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

NCT01951885 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: CASE6Z13
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Biphenotypic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Hodgkins Disease; Chronic Lymphocytic Leukemia; Multiple Myeloma

Outcome Measures

Primary Outcomes (4)

• 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

• 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

• 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

• 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 Outcomes (15)

• Length of Hospitalization

  Date of transplant to date of discharge, assessed up to 1 year

• Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days

  Up to day 100

• Overall Survival

  Up to 1 year

• Progression-free Survival

  Up to 1 year

• Incidence of Chronic GVHD

  at 6 months

Other Outcomes (1)

• Chimerism Results

  Up to one year

Study Arms (2)

Group A (tacrolimus, methotrexate)

ACTIVE COMPARATOR

Participants receive tacrolimus IV over 24 hours beginning on day -1 (or tacrolimus orally beginning on day -3) and then PO BID after engraftment with a taper from day 100 to day 180 (in the absence of GVHD). Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Drug: tacrolimus; Drug: methotrexate

Group B (tacrolimus, methotrexate, mycophenolate mofetil)

EXPERIMENTAL

Patients receive tacrolimus as in group A and methotrexate (low dose) IV on days 1, 3, and 6. Patients also receive oral mycophenolate mofetil BID beginning on day 1, with a taper from day 45 to day 100 (in the absence of GVHD).

Drug: tacrolimus; Drug: Mycophenolate mofetil; Drug: Methotrexate (low dose)

Interventions

tacrolimus DRUG

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

Also known as: FK 506, Prograf

Group A (tacrolimus, methotrexate); Group B (tacrolimus, methotrexate, mycophenolate mofetil)

methotrexate DRUG

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.

Also known as: amethopterin, Folex, methylaminopterin, Mexate, MTX

Group A (tacrolimus, methotrexate)

Mycophenolate mofetil DRUG

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

Also known as: Cellcept, MMF

Group B (tacrolimus, methotrexate, mycophenolate mofetil)

Methotrexate (low dose) DRUG

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.

Also known as: amethopterin, Folex, methylaminopterin, Mexate, MTX

Group B (tacrolimus, methotrexate, mycophenolate mofetil)

Eligibility Criteria

• Age: Up to 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead

Study Sites (1)

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

Related Publications (1)

• Hamilton BK, Rybicki LA, Li H, Lucas T, Corrigan D, Kalaycio M, Sobecks R, Hanna R, Rotz SJ, Dean RM, Gerds AT, Jagadeesh D, Brunstein C, Sauter CS, Copelan EA, Majhail NS. Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-versus-host disease prevention. Blood Adv. 2023 Aug 22;7(16):4505-4513. doi: 10.1182/bloodadvances.2023010310.

  PMID: 37352262 DERIVED

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia, Biphenotypic, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Lymphoma, Non-Hodgkin; Hodgkin Disease; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma

Interventions

Tacrolimus; Methotrexate; merphos; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma; Leukemia, B-Cell; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Betty Hamilton MD
• Organization: Case Comprehensive Cancer Center

TaussigResearch@ccf.org

866-223-8100

Study Officials

• Betty Hamilton, MD

  Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2013
• First Posted: September 27, 2013
• Study Start: July 7, 2014
• Primary Completion: October 9, 2020
• Study Completion: August 11, 2021
• Last Updated: September 11, 2023
• Results First Posted: January 31, 2023

Record last verified: 2023-08

Locations

US (1)