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

Hematologic Malignancies Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00369226
• Other study ID #: 06-065
• Secondary ID: X05175
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: August 24, 2006
• Last updated: June 19, 2013
• Start date: August 2006
• Est. completion date: September 2011

Study information

• Verified date: June 2013
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: September 2011
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Graft vs Host Disease
• Hematologic Malignancies

Intervention

Drug:
• Bortezomib (Velcade)
Infusion for a total of 3 doses
• Tacrolimus
Taken until Doctor determines it is not necessary any more
• Methotrexate
Infusion for a total of 4 doses

Procedure:
• blood stem cell transplantation
Allogeneic Non-myeloablative peripheral blood stem cell transplantation

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts

Sponsors (3)

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	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	No
Primary	Incidence of Grade II-IV Acute Graft Versus Host Disease (GVHD) by Day 100.		by day 100 after peripheral blood stem cell (PBSC) infusion	Yes
Secondary	Sustained Engraftment Following Transplant.	As measured by median total donor chimerism at day 100.	by day 100 post transplant	No
Secondary	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	Yes
Secondary	Overall Survival and Progression-free Survival.	Progression is defined as disease relapse or disease progression since transplant.	by 1 year after PBSC infusion	No