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

Refractory Multiple Myeloma Clinical Trial

Official title:

A Pilot Study Using High Dose Busulfan and Bortezomib as Part of Allogeneic Transplant Conditioning Regimen for High Risk Multiple Myeloma Patients.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01534143
• Other study ID #: 2011-151
• Secondary ID: NCI-2012-00120
• Status: Terminated
• Phase: Phase 2
• First received: February 13, 2012
• Last updated: December 9, 2015
• Start date: February 2012
• Est. completion date: May 2013

Study information

• Verified date: December 2015
• Source: Barbara Ann Karmanos Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: May 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 (ß-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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Refractory Multiple Myeloma
• Stage I Multiple Myeloma
• Stage II Multiple Myeloma
• Stage III Multiple Myeloma

Intervention

Other:
• pharmacological study
Correlative studies

Drug:
• tacrolimus
Given IV
• sirolimus
Given PO

Biological:
• anti-thymocyte globulin
Given IV

Drug:
• fludarabine phosphate
Given IV
• busulfan
Given IV
• bortezomib
Given IV

Procedure:
• allogeneic hematopoietic stem cell transplantation
Undergo allogeneic HSCT

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Barbara Ann Karmanos Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	First 6 months post-transplant	No
Primary	Time to Platelet Absolute Neutrophil Recovery (Engraftment)	Estimated using Kaplan-Meier method.	First 6 months post-transplant	No
Primary	Treatment Related Mortality Defined as Death in Continuous or Complete Remission	Based on National Cancer Institute (NCI) CTCAE version 4.	From the date of transplant to the date of death, assessed up to 6 months post transplant	Yes
Primary	Grade III and IV Non Hematologic Toxicities	Based on NCI CTCAE version 4.	First 6 months post transplant	Yes
Secondary	Incidence of Myeloma Progression		Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant	No
Secondary	Incidence of Transplant Related Mortality and Morbidity		Up to 2 years post transplant	No
Secondary	Incidence of TTP		Up to 2 years post transplant	No
Secondary	Incidence of SOS		Up to 2 years post transplant	No
Secondary	Incidence and Severity of Chronic GVHD		Up to 2 years post transplant	No
Secondary	Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation		Weekly to day 100	No
Secondary	Overall Survival		Up to 2 years post transplant	No
Secondary	Progression Free Survival		From the day of transplant to progression, death, or last contact, assessed up to 2 years	No
Secondary	Recovery of T-cell, B Cell and NK Cell Phenotypes		Days 30, 60, 90, and at 6 months after transplant	No