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High Dose Busulfan and Bortezomib in Treating Patients With High Risk Multiple Myeloma Undergoing Stem Cell Transplant

Primary Purpose

Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
pharmacological study
tacrolimus
sirolimus
anti-thymocyte globulin
fludarabine phosphate
busulfan
bortezomib
allogeneic hematopoietic stem cell transplantation
laboratory biomarker analysis
Sponsored by
Barbara Ann Karmanos Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Refractory Multiple Myeloma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Ability to provide informed consent
  • Karnofsky Performance Status (KPS) >= 70
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Availability of a suitable allogeneic hematopoietic stem cell donor; minimum of human leukocyte antigen (HLA) 7/8 matched related or unrelated donor
  • High risk multiple myeloma with poor prognostic features based on having one or more of the following criteria:
  • Progressive disease after autologous transplant. No less than 3 months post auto transplant
  • Progressive or stable disease after induction chemotherapy using the most potent myeloma agents Lenalidomide and/or Bortezomib
  • Patients with high risk cytogenetic abnormalities documented on conventional cytogenetics or fluorescence in situ hybridization (FISH) (hypodiploidy, t(4:14), t(14:16) chromosome translocation, p53 and or complex cytogenetics) additionally, chromosome 13 deletion by standard cytogenetics
  • Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test for women, as well as implementation of birth control for men and women

Exclusion Criteria:

  • Patients with prior allogeneic transplant, or more than one prior autologous transplant for any medical reason
  • Prior treatment with busulfan or gemtuzumab (Mylotarg ®) for any reason
  • Patient with history of allergy to boron, mannitol, or bortezomib
  • Creatinine clearance (CrCl) =< 50 ml/min
  • Ejection Fraction < 50%
  • Diffusion capacity of carbon monoxide (DLCO) < 50% predicted
  • Forced expiratory volume in 1 second (FEV1) < 50% predicted
  • Forced vital capacity (FVC) < 50% predicted
  • Patients with uncontrolled arrhythmia or uncontrolled heart disease at the screening time; patients with coronary heart disease (recent myocardial infarctions, angina, cardiac stent, or bypass surgery in the last 6 months) need to be cleared with a stress echo or nuclear myocardial perfusion stress test, and cardiology consult; all other cardiac history will be at the discretion of the principal investigator
  • Liver enzymes > 3 times upper limit normal
  • Bilirubin > 2 mg/dl (except Gilbert's disease)
  • International normalized ratio (INR) > 2
  • Any previous history of liver failure, hepatitis, or cirrhosis
  • Systemic Amyloidosis Known history of hepatitis B, C, human immunodeficiency virus (HIV) or any current uncontrolled infection
  • Grade > I neuropathy
  • Women who are pregnant or lactating
  • Current or history of alcohol or drug abuse
  • Use of other investigational agents within 30 days of enrollment to this study
  • Any patient with ascites
  • Any patient on home oxygen
  • Any clinical findings on history or physical exam which would in the opinion of the treating physician or principal investigator preclude the patient from participating in the study

Sites / Locations

  • Barbara Ann Karmanos Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (chemotherapy, enzyme inhibitor)

Arm Description

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -7 to -3, busulfan IV on days -6 to -3, and bortezomib IV on day -2. GVHD PROPHYLAXIS: Patients receive thymoglobulin IV on days -3 to -1, sirolimus PO on day -3, and tacrolimus IV on day -3. Patients undergo allogeneic HSCT on day 0.

Outcomes

Primary Outcome Measures

Incidence and Severity of Acute GVHD Using Fludarabine Phosphate / Busulfan / Bortezomib Preparative Regimen and Triple Immune Suppression With Tacrolimus, Sirolimus and Anti-thymocyte Globulin
Graded using the Glucksberg scale. Proportions and confidence intervals will be estimated. Estimated using binary proportion estimates as well as competing risk method.
Time to Platelet Absolute Neutrophil Recovery (Engraftment)
Estimated using Kaplan-Meier method.
Treatment Related Mortality Defined as Death in Continuous or Complete Remission
Based on National Cancer Institute (NCI) CTCAE version 4.
Grade III and IV Non Hematologic Toxicities
Based on NCI CTCAE version 4.

Secondary Outcome Measures

Incidence of Myeloma Progression
Incidence of Transplant Related Mortality and Morbidity
Incidence of TTP
Incidence of SOS
Incidence and Severity of Chronic GVHD
Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation
Overall Survival
Progression Free Survival
Recovery of T-cell, B Cell and NK Cell Phenotypes

Full Information

First Posted
February 13, 2012
Last Updated
March 8, 2017
Sponsor
Barbara Ann Karmanos Cancer Institute
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01534143
Brief Title
High Dose Busulfan and Bortezomib in Treating Patients With High Risk Multiple Myeloma Undergoing Stem Cell Transplant
Official Title
A Pilot Study Using High Dose Busulfan and Bortezomib as Part of Allogeneic Transplant Conditioning Regimen for High Risk Multiple Myeloma Patients.
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Terminated
Why Stopped
Data was not collected, because funding was unavailable to continue study.
Study Start Date
February 2012 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
May 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Barbara Ann Karmanos Cancer Institute
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot phase II trial studies how well giving high dose busulfan together with bortezomib works in treating patients with high risk multiple myeloma undergoing stem cell transplant. Drugs used in chemotherapy, such as busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cells growth. Giving busulfan together with bortezomib before a stem cell transplant may kill more cancer cells
Detailed Description
PRIMARY OBJECTIVES: I. To determine time to engraftment absolute neutrophil count (> 0.5 x 10^9/L for 3 consecutive days), and platelet (> 20X 109^/L for 3 consecutive days). 2. Incidence and severity of acute graft-versus-host disease (GVHD) using fludarabine (fludarabine phosphate) / busulfan / bortezomib preparative regimen and triple immune suppression with tacrolimus, sirolimus and Thymoglobulin (anti-thymocyte globulin). 3. To determine the safety related to this combination in the first six months post transplant, specifically, treatment related mortality and grade III and IV non hematologic toxicities, based on Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v4). SECONDARY OBJECTIVES: I. Incidence of myeloma progression in this high risk group of patients. II. Incidence of transplant related mortality and morbidity. III. Incidence of thrombotic thrombocytopenic purpura (TTP) and sinusoidal obstructive syndrome (SOS). IV. Incidence and severity of chronic GVHD. V. Incidence of opportunistic infections including cytomegalovirus (CMV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV) reactivation. I. Overall and progression free survival (PFS) at Day 100, 6 months, 1 & 2 years post transplant. VII. To determine recovery of T-cell, B cell, and natural killer (NK) cell phenotypes post transplant. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -7 to -3, busulfan IV on days -6 to -3, and bortezomib IV on day -2. GVHD PROPHYLAXIS: Patients receive anti-thymocyte globulin IV on days -3 to -1, sirolimus orally (PO) on day -3, and tacrolimus IV on day -3. Patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. After completion of study treatment, patients are followed up for up to 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (chemotherapy, enzyme inhibitor)
Arm Type
Experimental
Arm Description
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -7 to -3, busulfan IV on days -6 to -3, and bortezomib IV on day -2. GVHD PROPHYLAXIS: Patients receive thymoglobulin IV on days -3 to -1, sirolimus PO on day -3, and tacrolimus IV on day -3. Patients undergo allogeneic HSCT on day 0.
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
FK 506, Prograf
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
sirolimus
Other Intervention Name(s)
AY 22989, Rapamune, rapamycin, SLM
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
anti-thymocyte globulin
Other Intervention Name(s)
ATG, ATGAM, lymphocyte immune globulin, Thymoglobulin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
BSF, BU, Misulfan, Mitosan, Myeloleukon
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, VELCADE
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic HSCT
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Incidence and Severity of Acute GVHD Using Fludarabine Phosphate / Busulfan / Bortezomib Preparative Regimen and Triple Immune Suppression With Tacrolimus, Sirolimus and Anti-thymocyte Globulin
Description
Graded using the Glucksberg scale. Proportions and confidence intervals will be estimated. Estimated using binary proportion estimates as well as competing risk method.
Time Frame
First 6 months post-transplant
Title
Time to Platelet Absolute Neutrophil Recovery (Engraftment)
Description
Estimated using Kaplan-Meier method.
Time Frame
First 6 months post-transplant
Title
Treatment Related Mortality Defined as Death in Continuous or Complete Remission
Description
Based on National Cancer Institute (NCI) CTCAE version 4.
Time Frame
From the date of transplant to the date of death, assessed up to 6 months post transplant
Title
Grade III and IV Non Hematologic Toxicities
Description
Based on NCI CTCAE version 4.
Time Frame
First 6 months post transplant
Secondary Outcome Measure Information:
Title
Incidence of Myeloma Progression
Time Frame
Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant
Title
Incidence of Transplant Related Mortality and Morbidity
Time Frame
Up to 2 years post transplant
Title
Incidence of TTP
Time Frame
Up to 2 years post transplant
Title
Incidence of SOS
Time Frame
Up to 2 years post transplant
Title
Incidence and Severity of Chronic GVHD
Time Frame
Up to 2 years post transplant
Title
Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation
Time Frame
Weekly to day 100
Title
Overall Survival
Time Frame
Up to 2 years post transplant
Title
Progression Free Survival
Time Frame
From the day of transplant to progression, death, or last contact, assessed up to 2 years
Title
Recovery of T-cell, B Cell and NK Cell Phenotypes
Time Frame
Days 30, 60, 90, and at 6 months after transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ability to provide informed consent Karnofsky Performance Status (KPS) >= 70 Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Availability of a suitable allogeneic hematopoietic stem cell donor; minimum of human leukocyte antigen (HLA) 7/8 matched related or unrelated donor High risk multiple myeloma with poor prognostic features based on having one or more of the following criteria: Progressive disease after autologous transplant. No less than 3 months post auto transplant Progressive or stable disease after induction chemotherapy using the most potent myeloma agents Lenalidomide and/or Bortezomib Patients with high risk cytogenetic abnormalities documented on conventional cytogenetics or fluorescence in situ hybridization (FISH) (hypodiploidy, t(4:14), t(14:16) chromosome translocation, p53 and or complex cytogenetics) additionally, chromosome 13 deletion by standard cytogenetics Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test for women, as well as implementation of birth control for men and women Exclusion Criteria: Patients with prior allogeneic transplant, or more than one prior autologous transplant for any medical reason Prior treatment with busulfan or gemtuzumab (Mylotarg ®) for any reason Patient with history of allergy to boron, mannitol, or bortezomib Creatinine clearance (CrCl) =< 50 ml/min Ejection Fraction < 50% Diffusion capacity of carbon monoxide (DLCO) < 50% predicted Forced expiratory volume in 1 second (FEV1) < 50% predicted Forced vital capacity (FVC) < 50% predicted Patients with uncontrolled arrhythmia or uncontrolled heart disease at the screening time; patients with coronary heart disease (recent myocardial infarctions, angina, cardiac stent, or bypass surgery in the last 6 months) need to be cleared with a stress echo or nuclear myocardial perfusion stress test, and cardiology consult; all other cardiac history will be at the discretion of the principal investigator Liver enzymes > 3 times upper limit normal Bilirubin > 2 mg/dl (except Gilbert's disease) International normalized ratio (INR) > 2 Any previous history of liver failure, hepatitis, or cirrhosis Systemic Amyloidosis Known history of hepatitis B, C, human immunodeficiency virus (HIV) or any current uncontrolled infection Grade > I neuropathy Women who are pregnant or lactating Current or history of alcohol or drug abuse Use of other investigational agents within 30 days of enrollment to this study Any patient with ascites Any patient on home oxygen Any clinical findings on history or physical exam which would in the opinion of the treating physician or principal investigator preclude the patient from participating in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zaid Al-Kadhimi
Organizational Affiliation
Barbara Ann Karmanos Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States

12. IPD Sharing Statement

Learn more about this trial

High Dose Busulfan and Bortezomib in Treating Patients With High Risk Multiple Myeloma Undergoing Stem Cell Transplant

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