B (Tacrolimus, Metho…
nausea	Gastrointestinal disorders	—	—
diarrhea	Gastrointestinal disorders	—	—
vomiting	Gastrointestinal disorders	—	—
FATIGUE	General disorders	—	—
fever	General disorders	—	—
hypomagnesemia	Metabolism and nutrition disorders	—	—
HEADACHE	Nervous system disorders	—	—
abdominal pain	Gastrointestinal disorders	—	—
constipation	Gastrointestinal disorders	—	—
RASH	Skin and subcutaneous tissue disorders	—	—
acute kidney injury	Renal and urinary disorders	—	—
cough	Respiratory, thoracic and mediastinal disorders	—	—
PLATELET COUNT DECREASED	Investigations	—	—
anemia	Blood and lymphatic system disorders	—	—
hypertension	Vascular disorders	—	—
edema limbs	General disorders	—	—
INSOMNIA	Psychiatric disorders	—	—
HYPOTENSION	Vascular disorders	—	—
NEUTROPHIL COUNT DECREASED	Investigations	—	—
WHITE BLOOD CELL DECREASED	Investigations	—	—
dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
anorexia	Metabolism and nutrition disorders	—	—
anxiety	Psychiatric disorders	—	—
febrile neutropenia	Blood and lymphatic system disorders	—	—
hypokalemia	Metabolism and nutrition disorders	—	—
dizziness	Nervous system disorders	—	—
TACHYCARDIA	Cardiac disorders	—	—
NASAL CONGESTION	Respiratory, thoracic and mediastinal disorders	—	—
back pain	Musculoskeletal and connective tissue disorders	—	—
HEMORRHOIDS	Gastrointestinal disorders	—	—
GENERALIZED MUSCLE WEAKNESS	Musculoskeletal and connective tissue disorders	—	—
PRURITUS	Skin and subcutaneous tissue disorders	—	—
Renal and urinary disorders - Other, specify: dysuria	Renal and urinary disorders	—	—
hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
delirium	Psychiatric disorders	—	—
dry mouth	Gastrointestinal disorders	—	—
HYPONATREMIA	Metabolism and nutrition disorders	—	—
RECTAL PAIN	Gastrointestinal disorders	—	—
UPPER RESPIRATORY INFECTION	Infections and infestations	—	—
hyperglycemia	Metabolism and nutrition disorders	—	—

Most-reported serious reactions: Hepatic failure, Acute kidney injury, Adult respiratory distress syndrome, Encephalopathy, Escherichia Coli (E-Coli), Pulmonary hypertension, Idiopathic pneumonia syndrome, Seizure.

Data from ClinicalTrials.gov NCT01951885 adverse events section.

Sponsor's own description

This randomized clinical trial studies standard GVHD prophylaxis with tacrolimus and methotrexate compared to tacrolimus, mycophenolate mofetil and a reduced-dose methotrexate in patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant. Both mycophenolate mofetil and reduced-dose methotrexate, in combination with a calcineurin inhibitor, have been shown to be safe and effective in GVHD prevention with less toxicity than standard dose methotrexate. It is not yet known, however, whether this combination of mycophenolate mofetil and reduced-dose methotrexate with tacrolimus is more effective than tacrolimus and standard dose methotrexate in preventing GVHD.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Prevention and Treatment of Acute Graft-versus-Host Disease in Children, Adolescents, and Young Adults.
   Gatza E, Reddy P, Choi SW. · · 2020 · cited 41× · PMID 31931115 · DOI 10.1016/j.bbmt.2020.01.004
2. Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-versus-host disease prevention.
   Hamilton BK, Rybicki LA, Li H, Lucas T, et al · · 2023 · cited 9× · PMID 37352262 · DOI 10.1182/bloodadvances.2023010310