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

Phase 2

Terminated

• Conditions: Stage I Multiple Myeloma; Stage III Multiple Myeloma; Refractory Multiple Myeloma; Stage II Multiple Myeloma
• Interventions: 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

• Registration Number: NCT01534143
• Lead Sponsor: Barbara Ann Karmanos Cancer Institute

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.

Study Timeline

• Study Start: 2012-02
• Study First Submitted: 2012-02-13
• Study First Submitted QC: 2012-02-15
• Study First Posted: 2012-02-16
• Primary Completion: 2013-05
• Study Completion: 2013-05
• Results First Submitted: 2013-10-22
• Results First Submitted QC: 2013-10-25
• Results First Posted: 2013-12-16
• Status Verified: 2017-03
• Last Update Submitted: 2017-03-08
• Last Update Posted: 2017-04-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemotherapy, enzyme inhibitor)	pharmacological study	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.
Treatment (chemotherapy, enzyme inhibitor)	anti-thymocyte globulin	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.
Treatment (chemotherapy, enzyme inhibitor)	fludarabine phosphate	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.
Treatment (chemotherapy, enzyme inhibitor)	busulfan	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.
Treatment (chemotherapy, enzyme inhibitor)	bortezomib	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.
Treatment (chemotherapy, enzyme inhibitor)	allogeneic hematopoietic stem cell transplantation	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.
Treatment (chemotherapy, enzyme inhibitor)	laboratory biomarker analysis	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.
Treatment (chemotherapy, enzyme inhibitor)	tacrolimus	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.
Treatment (chemotherapy, enzyme inhibitor)	sirolimus	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.

Primary Outcome Measures

Name	Time	Method
Time to Platelet Absolute Neutrophil Recovery (Engraftment)	First 6 months post-transplant	Estimated using Kaplan-Meier method.
Treatment Related Mortality Defined as Death in Continuous or Complete Remission	From the date of transplant to the date of death, assessed up to 6 months post transplant	Based on National Cancer Institute (NCI) CTCAE version 4.
Grade III and IV Non Hematologic Toxicities	First 6 months post transplant	Based on NCI CTCAE version 4.
Incidence and Severity of Acute GVHD Using Fludarabine Phosphate / Busulfan / Bortezomib Preparative Regimen and Triple Immune Suppression With Tacrolimus, Sirolimus and Anti-thymocyte Globulin	First 6 months post-transplant	Graded using the Glucksberg scale. Proportions and confidence intervals will be estimated. Estimated using binary proportion estimates as well as competing risk method.

Secondary Outcome Measures

Name	Time	Method
Incidence of Myeloma Progression	Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant
Incidence of SOS	Up to 2 years post transplant
Incidence and Severity of Chronic GVHD	Up to 2 years post transplant
Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation	Weekly to day 100
Incidence of Transplant Related Mortality and Morbidity	Up to 2 years post transplant
Incidence of TTP	Up to 2 years post transplant
Overall Survival	Up to 2 years post transplant
Progression Free Survival	From the day of transplant to progression, death, or last contact, assessed up to 2 years
Recovery of T-cell, B Cell and NK Cell Phenotypes	Days 30, 60, 90, and at 6 months after transplant

Trial Locations

Locations (1)

Barbara Ann Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States