Post-Transplant Bortezomib and High Dose Cyclophosphamide as Graft-Versus-Host Disease (GVHD) Prophylaxis

Phase 1

Completed

Interventions: Drug: Cohort 1-Bortezomib (Velcade ®)
Drug: Cohort 2-Bortezomib (Velcade ®)
Drug: Cohort 3-Bortezomib (Velcade ®)

Brief Summary: The purpose of this study is to determine if Bortezomib, known commercially as Velcade is safe and tolerated at different dose levels (amounts) with high dose Cyclophosphamide to be used as graft versus host disease prevention after reduced-intensity allogeneic hematopoietic stem cell transplantation.

Detailed Description: It is hypothesized that the administration of an early and short course cyclophosphamide and bortezomib after allogeneic hematopoietic stem cell transplantationin in the setting of matched related or unrelated donor transplantation using a standard reduced-intensity conditioning regimen is feasible.

The study is a phase I study. The primary objective of the study is to determine the feasibility and safety of increasing doses of bortezomib administered post-transplant in conjunction with fixed high dose cyclophosphamide, also administered post-transplant in the setting of reduced-intensity allogeneic hematopoietic stem cell transplant, as GVHD prophylaxis strategy. Eligible patients will receive a conditioning regimen based on a combination of fludarabine and busulfan with or without rATG.

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Age <18 years
Poor performance status (<70%)
Active infections
Abnormal creatinine clearance <40ml/min
Elevated bilirubin >1.5 and ALT and AST .2 times the upper limit of normal
Poor ejection fraction <40%
DLCO <50%
Pregnant female.
HIV positive
Inability to provide informed consent
Patient has >/= Grade 2 peripheral neuropathy
Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
Patient has hypersensitivity to bortezomib, boron, or mannitol.
Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.

Arm && Interventions

Group	Intervention	Description
Cohort 1-Bortezomib (Velcade®)	Cohort 1-Bortezomib (Velcade ®)	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.
Cohort 2-Bortezomib (Velcade®)	Cohort 2-Bortezomib (Velcade ®)	Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.
Cohort 3-Bortezomib (Velcade®)	Cohort 3-Bortezomib (Velcade ®)	Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicity	Assessed daily (while inpatient) through clinical and laboratory examination up to 90 days.	Grade 3 non-hematologic Common Toxicity Criteria toxicity directly related to bortezomib (such as peripheral neuropathy) or Grade 2 or \> hepatic bilirubin Common Toxicity Criteria Graft failure

Secondary Outcome Measures

Name	Time	Method
Engraftment	Assessed daily by laboratory evaluation until engraftment or up to 90 days.	Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) \> 0.5 109/L for 3 consecutive measurements on different days. The first of the 3 days will be considered the day of neutrophil engraftment. Platelet engraftment is defined as platelet count \> 20 109/L for 3 consecutive measurements over at least 3 days. The first of the 3 days will be considered the day of platelet engraftment. In this study, graft failure is defined as lack of achieving neutrophil engraftment by day 22 and donor chimerism \> 50% by day 45.