The Effect of Folinic Acid Rescue Following MTX GVHD Prophylaxis on Regimen Related Toxicity and Transplantation Outcome

Graft vs Host Disease Clinical Trial

Official title:

The Effect of Folinic Acid Rescue Following Methotrexate (MTX) Graft-versus-host Disease (GVHD) Prophylaxis on Regimen Related Toxicity and Transplantation Outcome: a Double Blind Randomized Controlled Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02506231
• Other study ID #: 0197-15-RMC
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• First received: July 13, 2015
• Last updated: July 23, 2015
• Start date: October 2015

Study information

• Verified date: June 2015
• Source: Rabin Medical Center
• Contact: Moshe Yeshurun, MD
• Phone: 972-50-4065543
• Email: moshey[@]clalit.org.il
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the impact of folinic acid (FA) -rescue following methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis on regimen related toxicity and transplantation outcomes after allogeneic hematopoietic cell transplantation (alloHCT) in a double blind randomized controlled trial.

Description:

A regimen consisted on a combination of a calcineurin inhibitor (CNI) with a short course of methotrexate (MTX) is the most widely used regimen for the prevention of GVHD after allogeneic hematopoietic cell transplantation (alloHCT). While the CNI is given in an adjusted dose, based on blood levels, MTX is given at a fixed 3 or 4 doses (15 mg/m2 on day +1, 10 mg/m2 on days +3, +6 +/- day +11). However, its use may be associated with considerable toxicity, including delayed engraftment, hepatotoxicity, nephrotoxicity and particularly oral mucositis (OM). The basis for OM is integrated: conditioning regimen and MTX prophylaxis for acute GVHD. OM has been shown to be associated with increased mortality and morbidity (principally from infection), significant pain, dysgeusia, difficulty speaking, difficulty receiving nutrition, hydration and oral medications, prolonged hospitalization and increased costs of care.

Reducing and even omitting doses of MTX due to regimen related toxicities (mucositis, hepatic and renal toxicities) is common. However, dose reduction of MTX may be associated with increased risk of acute GVHD and early death. Several non-randomized studies have shown that folinic acid (FA, leucovorin) administration may reduce MTX toxicity. Nevertheless, the efficacy and safety of its administration remain controversial. Despite limited and uncontrolled data, the European Group for Blood and Marrow Transplantation (EBMT) and the European LeukemiaNet working group recently recommended the use of FA-rescue and proposed a uniform policy of FA-rescue 24h after each MTX dose: 15mg every 8h after MTX administration on day 1, and every 6h on days 3, 6 and 11. Yet, according to several surveys (including by EBMT-ELN) only half of bone marrow transplantation (BMT) centers use to give post MTX FA-rescue.

The aim of this study is to assess the impact of FA-rescue following MTX GVHD prophylaxis on regimen related toxicity and transplantation outcomes after alloHCT in a double blind randomized controlled trial.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 160
• Est. primary completion date: October 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Acute leukemia in complete remission (CR) or myelodysplastic syndrome;

• First transplantation;

• Peripheral blood graft;

• Matched sibling or unrelated donor or one antigen or allelic mismatched sibling or unrelated donor (10/10 or 9/10 human leukocyte antigen match );

• Myeloablative or reduced intensity preparative regimen;

• Post-transplant GVHD prophylaxis consisting of a calcineurin inhibitor (CSA or tacrolimus) and methotrexate;

• Glutamate Pyruvate Transaminase (GPT) < 3 times upper normal limit (UNL) and creatinine = 1.4 mg%;

• Written informed consent;

Exclusion Criteria:

• True non-myeloablative preparative regimen (TBI 200 +/- fludarabine);

• Acute leukemia not in remission;

• GPT > 3 times upper normal limit or creatinine > 1.4 mg%;

• Bone marrow, haploidentical or cord blood grafts;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Allogeneic Hematopoietic Cell Transplantation
• Graft vs Host Disease
• Mucositis

Intervention

Drug:
• Folinic acid

• Placebo

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Rabin Medical Center

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of severe (grade 3-4) oral mucositis according to the WHO scale	According to the WHO (world health organization) oral mucositis grading scale	30 days	No
Primary	Duration (in days) of severe (grade 3-4) oral mucositis according to the WHO scale	According to the WHO (world health organization) oral mucositis grading scale	30 days	No
Secondary	Incidence of oral mucositis		30 days	No
Secondary	Grade of oral mucositis	According to the WHO (world health organization) oral mucositis grading scale	30 days	No
Secondary	Time to neutrophil recovery		30 days	No
Secondary	Time to platelet recovery		60 days	No
Secondary	Adherence to methotrexate schedule	Number of methotrexate doses that were actually given (out of 3 doses on days 1, 3 and 6)	14 days	No
Secondary	Adherence to methotrexate doses	Actual methotrexate doses given in mg/sqm divided by scheduled doses in mg/sqm X 100	14 days	No
Secondary	Days of opiate use		30 days	No
Secondary	Days of total parenteral nutrition use		100 days	No
Secondary	Incidence of veno-occlusive disease of the liver (VOD)		30 days	Yes
Secondary	Severity of veno-occlusive disease of the liver (VOD)	According to the Seattle criteria	30 days	Yes
Secondary	Incidence of renal toxicity	Creatinine > 2 mg%	30 days	Yes
Secondary	Incidence of hepatic toxicity	total bilirubin > 2 mg%, unless mostly indirect	30 days	No
Secondary	Incidence of febrile neutropenia		30 days	No
Secondary	Duration of febrile neutropenia		30 days	No
Secondary	Documented infections		30 days	No
Secondary	Time from transplantation to discharge		60 days	No
Secondary	Incidence of acute graft-versus-host disease		100 days	No
Secondary	Severity of acute graft-versus-host disease	According to the consensus grading system	100 days	No
Secondary	Incidence of chronic graft-versus-host disease		24 months	No
Secondary	Severity of chronic graft-versus-host disease	According to the National Institutes of Health (NIH) consensus criteria	24 months	No
Secondary	Incidence of relapse		24 months	No
Secondary	Non relapse mortality		24 months	No
Secondary	Disease free survival		24 months	No
Secondary	Overall survival		24 months	No