IV Busulfan Plus Bortezomib Conditioning Regimen for Second Autologous Stem Cell Transplant in Multiple Myeloma Patients

Study Overview
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Brief Summary
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Study for the outcome and safety of individualized busulfan dosing with bortezomib for patients preparing for a second stem cell transplant to treat multiple myeloma.

Detailed Description
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Evaluation of six-month response in relapsed multiple myeloma subjects, who have had a prior autologous HSCT (greater than one year previously) receiving an IV busulfan-based conditioning regimen with the combination of pharmacokinetic (PK)-guided IV busulfan dosing and bortezomib, followed by a second autologous HSCT. Assessment of the safety profile of this conditioning regimen will also be completed.

Official Title
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A Phase 2a Study of Once Daily Intravenous Busulfan With Bortezomib, Followed by an Autologous Hematopoietic Stem Cell Transplant (HSCT) in Subjects With Relapsed Multiple Myeloma After Prior Autologous HSCT

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: IV busulfan
* Drug: bortezomib
* Procedure: Autologous Hematopoietic Stem Cell Transplant (HSCT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 75 years, inclusive. Subjects must have multiple myeloma which requires treatment for relapsed disease and are eligible for the planned autologous HSCT. Subjects must have had one previous autologous HSCT, at least one year prior to the planned autologous HSCT in this study. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test in all women of child-bearing potential. Subjects who are surgically sterile (ie, have undergone orchidectomy or hysterectomy); female subjects who have been postmenopausal for at least 12 consecutive months; or subjects who agree to remain abstinent or to practice double-barrier forms of birth control from trial screening through 30 days (for females) and 90 days (for males) from the last dose of the investigational medicinal product (IMP). If employing birth control, two of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device (IUD), birth control pill, birth control implant, condom, or sponge with spermicide. Subjects in whom the minimum stem cell dose of 2.0 x 10^6 cluster of differentiation 34 (CD34)+ cells/kg has been collected. Ability to provide written informed consent prior to initiation of any study-related procedures, and ability, in the opinion of the Principal Investigator, to comply with all requirements of the study. Exclusion Criteria: Prior treatment history of allogeneic HSCT for any medical reason, not limited to myeloma treatment. Prior treatment history of more than one autologous HSCT or high-dose chemotherapy with stem cell rescue for any medical reason, not limited to myeloma treatment. Prior treatment with busulfan or gemtuzumab ozogamicin for any reason. Presence of a t(4;14) or p53 gene deletion as determined by fluorescence in situ hybridization (FISH) during the screening process or documented t(4; 14) or p53 gene deletion obtained during a time of active disease by any method. Systemic amyloidosis. Known allergy to boron or any components of bortezomib. Left ventricular ejection fraction (LVEF) < 45% as measured by either multi-gated acquisition scan (MUGA) or echocardiogram (ECHO) performed within 75 days prior to day of busulfan test dose. If cyclophosphamide was used for stem cell harvest, an ECHO or MUGA must be done prior to enrollment to confirm adequate cardiac function. Uncontrolled arrhythmia or symptomatic cardiac disease at the time of screening. Symptomatic pulmonary disease, based on Forced Expiratory Volume in 1 Second (FEV1), Forced Vital Capacity (FVC) or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) < 50% of predicted (corrected for hemoglobin) measured within 75 days prior to day of busulfan test dose. Aspartate transaminase (AST)/alanine transaminase (ALT) ≥ 3 x the upper limit of normal (ULN), History of elevated total serum bilirubin >2 mg/dL that had been caused by previous chemotherapy at any point, or total bilirubin > 2.0 mg/dL at the time of screening with the exception of Gilbert's disease. Hepatic synthetic dysfunction evident International Normalized Ratio (INR) ≥ 2.0 at the time of screening. Any previous history of fulminant liver failure, cirrhosis, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, and symptomatic biliary disease. Prior total body irradiation therapy or radiation therapy directly applied to the liver. Known history of or current hepatitis B, hepatitis C, HIV, or uncontrolled active infection of any kind at the time of test dose. If serology antibody studies are positive, a quantitative polymerase chain reaction (PCR) must be completed to confirm lack of active infection. Serum creatinine >2.0 mg/dL at the time of Screening. ≥ Grade 1 neuropathy with pain, or > Grade 2 neuropathy without pain (subjects with neuropathy caused by a previous regimen that is recovered to ≤ Grade 2 and stable without pain may be included). Women who are pregnant or lactating. Current or history of drug and/or alcohol abuse. Use of other investigational therapies within 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV busulfan<br>Intravenous (IV) busulfan was administered as a single daily 3-hour continuous infusion based on the PK-directed dose recommendation for 4 days beginning on Day -5 followed by a single bortezomib 1.3 mg/m^2 dose administered as a 3 to 5-second bolus IV injection on Day -1 prior to HSCT. | Drug: IV busulfan<br>* PK-directed dosing of IV busulfan for 4 days<br>* Other names: Busulfex®;Drug: bortezomib<br>* Single IV bortezomib at a dose of 1.3 mg/m^2.<br>* Other names: Velcade®;Procedure: Autologous Hematopoietic Stem Cell Transplant (HSCT)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Disease Response at Month 6 | The percentage of participants reported in each disease category by International Myeloma Working Group (IMWG) uniform response criteria for Multiple Myeloma 6 months after autologous Hematopoietic stem cell transplant. Overall Disease Response categories were: [stringent Complete Response (sCR)=CR + normal Free Light Chain (FLC) ratio + absence of clonal cells in bone marrow], [Complete Response (CR)=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow], [Very Good Partial Response (VGPR)=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein + urine M-protein level <100 mg/24 hour], [Partial Response (PR)=≥50% reduction of serum M-protein and reduction in 24 hour urine M-protein by ≥90% or to <200 mg per 24 hour], [Stable Disease (SD)=Not meeting criteria for CR, VGPR, PR or progressive disease] or [Progressive Disease (PD)]. | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival was defined as the time in days from transplantation to death due to all causes. | 6 Months | 
| Percentage of Participants With Overall Survival Events | Overall Survival Event was death. | 6 Months | 
| Progression-free Survival | Progression-free Survival (PFS) defined as the time from transplantation to the occurrence of the event that was death or first recurrence of progressive disease (PD) by IMWG criteria. PD was defined as an Increase of ≥25% from the lowest response value in any one or more of the following: 1)Serum M-component and/or (the absolute increase must be ≥0.5 g/dL), 2)Urine M-component and/or (the absolute increase must be ≥200 mg/24 hr), 3)In patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL, 4)Bone marrow plasma cell percentage; the absolute percentage must be ≥10%, 5)Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas and/or 6)Development of hypercalcaemia that can be attributed solely to the plasma cell proliferative diso | 6 Months | 
| Percentage of Participants With Progression-free Survival Events | Progression-free survival events are death or first recurrence of progressive disease by International Myeloma Working Group Criteria. | 6 Months | 
| Percent Change in IV Busulfan Dose | The percent change in dose is relative to the busulfan dose administered at the Baseline Visit (Day -12 to -9) when a dose of 0.8 mg/kg was administered and on Day -5 when the Seattle Cancer Care Alliance recommended PK-adjusted dose was administered. | Baseline (Day -12 to -9), Day -5 | 
| Ratio Area Under Curve (AUC)/Target AUC | A test dose of IV busulfan 0.8 mg/kg was infused at Baseline (Day -12 to -9) to verify a target busulfan integrated AUC of 20,000 μM*min with a range of 16,000 to 24,000. If necessary the dose could be adjusted. The PK-directed dose recommendation based on the test dose was administered at Day -5. Blood samples for PK analysis were collected at 0, 15, 30 minutes after the End of Infusion and 240, 300, 360 minutes after start of the infusion. Gas chromatography with mass selective detection (GC-MS) was used to determine the busulfan level in plasma. The ratio was calculated: AUC/Target AUC. | Baseline (Day -12 to -9), Day -5 | 
| Percent Difference Between Area Under Curve (AUC) and Target AUC | A test dose of IV busulfan 0.8 mg/kg was infused at Baseline (Day -12 to -9) to verify a target busulfan integrated AUC of 20,000 μM*min with a range of 16,000 to 24,000. If necessary the dose could be adjusted. The PK-directed dose recommendation based on the test dose was administered at Day -5. Blood samples for PK analysis were collected at 0, 15, 30 minutes after the End of Infusion and 240, 300, 360 minutes after start of the infusion. GC-MS was used to determine the busulfan level in plasma. The percent difference was calculated between AUC and the Target AUC. | Baseline (Day -12 to -9), Day -5 | 
| Percentage of Participants With Transplant-Related Mortality | The percentage of participants with death related to transplant. | 6 Months | 
| Percentage of Participants With Hepatic Veno-Occlusive Disease Based on Baltimore Criteria | The Baltimore criteria for veno-occlusive disease was defined as the development of hyperbilirubinemia with serum bilirubin > 2 mg/dl within 21 days after transplantation and at least 2 of the following clinical signs and symptoms: (1) hepatomegaly, usually painful, (2) > 5% weight gain, or (3) ascites. | 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Bone marrow transplant, Stem cell transplant, Busulfan, Bortezomib