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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01951885
Other study ID # CASE6Z13
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date July 7, 2014
Est. completion date August 11, 2021

Study information

Verified date August 2023
Source Case Comprehensive Cancer Center
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

Study Design This is a prospective randomized trial to determine the effectiveness of different doses of GVHD prophylaxis on mucositis, engraftment and aGVHD. Study consists of two study groups of 50 subjects each. Group A will receive Tac and MTX (15 mg/m2 day +1, 10 mg/m2 day +3, +6, +11). Group B will receive Tac, Mini-dose MTX (5 mg/m2 on day +1, +3, +6) and MMF.


Recruitment information / eligibility

Status Completed
Enrollment 101
Est. completion date August 11, 2021
Est. primary completion date October 9, 2020
Accepts healthy volunteers No
Gender All
Age group N/A to 70 Years
Eligibility Inclusion Criteria: - Patients must have one of the following documented diseases: - Chronic myelogenous leukemia - Chronic lymphocytic leukemia - Multiple myeloma - Myelodysplasia - Myeloproliferative disorder - Non-Hodgkin's lymphoma - Hodgkin's disease - Acute myelogenous leukemia - Acute lymphoblastic leukemia - Acute biphenotypic leukemia - Patients must be undergoing a myeloablative allogeneic hematopoietic cell transplant with one of the following conditioning regimens: - Busulfan (= 12.8 mg/kg IV or PO) and cyclophosphamide (= 120 mg/kg) --- Busulfan dose may be adjusted according to pharmacokinetics targeting a daily AUC of 5000 µmol-min/L, per institution standard of practice. - Total body irradiation (TBI) (= 1200 cGy) and etoposide (60 mg/kg) - TBI (= 1200 cGy) and cyclophosphamide (120 mg/kg) - Patient must have achieved and be in complete morphologic remission prior to starting conditioning regimen - Patient's donor must be a related or unrelated human leukocyte antigen (HLA) 8/8 allele-level match (HLA-A, B, C and DRB1) - Adult patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; pediatric patients must have Lansky score = 60% - Patients must have a life expectancy of 100 days - Patients must sign written informed consent Exclusion Criteria: - Patients who have undergone any prior transplant - Patients who are seropositive for human immunodeficiency virus (HIV) - Patients with any medical illness or concurrent psychiatric illness which, in the investigators' opinion, cannot be adequately controlled with appropriate therapy - Patients who are pregnant or lactating

Study Design


Intervention

Drug:
tacrolimus
Tacrolimus 0.03 mg/kg/day beginning day -1 or tacrolimus 0.03mg/kg/dose BID orally beginning on day -3. If Tac is administered intravenously, it will be given over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and/or can tolerate oral medication. Levels of Tac will be obtained to maintain a recommended target serum level of 5-12 ng/mL
methotrexate
MTX 15mg/m2 IV on day +1, followed by 10mg/m2 on day +3, +6, +11. If patient < 10 kg then MTX will be given at 0.5 mg/kg IV on day +1. Then MTX will be given at 0.33 mg/kg on days +3, +6 and +11.
Mycophenolate mofetil
Patients will receive Mycophenolate beginning on day +1. Patients >40 kg will receive Mycophenolate 1000 mg twice a day. Mycophenolate should be given orally twice a day. IV formulation may be used if the patient cannot tolerate oral route. Patients < 40 kg will receive MMF 45 mg/kg/day (15 mg/kg three times a day). MMF may be given orally or intravenously as per institutional protocol
Methotrexate (low dose)
MTX 5mg/m2 IV on day +1, +3, +6. If patient<10 kg MTX will be given at 0.17 mg/kg on day +1, +3, and +6.

Locations

Country Name City State
United States Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland Ohio

Sponsors (1)

Lead Sponsor Collaborator
Case Comprehensive Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Other Chimerism Results Donor chimerism will be assessed by analysis of single-tandem repeats on whole marrow and in lymphocyte enriched or sorted CD3+ T cells and CD33+ granulocytes. Blood will be obtained for donor chimerism "Bone Marrow Engraftment analysis" at approximately 1, 2, 3, 6, 9 and 12 months or as clinically indicated. Up to one year
Primary Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale 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 impossible
Up to day 28
Primary Time to Neutrophil Engraftment 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. Up to 28 days
Primary Time to Platelet Engraftment 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. The date the participant engrafts, up to 28 days
Primary Cumulative Incidence of Participants With Acute GVHD 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 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI.
A greater stage of GVHD involves worsening end-organ involvement and worse participant outcomes based on the skin, liver, lower GI, and upper GI.
Day 7- Day 100
Secondary Length of Hospitalization Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test. Date of transplant to date of discharge, assessed up to 1 year
Secondary Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days TPN use will be compared using the Chi-square test. Up to day 100
Secondary Overall Survival Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. Up to 1 year
Secondary Progression-free Survival Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. Up to 1 year
Secondary Incidence of Chronic GVHD 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 3 OR Lung score of 2 or 3
Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes.
Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract
at 6 months
Secondary Incidence of Chronic GVHD 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 3 OR Lung score of 2 or 3
Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes.
Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract
at 12 months
Secondary Length of Time on Continuous Infusion Narcotics 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. up to +28 day
Secondary Incidence of Infection 100-day incidence of infection will be compared using a the Gray test. Up to day +100
Secondary Incidence of Hepatotoxicity as Measured by Bilirubin 100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL), Up to day +100
Secondary Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes 100-day incidence of hepatotoxicity will be compared using a Gray test. Percentage of patients with elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline phosphatase and a 95% confidence interval Up to day +100
Secondary Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD) 100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval Up to day +100
Secondary Incidence of Nephrotoxicity 100-day incidence of nephrotoxicity will be compared using a Chi-squared test. Percentage of patients requiring dialysis and those with elevated creatinine using a 95% confidence interval Up to day +100
Secondary Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary hemorrhage and 95% confidence interval Up to day +180
Secondary Incidence of Pulmonary Toxicity Measured by Pulmonary Edema 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary edema and 95% confidence interval Up to day +180
Secondary Incidence of Pulmonary Toxicity Measured by Respiratory Failure 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with respiratory failure and 95% confidence interval Up to day +180
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