Bortezomib Plus Tacrolimus and Methotrexate to Prevent Graft Versus Host Disease (GVHD) After Mismatched Allogeneic Non-Myeloablative Blood Stem Cell Transplantation

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00369226
• Collaborator: Brigham and Women's Hospital (Other), Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 45
• Locations: 2
• Arm: 1
• Duration (Months): 61
• Patients Per Site: 22.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if Velcade (also known as bortezomib) can help prevent graft versus host disease (GVHD) developing after transplantation. This is done by using a combination of three immune suppressive medications: Velcade, tacrolimus and methotrexate. Stem cell transplantation is one of the options for patients with cancer of the blood or blood forming organs. Recently, allogeneic stem cell transplants have been performed using lower doses of chemotherapy and radiotherapy: non-myeloablative or "mini" transplants. GVHD is a significant problem that may occur even after "mini" transplantations. Information from other research studies, suggests that Velcade may help to reduce the risk of developing GVHD when given early after transplantation.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancies	Drug: Bortezomib (Velcade); Drug: Tacrolimus; Drug: Methotrexate; Procedure: blood stem cell transplantation	Phase 1/Phase 2

Detailed Description

• In this study we are looking for the highest dose of Velcade that can be given to people safely when given with tacrolimus and methotrexate. Not everyone who participates in the study will receive the same amount of the study drug. The dose the participant will receive depends upon the number of subjects enrolled on the study and how well they have tolerated their doses of the drug.

• Before Transplant: In addition to the chemotherapy drugs, fludarabine and busulfex, for the participants non-myeloablative transplant, they will also start taking tacrolimus orally three days before their transplant.

• After Transplant Medication: Methotrexate; Intravenously on days 1, 3, 6 & 11 after transplant for a total of 4 doses. Tacrolimus; Continue taking orally once daily. Velcade: Intravenously on days 1, 4 & 7 after transplant, a total of 3 doses. Filgrastim: Subcutaneous injection daily starting the day after transplant and continuing until the participant blood counts have recovered.

• After Transplant Physical Exams & Tests: Participants will have physical exams and blood tests every week for 1 month. After 1 month, a none marrow biopsy will be performed to look for evidence of the donor's cells in the participants bone marrow.

• Following the 1 month period of time, participants will be seen every few weeks. Another bone marrow biopsy, as well as blood tests, will be taken 3-4 months after the transplant to review the disease status. At this point, participants will come into the clinic about every 3 months, or as determined by their physician for about one year.

• While the study ends at 12 months after transplant, we would like to keep track of the participants medical condition for the rest of their life.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Phase I/II Trial of Bortezomib (Velcade) in Addition to Tacrolimus and Methotrexate to Prevent Graft Versus Host Disease (GVHD) After Mismatched Allogeneic Non-Myeloablative Peripheral Blood Stem Cell Transplantation
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bortezomib/Tacrolimus/Methotrexate post HSCT	Drug: Bortezomib (Velcade); Infusion for a total of 3 doses; Drug: Tacrolimus; Taken until Doctor determines it is not necessary any more; Drug: Methotrexate; Infusion for a total of 4 doses; Procedure: blood stem cell transplantation; Allogeneic Non-myeloablative peripheral blood stem cell transplantation

Outcome Measures

Primary Outcome Measures

1. The Maximally Tolerated Dose (MTD) of Bortezomib (Velcade) That Can be Administered With Tacrolimus and Methotrexate After Mismatched Allogeneic Non-myeloablative Peripheral Blood Stem Cell (PBSC) Transplantation [by day 45 post PBSC infusion]

   The MTD of bortezomib was evaluated at 3 dose levels: Dose level 1: 1.0 mg/m^2 Dose level 2: 1.3 mg/m^2 Dose level 3: 1.5 mg/m^2 Cohorts of 3-5 pts were enrolled at each dose level. At any dose level, if no DLT in the first 3, 4, or 5 pts, then dose escalation would occur. If 3 evaluable pts in cohort, and 1 of 3 experiences DLT then 2 additional pts treated at the same dose level. If >=1 of 2 additional pts experience DLT then previous dose level will be MTD. If no DLT in additional 2 pts then dose escalation will occur. If 4 evaluable pts in cohort, and 1 of the 4 experiences DLT then 1 additional pt treated at same dose level. If this additional pt experiences DLT then the previous dose will be declared to be the MTD. If additional pt does not experience DLT, then dose escalation will take place. If 5 evaluable pts in cohort, and 1 experiences DLT, then dose escalation will take place. If >=2 of first 3, 4, or 5 pts experience DLT then the previous dose will be declared MTD.

2. Successful Initial Engraftment by Day 45 Post Peripheral Blood Stem Cell (PBSC) Infusion and Administration of Bortezomib (Velcade), Tacrolimus and Methotrexate [by day 45 post PBSC infusion]

   Percentage of participants who did not experience failure to engraft or relapse or death before assessment.

3. Incidence of Grade II-IV Acute Graft Versus Host Disease (GVHD) by Day 100. [by day 100 after peripheral blood stem cell (PBSC) infusion]

Secondary Outcome Measures

1. Sustained Engraftment Following Transplant. [by day 100 post transplant]

   As measured by median total donor chimerism at day 100.

2. Incidence of Chronic Graft Versus Host Disease (Chronic GVHD). [by 1 year after PBSC infusion]

   Number of participants with chronic GVHD at 1 year post transplant.

3. Overall Survival and Progression-free Survival. [by 1 year after PBSC infusion]

   Progression is defined as disease relapse or disease progression since transplant.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients with hematologic malignancies including myelodysplastic syndrome (MDS), who are at a high risk of complications after myeloablative transplantation

• Patients have a donor (both related and unrelated) who are mismatched according to protocol criteria

• 18 years of age or older

• Performance status 0-2

• Life expectancy of > 100 days

• Female subject is either post-menopausal or sterilized or willing to use an acceptable form of birth control

• Male subject agrees to use an acceptable form of birth control

Exclusion Criteria:

• Evidence of HIV infection

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

• Aspartate aminotransferase (AST) > 90

• Known active hepatitis B or C

• Serum creatinine > 2.0

• Greater than or equal to Grade 2 peripheral neuropathy within 21 days of enrollment

• Prior allogeneic stem cell transplant

• Patients with myeloproliferative disease (e.g. myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia)

• Myocardial infarction within 6 months prior to enrollment or has NYHA Class III or IV hear failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

• Hypersensitivity to Velcade, boron or mannitol

• Pregnant or breast feeding

• Patient has received other investigational drugs 14 days before enrollment

• Serious medical or psychiatric illness

• Another active solid tumor malignancy at the time of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: John Koreth, MD, Dana-Farber Cance Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: John Koreth, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00369226
• Other Study ID Numbers: 06-065; X05175
• First Posted: Aug 29, 2006
• Last Update Posted: Jul 25, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by John Koreth, MD, Principal Investigator, Dana-Farber Cancer Institute: Velcade; Bortezomib; Allogeneic Stem Cell Transplant; GVHD
• Additional relevant MeSH terms: Hematologic Neoplasms; Graft vs Host Disease; Methotrexate; Bortezomib; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Phase I (45 Days)	Phase II (45 Days)
Arm/Group Description	Bortezomib plus tacrolimus and methotrexate after mismatched allogeneic non-myeloablative hematopoietic stem cell transplantation (HSCT).
Period Title: Phase I (45 Days)
STARTED	13	0
COMPLETED	13	0
NOT COMPLETED	0	0
Period Title: Phase I (45 Days)
STARTED	0	32
COMPLETED	0	32
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Phase I	Phase II	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	13	32	45
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	25 78.1%	38 84.4%
>=65 years	0 0%	7 21.9%	7 15.6%
Sex: Female, Male (Count of Participants)
Female	7 53.8%	14 43.8%	21 46.7%
Male	6 46.2%	18 56.3%	24 53.3%
Region of Enrollment (participants) [Number]
United States	13 100%	32 100%	45 100%

Outcome Measures

1. Primary Outcome

Title	The Maximally Tolerated Dose (MTD) of Bortezomib (Velcade) That Can be Administered With Tacrolimus and Methotrexate After Mismatched Allogeneic Non-myeloablative Peripheral Blood Stem Cell (PBSC) Transplantation
Description	The MTD of bortezomib was evaluated at 3 dose levels: Dose level 1: 1.0 mg/m^2 Dose level 2: 1.3 mg/m^2 Dose level 3: 1.5 mg/m^2 Cohorts of 3-5 pts were enrolled at each dose level. At any dose level, if no DLT in the first 3, 4, or 5 pts, then dose escalation would occur. If 3 evaluable pts in cohort, and 1 of 3 experiences DLT then 2 additional pts treated at the same dose level. If >=1 of 2 additional pts experience DLT then previous dose level will be MTD. If no DLT in additional 2 pts then dose escalation will occur. If 4 evaluable pts in cohort, and 1 of the 4 experiences DLT then 1 additional pt treated at same dose level. If this additional pt experiences DLT then the previous dose will be declared to be the MTD. If additional pt does not experience DLT, then dose escalation will take place. If 5 evaluable pts in cohort, and 1 experiences DLT, then dose escalation will take place. If >=2 of first 3, 4, or 5 pts experience DLT then the previous dose will be declared MTD.
Time Frame	by day 45 post PBSC infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I
Arm/Group Description
Measure Participants	13
Number [mg/m^2]	1.3

2. Primary Outcome

Title	Successful Initial Engraftment by Day 45 Post Peripheral Blood Stem Cell (PBSC) Infusion and Administration of Bortezomib (Velcade), Tacrolimus and Methotrexate
Description	Percentage of participants who did not experience failure to engraft or relapse or death before assessment.
Time Frame	by day 45 post PBSC infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Phase I Plus Phase II
Arm/Group Description	This reports on the total phase I plus phase II patients who were evaluable for chimerism endpoint (37 of the 45 patients).
Measure Participants	37
Number [percentage of participants]	97 746.2%

3. Primary Outcome

Title	Incidence of Grade II-IV Acute Graft Versus Host Disease (GVHD) by Day 100.
Time Frame	by day 100 after peripheral blood stem cell (PBSC) infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I and Phase II
Arm/Group Description	This reports on all treated patients across both phase I and phase II (n=45)
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	22 169.2%

4. Secondary Outcome

Title	Sustained Engraftment Following Transplant.
Description	As measured by median total donor chimerism at day 100.
Time Frame	by day 100 post transplant

Outcome Measure Data

Analysis Population Description

Several subjects experienced failure to graft, relapse or death prior to assessment and were removed from analysis.

Arm/Group Title	Phase I and Phase II
Arm/Group Description	Engraftment is determined for all treated patients across both phase I and phase II (n=45) who are evaluable for this endpoint (n=35)
Measure Participants	35
Number [percentage of participants]	97 746.2%

5. Secondary Outcome

Title	Incidence of Chronic Graft Versus Host Disease (Chronic GVHD).
Description	Number of participants with chronic GVHD at 1 year post transplant.
Time Frame	by 1 year after PBSC infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I and Phase II
Arm/Group Description	This reports on all treated patients across both phase I and phase II (n=45)
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	29 223.1%

6. Secondary Outcome

Title	Overall Survival and Progression-free Survival.
Description	Progression is defined as disease relapse or disease progression since transplant.
Time Frame	by 1 year after PBSC infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Progression-free Survival (PFS)	Overall Survival (OS)
Arm/Group Description	This reports on all treated patients across both phase I and phase II (n=45)	This reports on all treated patients across both phase I and phase II (n=45)
Measure Participants	45	45
Number (95% Confidence Interval) [percentage of participants]	60 461.5%	76 237.5%

Adverse Events

Time Frame	By day 45 post PBSC infusion.
Arm/Group Title	Phase I-II
Arm/Group Description
All Cause Mortality
	Phase I-II
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Phase I-II
	Affected / at Risk (%)	# Events
Total	7/45 (15.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/45 (2.2%)	1
Infections and infestations
Parainfluenzae sinusitis	1/45 (2.2%)	1
Clostridium difficile diarrhea	1/45 (2.2%)	1
Coagulase-negative staphylococcal bacteremia	1/45 (2.2%)	1
Injury, poisoning and procedural complications
Cerebrovascular accident with parathesias	1/45 (2.2%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/45 (2.2%)	1
Vascular disorders
Deep vein thrombosis/pulmonary embolus	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Phase I-II
	Affected / at Risk (%)	# Events
Total	0/45 (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.