Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease (GVHD) Prophylaxis After Reduced Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00548717
• Collaborator: Wyeth is now a wholly owned subsidiary of Pfizer (Industry), PDL BioPharma, Inc. (Industry)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 71
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial will test the hypothesis that the combination of sirolimus, mycophenolate mofetil, and bortezomib will be effective in preventing both acute and chronic GVHD after reduced intensity allogeneic stem cell transplantation.

Condition or Disease	Intervention/Treatment	Phase
Graft-vs-Host Disease	Drug: Sirolimus; Drug: Mycophenolate mofetil; Drug: Bortezomib	Phase 2

Detailed Description

The combination of tacrolimus and methotrexate is standard therapy for prevention of GVHD, however, our recent experience has demonstrated that the substitution of sirolimus for methotrexate provides superior GVHD control with reduced transplant-related toxicity. One limitation to the use of calcineurin inhibitors in GVHD prevention is the disruption in Treg function and proliferation. Based on our evolving understanding of the role of Treg in the development of chronic GVHD, we propose a GVHD prophylactic regimen that is effective in prevention of acute GVHD, but by virtue of the maintenance of Treg activity may be able to prevent chronic GVHD. We hypothesize that the substitution of mycophenolate mofetil for tacrolimus as well as the addition of bortezomib may provide similar protection against acute GVHD and prevent chronic GVHD while minimizing renal toxicity after transplantation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Sirolimus, Mycophenolate Mofetil and Bortezomib as Graft-Versus-Host Disease Prophylaxis After Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Siro/MMF Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF)	Drug: Sirolimus; Other Names: Rapamycin ; Drug: Mycophenolate mofetil; Other Names: Cellcept
Experimental: Siro/MMF/Bort Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *added with study reopening in 2012	Drug: Sirolimus; Other Names: Rapamycin ; Drug: Mycophenolate mofetil; Other Names: Cellcept ; Drug: Bortezomib; Other Names: Velcade

Outcome Measures

Primary Outcome Measures

1. To Determine the Rate of Grade II-IV Acute GVHD When Sirolimus and Mycophenolate Mofetil or Sirolimus, Mycophenolate Mofetil and Bortezomib is Used for GVHD Prophylaxis After Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies [150 days]

Secondary Outcome Measures

1. Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant [30 days]

   Engraftment of donor cells by week 4 after transplantation. Assessment of donor stem cell engraftment will include donor-host hematopoietic chimerism analyses at 4 weeks and every 3 months after transplantation. Chimerism measured from peripheral blood or from bone marrow.

2. The Rate of Renal Insufficiency [1 year]

   Renal function will be measured weekly after transplant for 4 weeks, at 8 weeks and then at 3 month intervals from transplantation. Sentinel renal events such as the occurrence of thrombotic microangiopathy will be noted. The rationale for the substitution of mycophenolate mofetil for tacrolimus is to continue to prevent acute GVHD, but minimize renal toxicity after transplantation. We will thus monitor renal toxicity closely in this study. In our previous experience, the rate of grade III-V renal toxicity by day 100 after transplantation was about 10%. Here, grade III is defined as a creatinine level between 3.1 to 6 times the normal level, grade IV is defined as a creatinine level 6 times or more the normal level, and grade V is defined as a fatality due to renal toxicity.

3. To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence [1 year]

   This outcome measure was presented as a comparison between incidence of Grade 0-I aGVHD and Grade II-IV aGVHD across 5 time points (Weeks 1,2,3,8, and 12).

4. Incidence of 100 Day Mortality [100 days]

5. Incidence of Chronic GVHD [1 year]

   Chronic GVHD will be graded according to the modified Seattle criteria. Chronic GVHD divided into limited and extensive and evaluated across the following systems: skin, cutaneous structures, liver, mouth, eyes, esophagus, intestines, lung, musculoskeletal, serous, nervous, urologic, vagina, hematopoietic, and immune. Localized skin involvement with or without hepatic dysfunction is classified as limited disease. Generalized skin involvement or limited disease plus eye involvement, oral involvement, hepatic dysfunction with abnormal liver histology, or involvement of any other target organ was classified as extensive disease. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215-33.

6. Overall Survival [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with hematologic malignancies, who are at high risk of complications after conventional myeloablative transplantation

2. Patients must have a 6/6 matched, related donor. Matching at HLA Class II will be based on PCR of sequence specific primers (SSP). Among family member transplants, serologic matching at Class I is sufficient

3. Patient age greater than 18

4. Performance status 0-2

5. Life expectancy of > 100 days without transplantation

6. Written informed consent must be obtained in all cases from the patient

Exclusion Criteria:

1. Pregnancy

2. Prior Allogeneic Stem Cell Transplantation from any donor

3. Evidence of HIV infection or active Hepatitis B or C infection

4. Heart failure uncontrolled by medications

5. Total bilirubin > 2.0 mg/dl that is due to hepatocellular dysfunction

6. AST > 90

7. Cholesterol > 300 mg/dl or Triglycerides > 400 mg/dl while adequately treated

8. Uncontrolled bacterial, viral or fungal infection

9. Requirement for voriconazole at the time of hospital admission

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Wyeth is now a wholly owned subsidiary of Pfizer
• PDL BioPharma, Inc.

Investigators

• Principal Investigator: Corey Cutler, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Corey S. Cutler, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00548717
• Other Study ID Numbers: DFCI 07-197
• First Posted: Oct 24, 2007
• Last Update Posted: Oct 21, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Corey S. Cutler, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute: GVHD; Stem cell transplantation; Sirolimus
• Additional relevant MeSH terms: Graft vs Host Disease; Mycophenolic Acid; Sirolimus; Bortezomib

Study Results

Participant Flow

Recruitment Details	Participants were recruited at Dana Farber Cancer Institute. The first participant was enrolled in November 2007. Enrollment was halted May 2008 due to an unacceptable rate of acute GVHD. The study reopened in November 2012 with addition of bortezomib. The last participant enrolled May 2013. The study was permanently closed to accural August 2013.

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin) Mycophenolate Mofetil (MMF)	Sirolimus, Mycophenolate Mofetil, and Bortezomib for GVHD prophylaxis Sirolimus (Rapamycin) Mycophenolate Mofetil (MMF) Bortezomib (Velcade) *Bortezomib added when study reopened in November 2012
Period Title: Overall Study
STARTED	13	2
COMPLETED	4	0
NOT COMPLETED	9	2

Baseline Characteristics

Arm/Group Title	Siro/MMF	Siro/MMF/Bort	Total
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012	Total of all reporting groups
Overall Participants	13	2	15
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 84.6%	0 0%	11 73.3%
>=65 years	2 15.4%	2 100%	4 26.7%
Sex: Female, Male (Count of Participants)
Female	4 30.8%	0 0%	4 26.7%
Male	9 69.2%	2 100%	11 73.3%
Region of Enrollment (participants) [Number]
United States	13 100%	2 100%	15 100%

Outcome Measures

1. Primary Outcome

Title	To Determine the Rate of Grade II-IV Acute GVHD When Sirolimus and Mycophenolate Mofetil or Sirolimus, Mycophenolate Mofetil and Bortezomib is Used for GVHD Prophylaxis After Allogeneic Stem Cell Transplantation in Patients With Hematologic Malignancies
Time Frame	150 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	2
Number [percentage of participants]	77 592.3%	100 5000%

2. Secondary Outcome

Title	Donor Stem Cell Engraftment, Including Donor-host Hematopoietic Chimerism Studies Post Transplant
Description	Engraftment of donor cells by week 4 after transplantation. Assessment of donor stem cell engraftment will include donor-host hematopoietic chimerism analyses at 4 weeks and every 3 months after transplantation. Chimerism measured from peripheral blood or from bone marrow.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	2
Number [participants]	9 69.2%	2 100%

3. Secondary Outcome

Title	The Rate of Renal Insufficiency
Description	Renal function will be measured weekly after transplant for 4 weeks, at 8 weeks and then at 3 month intervals from transplantation. Sentinel renal events such as the occurrence of thrombotic microangiopathy will be noted. The rationale for the substitution of mycophenolate mofetil for tacrolimus is to continue to prevent acute GVHD, but minimize renal toxicity after transplantation. We will thus monitor renal toxicity closely in this study. In our previous experience, the rate of grade III-V renal toxicity by day 100 after transplantation was about 10%. Here, grade III is defined as a creatinine level between 3.1 to 6 times the normal level, grade IV is defined as a creatinine level 6 times or more the normal level, and grade V is defined as a fatality due to renal toxicity.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

One patient experienced grade 5 renal toxicity

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	2
Number [participants]	1 7.7%	0 0%

4. Secondary Outcome

Title	To Correlate the Serum Concentrations of Mycophenolate Mofetil and Its Metabolites With Acute GVHD Incidence
Description	This outcome measure was presented as a comparison between incidence of Grade 0-I aGVHD and Grade II-IV aGVHD across 5 time points (Weeks 1,2,3,8, and 12).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

In the Siro/MMF group, the overall number of participants analyzed was 13, however, the number of participants with the MMF level data available varies at each time point. For the Siro/MMF/Bort group, no data were analyzed due to no data available for this Outcome Measure.

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	0
Week 1 MMF level (0-I aGVHD), n=3	2.43 (1.19)
Week 1 MMF level (II-IV aGVHD), n=8	2.70 (1.25)
Week 2 MMF level (0-I aGVHD), n=3	3.40 (1.37)
Week 2 MMF level (II-IV aGVHD), n=6	3.07 (2.25)
Week 3 MMF level (0-I aGVHD), n=3	2.57 (1.35)
Week 3 MMF level (II-IV aGVHD), n=6	2.85 (2.09)
Week 8 MMF level (0-I aGVHD), n=3	2.37 (0.75)
Week 8 MMF level (II-IV aGVHD), n=4	2.13 (1.18)
Week 12 MMF level (0-I aGVHD), n=2	1.75 (0.07)
Week 12 MMF level (II-IV aGVHD), n=4	2.20 (1.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siro/MMF
	Comments	Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Siro/MMF
	Comments	Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 2.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Siro/MMF
	Comments	Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Siro/MMF
	Comments	Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 8.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Siro/MMF
	Comments	Comparison between Grade 0-I aGVHD vs Grade II-IV aGVHD in the Siro/MMF group at week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Incidence of 100 Day Mortality
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	2
Number [percentage of participants]	31 238.5%	0 0%

6. Secondary Outcome

Title	Incidence of Chronic GVHD
Description	Chronic GVHD will be graded according to the modified Seattle criteria. Chronic GVHD divided into limited and extensive and evaluated across the following systems: skin, cutaneous structures, liver, mouth, eyes, esophagus, intestines, lung, musculoskeletal, serous, nervous, urologic, vagina, hematopoietic, and immune. Localized skin involvement with or without hepatic dysfunction is classified as limited disease. Generalized skin involvement or limited disease plus eye involvement, oral involvement, hepatic dysfunction with abnormal liver histology, or involvement of any other target organ was classified as extensive disease. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215-33.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Siro /MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil,and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	2
Number [percentage of participants]	15 115.4%	50 2500%

7. Secondary Outcome

Title	Overall Survival
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Siro/MMF	Siro/MMF/Bort
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF);	Sirolimus, Mycophenolate Mofetil, and Bortezomib as GVHD Prophylaxis Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
Measure Participants	13	2
Number [percentage of participants]	39 300%	0 0%

Adverse Events

Time Frame	Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points during the study. All SAEs and grade 3 or higher treatment and/or transplant related toxicities (AEs) are recorded.
Adverse Event Reporting Description	It is not simple to segregate prophylactic regimen related from transplant related toxicities. We thus report transplant and/or regimen related toxicities combined and do not segregate toxicities by regimen. Moreover, since only 2 patients received Siro/MMF/Bort, comparison of toxicites between the two regimens is infeasible.
Arm/Group Title	Siro/MMF (+/- Bortezomib)
Arm/Group Description	Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis (+/- Bortezomib) Sirolimus (Rapamycin); Mycophenolate Mofetil (MMF); Bortezomib (Velcade) *added with study reopening in 2012
All Cause Mortality
	Siro/MMF (+/- Bortezomib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Siro/MMF (+/- Bortezomib)
	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)
Eye disorders
Temporary blindness	1/15 (6.7%)	1
General disorders
Fever	1/15 (6.7%)	1
Multi-organ Failure	1/15 (6.7%)	1
Immune system disorders
GVHD	2/15 (13.3%)	2
Infections and infestations
HHV6 encephalitis	1/15 (6.7%)	1
Sepsis	3/15 (20%)	3
Pneumonia	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Siro/MMF (+/- Bortezomib)
	Affected / at Risk (%)	# Events
Total	11/15 (73.3%)
Blood and lymphatic system disorders
Thrombotic microangiopathy	1/15 (6.7%)
Gastrointestinal disorders
Dehydration	1/15 (6.7%)
Diarrhea	1/15 (6.7%)
Necrosis-small bowel NOS	1/15 (6.7%)
Hepatobiliary disorders
Cholecystitis	1/15 (6.7%)
Infections and infestations
Documented infection	7/15 (46.7%)
Suspected Undocumented infection	4/15 (26.7%)
Metabolism and nutrition disorders
Hyperglycemia	1/15 (6.7%)
Hyponatremia	1/15 (6.7%)
Nervous system disorders
Encephalopathy	1/15 (6.7%)
Neurologic Toxicity	1/15 (6.7%)
Renal and urinary disorders
Renal Toxicity	1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis/pulmonary infiltrates	1/15 (6.7%)

Limitations/Caveats

Early termination leading to small numbers of subjects analyzed. Results are reported for transparency only, and should not be used to extrapolate significant conclusions.

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.