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

• ClinicalTrials.gov Identifier: NCT01860170
• Recruitment Status: Unknown
• First Posted: May 22, 2013
• Results First Posted: May 17, 2017
• Last Update Posted: May 17, 2017
• Sponsor: Spectrum Health Hospitals
• Collaborator: Millennium Pharmaceuticals, Inc.
• Information provided by (Responsible Party): A. Samer Al-Homsi, Spectrum Health Hospitals

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 (Clinical Trial)
• 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: April 2012
• Actual Primary Completion Date: March 2016
• Estimated Study Completion Date: March 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 [ Time Frame: 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 [ Time Frame: 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 [ 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. ]

   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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Michigan

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

More Information

• 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
• Results First Posted: May 17, 2017
• Last Update Posted: May 17, 2017
• Last Verified: April 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by A. Samer Al-Homsi, Spectrum Health Hospitals:

Blood and Marrow Transplant (BMT); MRD; MUD; GVHD

Additional relevant MeSH terms:

Hematologic Neoplasms; Graft vs Host Disease; Neoplasms; Immune System Diseases; Neoplasms by Site; Hematologic Diseases; Cyclophosphamide; Bortezomib; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists