Hematological Malignancy
Conditions
Keywords
Blood and Marrow Transplant (BMT), MRD, MUD, GVHD
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.
Interventions
DRUGCohort 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.
DRUGCohort 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.
DRUGCohort 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.
Sponsors
Millennium Pharmaceuticals, Inc.
Corewell Health West
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 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. | 3 |
| Cohort 2-Bortezomib (Velcade®) 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. | 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.
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. | 22 |
| Total | 28 |
Baseline characteristics
| Characteristic | Cohort 2-Bortezomib (Velcade®) | Cohort 3-Bortezomib (Velcade®) | Cohort 1-Bortezomib (Velcade®) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 5 Participants | 1 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 17 Participants | 2 Participants | 22 Participants |
| Age, Continuous | 56 years | 56.6 years | 60.3 years | 56.9 years |
| Region of Enrollment United States | 3 Participants | 22 Participants | 3 Participants | 28 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 15 Participants | 0 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 3 / 3 | 10 / 22 |
| other Total, other adverse events | 1 / 3 | 2 / 3 | 19 / 22 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 6 / 22 |
Outcome results
Primary
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
Time frame: Assessed daily (while inpatient) through clinical and laboratory examination up to 90 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1-Bortezomib (Velcade®) | Dose Limiting Toxicity | 0 Participants |
| Cohort 2-Bortezomib (Velcade®) | Dose Limiting Toxicity | 0 Participants |
| Cohort 3-Bortezomib (Velcade®) | Dose Limiting Toxicity | 0 Participants |
Secondary
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.
Time frame: Assessed daily by laboratory evaluation until engraftment or up to 90 days.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1-Bortezomib (Velcade®) | Engraftment | Platelet Engraftment | 3 Participants |
| Cohort 1-Bortezomib (Velcade®) | Engraftment | Neutrophil Engraftment | 3 Participants |
| Cohort 1-Bortezomib (Velcade®) | Engraftment | Graft Failure | 0 Participants |
| Cohort 2-Bortezomib (Velcade®) | Engraftment | Platelet Engraftment | 1 Participants |
| Cohort 2-Bortezomib (Velcade®) | Engraftment | Neutrophil Engraftment | 3 Participants |
| Cohort 2-Bortezomib (Velcade®) | Engraftment | Graft Failure | 0 Participants |
| Cohort 3-Bortezomib (Velcade®) | Engraftment | Neutrophil Engraftment | 22 Participants |
| Cohort 3-Bortezomib (Velcade®) | Engraftment | Graft Failure | 0 Participants |
| Cohort 3-Bortezomib (Velcade®) | Engraftment | Platelet Engraftment | 22 Participants |
Other Pre-specified
GVHD
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-Bortezomib (Velcade®) | GVHD | Acute GvHD Grade II-IV | 0 participants |
| Cohort 1-Bortezomib (Velcade®) | GVHD | Chronic GvHD | 1 participants |
| Cohort 1-Bortezomib (Velcade®) | GVHD | Acute GvHD Grade III-IV | 0 participants |
| Cohort 2-Bortezomib (Velcade®) | GVHD | Acute GvHD Grade II-IV | 0 participants |
| Cohort 2-Bortezomib (Velcade®) | GVHD | Chronic GvHD | 1 participants |
| Cohort 2-Bortezomib (Velcade®) | GVHD | Acute GvHD Grade III-IV | 0 participants |
| Cohort 3-Bortezomib (Velcade®) | GVHD | Chronic GvHD | 5 participants |
| Cohort 3-Bortezomib (Velcade®) | GVHD | Acute GvHD Grade III-IV | 3 participants |
| Cohort 3-Bortezomib (Velcade®) | GVHD | Acute GvHD Grade II-IV | 10 participants |