Clinical trial NCT01009840: IV Busulfan Plus Bortezomib Conditioning Regimen for Second Autologous Stem Cell Transplant in Multiple Myeloma Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Bone marrow transplant
Stem cell transplant
Busulfan
Bortezomib
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2009-11-09
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age 18 to 75 years, inclusive.
2. Subjects must have multiple myeloma which requires treatment for relapsed disease and are eligible for the planned autologous HSCT.
3. Subjects must have had one previous autologous HSCT, at least one year prior to the planned autologous HSCT in this study.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
5. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test in all women of child-bearing potential.
6. 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.
7. Subjects in whom the minimum stem cell dose of 2.0 x 10\^6 cluster of differentiation 34 (CD34)+ cells/kg has been collected.
8. 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:

1. Prior treatment history of allogeneic HSCT for any medical reason, not limited to myeloma treatment.
2. 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.
3. Prior treatment with busulfan or gemtuzumab ozogamicin for any reason.
4. 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.
5. Systemic amyloidosis.
6. Known allergy to boron or any components of bortezomib.
7. 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.
8. Uncontrolled arrhythmia or symptomatic cardiac disease at the time of screening.
9. 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.
10. Aspartate transaminase (AST)/alanine transaminase (ALT) ≥ 3 x the upper limit of normal (ULN),
11. 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.
12. Hepatic synthetic dysfunction evident International Normalized Ratio (INR) ≥ 2.0 at the time of screening.
13. 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.
14. Prior total body irradiation therapy or radiation therapy directly applied to the liver.
15. 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.
16. Serum creatinine \>2.0 mg/dL at the time of Screening.
17. ≥ 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).
18. Women who are pregnant or lactating.
19. Current or history of drug and/or alcohol abuse.
20. Use of other investigational therapies within 30 days

Primary outcomes:
measure: Percentage of Participants With Overall Disease Response at Month 6
timeFrame: 6 Months
Secondary outcomes:
measure: Overall Survival
timeFrame: 6 Months
measure: Percentage of Participants With Overall Survival Events
timeFrame: 6 Months
measure: Progression-free Survival
timeFrame: 6 Months
measure: Percentage of Participants With Progression-free Survival Events
timeFrame: 6 Months
measure: Percent Change in IV Busulfan Dose
timeFrame: Baseline (Day -12 to -9), Day -5
measure: Ratio Area Under Curve (AUC)/Target AUC
timeFrame: Baseline (Day -12 to -9), Day -5
measure: Percent Difference Between Area Under Curve (AUC) and Target AUC
timeFrame: Baseline (Day -12 to -9), Day -5
measure: Percentage of Participants With Transplant-Related Mortality
timeFrame: 6 Months
measure: Percentage of Participants With Hepatic Veno-Occlusive Disease Based on Baltimore Criteria
timeFrame: 6 Months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine - Marlene & Stewart Greenebaum Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Philadelphia
country: United States
facility: University of Pennsylvania -Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: The Western Pennsylvania Hospital
state: Pennsylvania
city: San Antonio
country: United States
facility: South Texas Veterans Health Care System
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Physician Group, PLLC
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
References: