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

This study has been terminated.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Zaid Al-Kadhimi, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier:
NCT01534143
First received: February 13, 2012
Last updated: October 25, 2013
Last verified: October 2013
  Purpose

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


Condition Intervention Phase
Refractory Multiple Myeloma
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Other: pharmacological study
Drug: tacrolimus
Drug: sirolimus
Biological: anti-thymocyte globulin
Drug: fludarabine phosphate
Drug: busulfan
Drug: bortezomib
Procedure: allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study Using High Dose Busulfan and Bortezomib as Part of Allogeneic Transplant Conditioning Regimen for High Risk Multiple Myeloma Patients.

Resource links provided by NLM:


Further study details as provided by Barbara Ann Karmanos Cancer Institute:

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 [ Time Frame: First 6 months post-transplant ] [ Designated as safety issue: No ]
    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) [ Time Frame: First 6 months post-transplant ] [ Designated as safety issue: No ]
    Estimated using Kaplan-Meier method.

  • Treatment Related Mortality Defined as Death in Continuous or Complete Remission [ Time Frame: From the date of transplant to the date of death, assessed up to 6 months post transplant ] [ Designated as safety issue: Yes ]
    Based on National Cancer Institute (NCI) CTCAE version 4.

  • Grade III and IV Non Hematologic Toxicities [ Time Frame: First 6 months post transplant ] [ Designated as safety issue: Yes ]
    Based on NCI CTCAE version 4.


Secondary Outcome Measures:
  • Incidence of Myeloma Progression [ Time Frame: Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant ] [ Designated as safety issue: No ]
  • Incidence of Transplant Related Mortality and Morbidity [ Time Frame: Up to 2 years post transplant ] [ Designated as safety issue: No ]
  • Incidence of TTP [ Time Frame: Up to 2 years post transplant ] [ Designated as safety issue: No ]
  • Incidence of SOS [ Time Frame: Up to 2 years post transplant ] [ Designated as safety issue: No ]
  • Incidence and Severity of Chronic GVHD [ Time Frame: Up to 2 years post transplant ] [ Designated as safety issue: No ]
  • Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation [ Time Frame: Weekly to day 100 ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: Up to 2 years post transplant ] [ Designated as safety issue: No ]
  • Progression Free Survival [ Time Frame: From the day of transplant to progression, death, or last contact, assessed up to 2 years ] [ Designated as safety issue: No ]
  • Recovery of T-cell, B Cell and NK Cell Phenotypes [ Time Frame: Days 30, 60, 90, and at 6 months after transplant ] [ Designated as safety issue: No ]

Enrollment: 1
Study Start Date: February 2012
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy, enzyme inhibitor)

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.

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Drug: tacrolimus
Given IV
Other Names:
  • FK 506
  • Prograf
Drug: sirolimus
Given PO
Other Names:
  • AY 22989
  • Rapamune
  • rapamycin
  • SLM
Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic HSCT
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01534143

Locations
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
Investigators
Principal Investigator: Zaid Al-Kadhimi Barbara Ann Karmanos Cancer Institute
  More Information

No publications provided

Responsible Party: Zaid Al-Kadhimi, Principal Investigator, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier: NCT01534143     History of Changes
Other Study ID Numbers: 2011-151, NCI-2012-00120
Study First Received: February 13, 2012
Results First Received: October 22, 2013
Last Updated: October 25, 2013
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
Antilymphocyte Serum
Bortezomib
Busulfan
Fludarabine
Fludarabine phosphate
Sirolimus
Tacrolimus
Vidarabine
Alkylating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on October 22, 2014