Tacrolimus and Mycophenolate Mofetil (MMF) in GVHD Prophylactic Regimen Compared to Tacrolimus and Methotrexate (MTX

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00360685
• Collaborator: (none)
• Enrollment: 89
• Location: 1
• Arms: 2
• Duration (Months): 64
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

A comparative trial where all patients will receive daily doses of tacrolimus (TAC) until day +60 when tapering will begin, in the absence of graft-versus-host disease (GVHD), and discontinued by day +180. In addition patients will be randomized to methotrexate (MTX) or mycophenolate mofetil (MMF) and again, in the absence of GVHD, a tapering schedule will begin on day +240 and be completed on day +360. Doses will be adjusted to maintain blood levels.

Condition or Disease	Intervention/Treatment	Phase
Mucositis; Graft-versus-host Disease	Drug: Tac+MTX; Drug: TAC + MMF	N/A

Detailed Description

The randomization for this comparative trial will be stratified by conditioning regimen and, for those patients enrolled on MCC-14178, by busulfan AUC level.

All patients will receive daily doses of TAC beginning day -3 (day 0 being the day of hematopoietic stem cell transplant (HCT)) and will be given until day +60 when tapering will begin in the absence of GVHD. Provided no GVHD develops, TAC should be discontinued by day +180. Doses will be adjusted to maintain blood levels.

In addition to TAC, patients will be randomized to one of the following additional anti-GVHD medications: MTX or MMF beginning day 0 at least 2 hours after the end of the HCT. In the absence of GVHD a tapering schedule will begin on day +240 and be completed on day +360.

Study participants will be extensively monitored as inpatients and then weekly as outpatients. Some tests will be conducted at least twice weekly (blood tests, toxicity data, GVHD and physical exams) one-month post-transplant and during the tapering off periods for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety of Tacrolimus And Methotrexate (MTX) Versus Tacrolimus And Mycophenolate Mofetil (MMF) As Graft Versus Host Disease Prophylaxis In Allogeneic Hematopoietic Cell Transplants (HCT)
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Other: TAC + MMF Tacrolimus and Mycophenolate	Drug: TAC + MMF; Tacrolimus- 0.03 mg/kg/24h as a continuous IV infusion, beginning day -3. Mycophenolate Mofetil- 30 mg/kg/day IV in 2 divided doses (q12 hours) beginning day 0 at least 2 hours after the end of the hematopoietic stem cell transplant; Other Names: Tacrolimus, Prograf(R) Mycophenolate mofetil, CellCept(R)
Other: TAC+MTX Tacrolimus and Methotrexate	Drug: Tac+MTX; Tacrolimus- 0.03mg/kg/24h IV beginning day-3 Methotrexate- 15mg/m2 IV day +1 then 10mg/m2 IV on days 3, 6, 11 post transplant.; Other Names: Tacrolimus, Prograf(R) Methotrexate,

Outcome Measures

Primary Outcome Measures

1. Incidence of Severe Mucositis [2 year]

   Mucositis was assessed prospectively daily while the patient was hospitalized and graded retrospectively based on nurse and clinician assessments according to the clinical criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). Severe mucositis as defined as grade 3 or grade 4.

Secondary Outcome Measures

1. Incidence of Acute Graft-vs-host Disease (aGVHD) [100 days post transplant]

   incidence of aGVHD (grades 2 - 4) 100 days post allogeneic hematopoietic cell transplantation

2. Overall Survival [1 year]

   number of participants alive at one year

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must be going through a T cell-replete allogeneic transplant

Exclusion Criteria:

• A contraindication to the use of tacrolimus, mycophenolate, or methotrexate

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute

Investigators

• Principal Investigator: Janelle Perkins, PharmD, H. Lee Moffitt Cancer Center and Research Institute
• Principal Investigator: Teresa Field, PhD, MD, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffiitt Cancer Center Clinical Trials Website

Publications

• Perkins J, Field T, Kim J, Kharfan-Dabaja MA, Fernandez H, Ayala E, Perez L, Xu M, Alsina M, Ochoa L, Sullivan D, Janssen W, Anasetti C. A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2010 Jul;16(7):937-47. doi: 10.1016/j.bbmt.2010.01.010. Epub 2010 Jan 25.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00360685
• Other Study ID Numbers: MCC-14418
• First Posted: Aug 7, 2006
• Last Update Posted: May 3, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Tacrolimus; Methotrexate; Mycophenolate mofetil; Mucositis; Acute graft-versus-host disease (aGVHD); Engraftment; hemolytic/uremic syndrome (HUS); Thrombotic thrombocytopenic purpura (TTP)
• Additional relevant MeSH terms: Mucositis; Graft vs Host Disease; Mycophenolic Acid; Methotrexate; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Tacrolimus And Methotrexate	Tacrolimus And Mycophenolate Mofetil
Arm/Group Description	All patients will receive TAC 0.03 mg/kg/24h as a continuous IV infusion beginning day -3 (day 0 being the anticipated day of hematopoietic stem cell infusion). Tacrolimus dosing should be based on ideal body weight. TAC levels should be measured on day 0 then at least twice weekly for the first month and the dose will be adjusted to maintain whole blood levels of 5-15ng/mL. When the patient is able to tolerate oral medications, the total daily dose of IV TAC will be converted to oral dosing at a 1:3 (IV:PO) ratio. The daily oral dose will be divided into twice daily dosing. Full dose TAC will be given until day +60 (+7) when tapering will begin in the absence of GVHD. Provided no GVHD develops, TAC should be discontinued by day +180 (+14). MTX 15 mg/m2 IV day +1 then 10 mg/m2 IV on days +3, +6, and +11.	All patients will receive TAC 0.03 mg/kg/24h as a continuous IV infusion beginning day -3. TAC levels should be measured on day 0 then at least twice weekly for the first month and the dose will be adjusted to maintain whole blood levels of 5-15ng/mL. When the patient is able to tolerate oral medications, the total daily dose of IV TAC will be converted to oral dosing. Full dose TAC will be given until day +60 (+7) when tapering will begin in the absence of GVHD. Provided no GVHD develops, TAC should be discontinued by day +180 (+14). MMF 30 mg/kg/day IV in 2 divided doses beginning day 0. Dosing should be based on the lesser of adjusted ideal body weight or actual body weight. The IV dose will be converted to the oral formulation when spatient is able to tolerate oral medications. Oral dosing may be capped at 1 gram twice daily. In the absence of GVHD a tapering schedule will begin on day +240 (+14) and be completed on day +360 (+14).
Period Title: Overall Study
STARTED	47	42
COMPLETED	47	42
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tacrolimus And Methotrexate	Tacrolimus And Mycophenolate Mofetil	Total
Arm/Group Description	Tacrolimus (TAC) And Methotrexate (MTX)	Tacrolimus (TAC) And Mycophenolate Mofetil (MMF)	Total of all reporting groups
Overall Participants	47	42	89
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	45 95.7%	39 92.9%	84 94.4%
>=65 years	2 4.3%	3 7.1%	5 5.6%
Sex: Female, Male (Count of Participants)
Female	18 38.3%	21 50%	39 43.8%
Male	29 61.7%	21 50%	50 56.2%
Region of Enrollment (participants) [Number]
United States	47 100%	42 100%	89 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Severe Mucositis
Description	Mucositis was assessed prospectively daily while the patient was hospitalized and graded retrospectively based on nurse and clinician assessments according to the clinical criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). Severe mucositis as defined as grade 3 or grade 4.
Time Frame	2 year

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Tacrolimus And Methotrexate	Tacrolimus And Mycophenolate Mofetil
Arm/Group Description	Tacrolimus And Methotrexate	Tacrolimus (TAC) And Mycophenolate Mofetil (MMF)
Measure Participants	47	42
Number [participants]	25 53.2%	14 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tacrolimus And Methotrexate, Tacrolimus And Mycophenolate Mofetil
	Comments	Sample size was based on the difference in the proportion of patients in each arm who were predicted to develop severe mucositis defined as clinical grade 3 or 4 per the CTCAE. A sample-size of 42 evaluable subjects per study-arm allowed detection of an absolute difference of 30%, which corresponds to a reduction in the incidence of severe mucositis from 60% in the methotrexate arm to 30% in the MMF arm (alpha=0.05, power=0.80).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Incidence of Acute Graft-vs-host Disease (aGVHD)
Description	incidence of aGVHD (grades 2 - 4) 100 days post allogeneic hematopoietic cell transplantation
Time Frame	100 days post transplant

Outcome Measure Data

Analysis Population Description

intent to treat

Arm/Group Title	Tacrolimus And Methotrexate	Tacrolimus And Mycophenolate Mofetil
Arm/Group Description	Tacrolimus (TAC) And Methotrexate (MTX)	Tacrolimus (TAC) And Mycophenolate Mofetil (MMF)
Measure Participants	47	42
Number [participants]	45 95.7%	33 78.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tacrolimus And Methotrexate, Tacrolimus And Mycophenolate Mofetil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8
	Comments
	Method	K-sample tests for comparing the cumulat
	Comments

3. Secondary Outcome

Title	Overall Survival
Description	number of participants alive at one year
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

intent to treat

Arm/Group Title	Tacrolimus And Methotrexate	Tacrolimus And Mycophenolate Mofetil
Arm/Group Description	Tacrolimus (TAC) And Methotrexate (MTX)	Tacrolimus (TAC) And Mycophenolate Mofetil (MMF)
Measure Participants	47	42
Number [participants]	28 59.6%	27 64.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tacrolimus And Methotrexate, Tacrolimus And Mycophenolate Mofetil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	2 years
Arm/Group Title	Tacrolimus And Methotrexate		Tacrolimus And Mycophenolate Mofetil
Arm/Group Description	Tacrolimus (TAC) And Methotrexate (MTX)		Tacrolimus (TAC) And Mycophenolate Mofetil (MMF)
All Cause Mortality
	Tacrolimus And Methotrexate		Tacrolimus And Mycophenolate Mofetil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tacrolimus And Methotrexate		Tacrolimus And Mycophenolate Mofetil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/47 (53.2%)		19/42 (45.2%)
General disorders
Death	25/47 (53.2%)	25	19/42 (45.2%)	19
Other (Not Including Serious) Adverse Events
	Tacrolimus And Methotrexate		Tacrolimus And Mycophenolate Mofetil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/42 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.