Bortezomib-based GVHD Prophylaxis After Allogeneic Transplant for Patients Without Matched Related Donors

Study Overview
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Brief Summary
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A common problem after stem cell transplant is graft-versus-host-disease (GVHD). GVHD is a complication of transplantation where the donor graft attacks and damages some of your tissues. After stem cell transplant, all patients receive prophylactic medications against GVHD. In this research study, we are studying the safety and effectiveness of a bortezomib based GVHD prophylaxic drug combination in participants after myeloablative allogeneic stem call transplantation from a matched unrelated donor, mismatched related or unrelated donor.

Detailed Description
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Before your transplant you will receive conditioning therapy with fludarabine and busulfan given 7, 6, 5, and 4 days before your transplant. On day 0, you will receive selected blood cells taken from your sibling or unrelated donor. You will receive 3 drugs for your GVHD prophylaxis: Tacrolimus will be started 3 days before your transplant. It will be given intravenously and later by mouth. You will continue to take tacrolimus for 3 to 6 months after transplant. Methotrexate will be given intravenously 1, 3, 6 and 11 days after your transplant. Bortezomib will be given intravenously 1, 4, and 7 days after your transplant. On days 1, 4, 7, 30 and 3, 6 and 12 months after your transplant you will have a physical exam, blood work, and be asked to complete a questionnaire.

Official Title
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Bortezomib-based Graft-Versus-Host-Disease Prophylaxis After Myeloablative Allogeneic Stem Cell Transplantation for Patients Lacking HLA-matched Related Donors: A Phase 2 Study

Conditions
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Leukemia, Lymphoma, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Tacrolimus
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced and/or aggressive hematologic malignancy (including myelodysplastic syndrome) that is unlikely to be cured by alternative therapies HLA-Matched unrelated donor; or 1-locus HLA-mismatched related or unrelated donor ECOG performance status 0-2 Adequate organ function Able to understand and willing to sign a written informed consent document Agrees to practice adequate contraception per study requirements Exclusion Criteria: Pregnant or breastfeeding Recipient of prior allogeneic or autologous stem cell transplantation Prior abdominal radiation therapy HIV-positive on combination antiretroviral therapy Seropositive for hepatitis B or C Allergies to bortezomib, boron, or mannitol Myocardial infarction within last 6 months, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias Uncontrolled bacterial, viral or fungal infections Seizures or history of seizures History of another non-hematologic malignancy unless disease-free for at least 5 years Uncontrolled intercurrent illness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Velcade/Tac/MTX<br>Drug: Bortezomib. Other Names: Velcade. Bortezomib 1.3 mg/m^2 IV Drug: Tacrolimus. Tacrolimus 0.05 mg/kg PO bid Drug: Methotrexate. Methotrexate 15 mg/m^2 IV | Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2 IV<br>* Other names: Velcade;Drug: Tacrolimus<br>* Tacrolimus 0.05 mg/kg PO bid<br>Drug: Methotrexate<br>* Methotrexate 15 mg/m^2 IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Cumulative Incidence of Grade II-IV Acute GVHD up to Day 100 After Stem Cell Infusion | The primary outcome of this study is the cumulative incidence of grade II-IV acute GVHD up to Day 100 after stem cell infusion. Acute GHVD is graded according to the modified Glucksberg criteria (adapted from Thomas et al., NEJM ,1975, pp. 895-90), which is based on criteria by which the provider classifies acute GVHD per its objective organ staging. Acute GVHD is assessed in weekly standard of care visits post stem cell infusion and is captured in the protocol EDC upon evaluation of clinical notes up to Day 100. Data for acute GVHD organ staging and etiologies are collected in an acute GVHD separate case report form and do not include system organ class, expectedness or attribution. | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage Donor Engraftment up to Day 30 Post Stem Cell Infusion | To assess the percentage donor engraftment up to day 30 post stem cell infusion, defined as the first of 3 consecutive days tested of documented absolute netrophil count (ANC) >/= 500 cells/u/L | Day 30 | 
| The Non-relapse Mortality, Progression-free and Overall Survival up to 1 Year After Stem Cell Infusion | Progression free and overall survival by 1 year after stem cell infusion will be assessed using the method of Kaplan and Meier. Progression-free survival will be defined as the time from stem cell infusion to the time of disease progression or death from any cause. Overall survival will be defined as the time from stem cell infusion to the time to death from any cause. Patients will be censored at the time last documented alive. Cumulative incidence and Kaplan-Meier curves will be constructed as appropriate. Progression is defined per clinical presentation, not protocol specified, and vary per disease, e.g. blasts in bone marrow or peripheral blood for AML/MDS; lymphoma + on PET/CT re-staging etc. | 1 year | 
| The Cumulative Incidence of Chronic GVHD Requiring Systemic Immune Suppression up to 1 Year After Stem Cell Infusion |  | 1 year | 

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