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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I Trial of Post-Transplant Bortezomib and High Dose Cyclophosphamide as Graft-Versus-Host Disease (GVHD) Prophylaxis After Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)

Conditions
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Hematological Malignancy

Intervention / Treatment
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* Drug: Cohort 1-Bortezomib (Velcade ®)
* Drug: Cohort 2-Bortezomib (Velcade ®)
* Drug: Cohort 3-Bortezomib (Velcade ®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 8 out of 8 matched related or unrelated donor Age > 18 years Good performance status with a Karnofsky score >/= to 70% No evidence of progressive bacterial, viral or fungal infection despite adequate treatment Creatinine clearance > 40 mL/min/1.72m2 Total bilirubin < 1.5 and ALT and AST < 2 times the upper limit of normal Cardiac ejection fraction > 40% DLCO > 50% Negative pregnancy test Negative HIV serology Able to provide informed consent Female subject is either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse. Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse. 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.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1-Bortezomib (Velcade®)<br>Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. | Drug: Cohort 1-Bortezomib (Velcade ®)<br>* Conditioning Regimen: Fludarabine 30 mg/m2 on days -7, -6, -5, -4, -3 and -2; Busulfan 0.8 mg/kg, every 6 hours on days -3 and -2; Patients with matched unrelated donor also receive rATG (Thymoglobulin ®) 2 mg/kg on days -4, -3, -2 and -1. Cyclophosphamide 50 mg/kg, in 500 mL NS over 2 hours on days +3 and +4. Concomitant hydration with NS with 20 mEq/L at 250 mL/hr starting 4 hours before and continuing until 24 hours after the second dose is given. Furosemide on as needed basis to maintain fluid balance is also given. It is important to avoid administration of any immunosuppressive drugs include steroids after day 0. Bortezomib 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.<br>* Other names: Bortezomib (Velcade ®);|
| Active Comparator: Cohort 2-Bortezomib (Velcade®)<br>Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. | Drug: Cohort 2-Bortezomib (Velcade ®)<br>* Conditioning Regimen: Fludarabine 30 mg/m2 on days -7, -6, -5, -4, -3 and -2; Busulfan 0.8 mg/kg, every 6 hours on days -3 and -2; Patients with matched unrelated donor also receive rATG (Thymoglobulin ®) 2 mg/kg on days -4, -3, -2 and -1. Cyclophosphamide 50 mg/kg, in 500 mL NS over 2 hours on days +3 and +4. Concomitant hydration with NS with 20 mEq/L at 250 mL/hr starting 4 hours before and continuing until 24 hours after the second dose is given. Furosemide on as needed basis to maintain fluid balance is also given. It is important to avoid administration of any immunosuppressive drugs include steroids after day 0. Bortezomib 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.<br>* Other names: Bortezomib (Velcade ®);|
| Active Comparator: Cohort 3-Bortezomib (Velcade®)<br>Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. | Drug: Cohort 3-Bortezomib (Velcade ®)<br>* Conditioning Regimen: Fludarabine 30 mg/m2 on days -7, -6, -5, -4, -3 and -2; Busulfan 0.8 mg/kg, every 6 hours on days -3 and -2; Patients with matched unrelated donor also receive rATG (Thymoglobulin ®) 2 mg/kg on days -4, -3, -2 and -1. Cyclophosphamide 50 mg/kg, in 500 mL NS over 2 hours on days +3 and +4. Concomitant hydration with NS with 20 mEq/L at 250 mL/hr starting 4 hours before and continuing until 24 hours after the second dose is given. Furosemide on as needed basis to maintain fluid balance is also given. It is important to avoid administration of any immunosuppressive drugs include steroids after day 0. Bortezomib 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.<br>* Other names: Bortezomib (Velcade ®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | 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 | Assessed daily (while inpatient) through clinical and laboratory examination up to 90 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment | 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. | Assessed daily by laboratory evaluation until engraftment or up to 90 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRD, Blood and Marrow Transplant (BMT), MUD, GVHD