Clinical trial NCT00369226: Bortezomib Plus Tacrolimus and Methotrexate to Prevent Graft Versus Host Disease (GVHD) After Mismatched Allogeneic Non-Myeloablative Blood Stem Cell Transplantation
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematologic Malignancies
Keywords: Velcade
Bortezomib
Allogeneic Stem Cell Transplant
GVHD
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Brigham and Women's Hospital
name: Millennium Pharmaceuticals, Inc.
First posted: 2006-08-29
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: by day 45 post PBSC infusion
measure: Successful Initial Engraftment by Day 45 Post Peripheral Blood Stem Cell (PBSC) Infusion and Administration of Bortezomib (Velcade), Tacrolimus and Methotrexate
timeFrame: by day 45 post PBSC infusion
measure: Incidence of Grade II-IV Acute Graft Versus Host Disease (GVHD) by Day 100.
timeFrame: by day 100 after peripheral blood stem cell (PBSC) infusion
Secondary outcomes:
measure: Sustained Engraftment Following Transplant.
timeFrame: by day 100 post transplant
measure: Incidence of Chronic Graft Versus Host Disease (Chronic GVHD).
timeFrame: by 1 year after PBSC infusion
measure: Overall Survival and Progression-free Survival.
timeFrame: by 1 year after PBSC infusion
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cance Institute
name: John Koreth, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.