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

NCT ID: NCT01860170

Last Updated: 2023-06-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-04-30
• Study Completion Date: 2018-03-31

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.

Conditions

Hematological Malignancy

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Cohort 1-Bortezomib (Velcade®)

Bortezomib (Velcade®) 0.7 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.

Group Type: ACTIVE_COMPARATOR

Cohort 1-Bortezomib (Velcade ®)

Intervention Type: DRUG

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.

Cohort 2-Bortezomib (Velcade®)

Bortezomib (Velcade®) 1 mg/ m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.

Group Type: ACTIVE_COMPARATOR

Cohort 2-Bortezomib (Velcade ®)

Intervention Type: DRUG

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.

Cohort 3-Bortezomib (Velcade®)

Bortezomib (Velcade®) 1.3 mg/m2 rapid IV push on days 0 (at least 6 hours after transplant) and +3.

Group Type: ACTIVE_COMPARATOR

Cohort 3-Bortezomib (Velcade ®)

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Cyclophosphamide (Cytoxan ®); Bortezomib (Velcade ®); Cyclophosphamide (Cytoxan ®); Bortezomib (Velcade ®); Cyclophosphamide (Cytoxan ®); Bortezomib (Velcade ®)

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Spectrum Health Hospitals

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

A. Samer Al-Homsi, MD

Role: PRINCIPAL_INVESTIGATOR

Spectrum Health Hospitals

Locations

Spectrum Health

Grand Rapids, Michigan, United States

Countries

United States

Other Identifiers

2013-083

Identifier Type: -

Identifier Source: org_study_id