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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	45 participants
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 :	August 2006
Actual Primary Completion Date :	July 2010
Actual Study Completion Date :	September 2011

Arms and Interventions

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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

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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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: by day 100 after peripheral blood stem cell (PBSC) infusion ]

Secondary Outcome Measures :

1. Sustained Engraftment Following Transplant. [ Time Frame: 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). [ Time Frame: by 1 year after PBSC infusion ]
   Number of participants with chronic GVHD at 1 year post transplant.
3. Overall Survival and Progression-free Survival. [ Time Frame: by 1 year after PBSC infusion ]
   Progression is defined as disease relapse or disease progression since transplant.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

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Locations

United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Koreth J, Stevenson KE, Kim HT, Garcia M, Ho VT, Armand P, Cutler C, Ritz J, Antin JH, Soiffer RJ, Alyea EP 3rd. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors. Blood. 2009 Oct 29;114(18):3956-9. doi: 10.1182/blood-2009-07-231092. Epub 2009 Aug 27.

Responsible Party:	John Koreth, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT00369226 History of Changes
Other Study ID Numbers:	06-065; X05175
First Posted:	August 29, 2006
Results First Posted:	July 25, 2013
Last Update Posted:	July 25, 2013
Last Verified:	June 2013

Keywords provided by John Koreth, MD, Dana-Farber Cancer Institute:

Velcade; Bortezomib; Allogeneic Stem Cell Transplant; GVHD

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases; Methotrexate; Tacrolimus; Bortezomib; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites	Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors; Calcineurin Inhibitors