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

• Sponsor: Spectrum Health Hospitals (Other)
• Overall Status: Unknown status
• CT.gov ID: NCT01860170
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 28
• Location: 1
• Arms: 3
• Duration (Months): 71
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hematological Malignancy	Drug: Cohort 1-Bortezomib (Velcade ®); Drug: Cohort 2-Bortezomib (Velcade ®); Drug: Cohort 3-Bortezomib (Velcade ®)	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: 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)
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Mar 1, 2016
• Anticipated Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cohort 1-Bortezomib (Velcade®) 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 ®); 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.; Other Names: Cyclophosphamide (Cytoxan ®) Bortezomib (Velcade ®)
Active Comparator: Cohort 2-Bortezomib (Velcade®) Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.	Drug: Cohort 2-Bortezomib (Velcade ®); 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.; Other Names: Cyclophosphamide (Cytoxan ®) Bortezomib (Velcade ®)
Active Comparator: Cohort 3-Bortezomib (Velcade®) 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 ®); 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.; Other Names: Cyclophosphamide (Cytoxan ®) Bortezomib (Velcade ®)

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

Other Outcome Measures

1. GVHD [Assessed routinely by clinical and pathological evaluation. Acute GVHD will be assessed up to day 150 post-transplant. Chronic GVHD will be assess up to 2 years post-transplant.]

   aGVHD onset at a certain grade will be used to calculate the cumulative incidence for that grade (e.g., onset of grade 70 post-transplant , time to grade III is 70 days). This end point will be evaluated through day 150 post-transplant. The diagnosis of aGVHD is based on clinical and pathological evaluation by the treating physician. The first day of cGVHD will be used to calculate the cumulative incidence of cGVHD. The diagnosis of cGVHD is based on clinical and pathological evaluation by the treating physician.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. 8 out of 8 matched related or unrelated donor

2. Age > 18 years

3. Good performance status with a Karnofsky score >/= to 70%

4. No evidence of progressive bacterial, viral or fungal infection despite adequate treatment

5. Creatinine clearance > 40 mL/min/1.72m2

6. Total bilirubin < 1.5 and ALT and AST < 2 times the upper limit of normal

7. Cardiac ejection fraction > 40%

8. DLCO > 50%

9. Negative pregnancy test

10. Negative HIV serology

11. Able to provide informed consent

12. 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.

13. 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:

1. Age <18 years

2. Poor performance status (<70%)

3. Active infections

4. Abnormal creatinine clearance <40ml/min

5. Elevated bilirubin >1.5 and ALT and AST .2 times the upper limit of normal

6. Poor ejection fraction <40%

7. DLCO <50%

8. Pregnant female.

9. HIV positive

10. Inability to provide informed consent

11. Patient has >/= Grade 2 peripheral neuropathy

12. 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.

13. Patient has hypersensitivity to bortezomib, boron, or mannitol.

14. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

15. 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.

16. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Spectrum Health	Grand Rapids	Michigan	United States	49503

Sponsors and Collaborators

• Spectrum Health Hospitals
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: A. Samer Al-Homsi, MD, Spectrum Health Hospitals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: A. Samer Al-Homsi, Adult Blood and Marrow Transplant Physician, Spectrum Health Hospitals
• ClinicalTrials.gov Identifier: NCT01860170
• Other Study ID Numbers: 2013-083
• First Posted: May 22, 2013
• Last Update Posted: May 17, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by A. Samer Al-Homsi, Adult Blood and Marrow Transplant Physician, Spectrum Health Hospitals: Blood and Marrow Transplant (BMT); MRD; MUD; GVHD
• Additional relevant MeSH terms: Hematologic Neoplasms; Graft vs Host Disease; Cyclophosphamide; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Cohort 1-Bortezomib (Velcade®)	Cohort 2-Bortezomib (Velcade®)	Cohort 3-Bortezomib (Velcade®)
Arm/Group Description	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 1-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 2-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 3-Bortezomib (Velcade ®): 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.
Period Title: Overall Study
STARTED	3	3	22
COMPLETED	3	3	22
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1-Bortezomib (Velcade®)	Cohort 2-Bortezomib (Velcade®)	Cohort 3-Bortezomib (Velcade®)	Total
Arm/Group Description	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 1-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 2-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 3-Bortezomib (Velcade ®): 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.	Total of all reporting groups
Overall Participants	3	3	22	28
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	3 100%	17 77.3%	22 78.6%
>=65 years	1 33.3%	0 0%	5 22.7%	6 21.4%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	60.3	56	56.6	56.9
Sex: Female, Male (Count of Participants)
Female	3 100%	2 66.7%	7 31.8%	12 42.9%
Male	0 0%	1 33.3%	15 68.2%	16 57.1%
Region of Enrollment (Count of Participants)
United States	3 100%	3 100%	22 100%	28 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1-Bortezomib (Velcade®)	Cohort 2-Bortezomib (Velcade®)	Cohort 3-Bortezomib (Velcade®)
Arm/Group Description	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 1-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 2-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 3-Bortezomib (Velcade ®): 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.
Measure Participants	3	3	22
Count of Participants [Participants]	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Engraftment
Description	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.
Time Frame	Assessed daily by laboratory evaluation until engraftment or up to 90 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1-Bortezomib (Velcade®)	Cohort 2-Bortezomib (Velcade®)	Cohort 3-Bortezomib (Velcade®)
Arm/Group Description	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 1-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 2-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 3-Bortezomib (Velcade ®): 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.
Measure Participants	3	3	22
Neutrophil Engraftment	3 100%	3 100%	22 100%
Platelet Engraftment	3 100%	1 33.3%	22 100%
Graft Failure	0 0%	0 0%	0 0%

3. Other Pre-specified Outcome

Title	GVHD
Description	aGVHD onset at a certain grade will be used to calculate the cumulative incidence for that grade (e.g., onset of grade 70 post-transplant , time to grade III is 70 days). This end point will be evaluated through day 150 post-transplant. The diagnosis of aGVHD is based on clinical and pathological evaluation by the treating physician. The first day of cGVHD will be used to calculate the cumulative incidence of cGVHD. The diagnosis of cGVHD is based on clinical and pathological evaluation by the treating physician.
Time Frame	Assessed routinely by clinical and pathological evaluation. Acute GVHD will be assessed up to day 150 post-transplant. Chronic GVHD will be assess up to 2 years post-transplant.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1-Bortezomib (Velcade®)	Cohort 2-Bortezomib (Velcade®)	Cohort 3-Bortezomib (Velcade®)
Arm/Group Description	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 1-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 2-Bortezomib (Velcade ®): 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.	Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 3-Bortezomib (Velcade ®): 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.
Measure Participants	3	3	22
Acute GvHD Grade II-IV	0 0%	0 0%	10 45.5%
Acute GvHD Grade III-IV	0 0%	0 0%	3 13.6%
Chronic GvHD	1 33.3%	1 33.3%	5 22.7%

Adverse Events

Arm/Group Title	Cohort 1-Bortezomib (Velcade®)		Cohort 2-Bortezomib (Velcade®)		Cohort 3-Bortezomib (Velcade®)
Arm/Group Description	Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 1-Bortezomib (Velcade ®): 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.		Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 2-Bortezomib (Velcade ®): 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.		Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3. Cohort 3-Bortezomib (Velcade ®): 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.
All Cause Mortality
	Cohort 1-Bortezomib (Velcade®)		Cohort 2-Bortezomib (Velcade®)		Cohort 3-Bortezomib (Velcade®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		3/3 (100%)		10/22 (45.5%)
Serious Adverse Events
	Cohort 1-Bortezomib (Velcade®)		Cohort 2-Bortezomib (Velcade®)		Cohort 3-Bortezomib (Velcade®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/3 (33.3%)		6/22 (27.3%)
Blood and lymphatic system disorders
Syncope related to anemia	1/3 (33.3%)	1	0/3 (0%)	0	0/22 (0%)	0
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/3 (0%)	0	1/22 (4.5%)	1
General disorders
Hypovolemic shock	0/3 (0%)	0	0/3 (0%)	0	1/22 (4.5%)	1
Infections and infestations
Progressive multifocal leukoencephalopathy	0/3 (0%)	0	0/3 (0%)	0	1/22 (4.5%)	1
Fever	0/3 (0%)	0	1/3 (33.3%)	1	2/22 (9.1%)	2
HSV	1/3 (33.3%)	1	1/3 (33.3%)	1	0/22 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/3 (0%)	0	0/3 (0%)	0	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Cohort 1-Bortezomib (Velcade®)		Cohort 2-Bortezomib (Velcade®)		Cohort 3-Bortezomib (Velcade®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/3 (66.7%)		19/22 (86.4%)
Infections and infestations
Cytomegalovirus	1/3 (33.3%)	1	1/3 (33.3%)	1	14/22 (63.6%)	14
Epstein-Barr virus	0/3 (0%)	0	1/3 (33.3%)	1	9/22 (40.9%)	9
Respiratory syncytial virus	0/3 (0%)	0	1/3 (33.3%)	1	3/22 (13.6%)	3
BK virus	0/3 (0%)	0	0/3 (0%)	0	5/22 (22.7%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.