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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Drug: Bortezomib (Velcade)
* Drug: Tacrolimus
* Drug: Methotrexate
* Procedure: blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Engraftment Following Transplant. | As measured by median total donor chimerism at day 100. | by day 100 post transplant | 
| Incidence of Chronic Graft Versus Host Disease (Chronic GVHD). | Number of participants with chronic GVHD at 1 year post transplant. | by 1 year after PBSC infusion | 
| Overall Survival and Progression-free Survival. | Progression is defined as disease relapse or disease progression since transplant. | by 1 year after PBSC infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Velcade, Bortezomib, Allogeneic Stem Cell Transplant, GVHD