High Dose Busulfan and Bortezomib in Treating Patients With High Risk Multiple Myeloma Undergoing Stem Cell Transplant
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
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. |
- 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.
- 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 ]
| Estimated Enrollment: | 22 |
| Study Start Date: | February 2012 |
| Estimated Primary Completion Date: | December 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:
Drug: sirolimus
Given PO
Other Names:
Biological: anti-thymocyte globulin
Given IV
Other Names:
Drug: fludarabine phosphate
Given IV
Other Names:
Drug: busulfan
Given IV
Other Names:
Drug: bortezomib
Given IV
Other Names:
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 |
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| United States, Michigan | |
| Barbara Ann Karmanos Cancer Institute | Recruiting |
| Detroit, Michigan, United States, 48201 | |
| Contact: Zaid S. Al-Kadhimi 313-576-8022 alkadhiz@karmanos.org | |
| Principal Investigator: Zaid S. Al-Kadhimi | |
| Sub-Investigator: Muneer Abidi, M.D. | |
| Sub-Investigator: Lois Ayash, M.D. | |
| Sub-Investigator: Abhinav Deol, M.D. | |
| Sub-Investigator: Lawrence Lum, M.D. | |
| Sub-Investigator: Voravit Ratanatharathorn, M.D. | |
| Sub-Investigator: Joseph Uberti, M.D. | |
| Principal Investigator: | Zaid Al-Kadhimi | Barbara Ann Karmanos Cancer Institute |
More Information
No publications provided
| Responsible Party: | Al-Kadhimi, Zaid, 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 |
| Last Updated: | March 28, 2012 |
| Health Authority: | United States: Federal Government |
Additional relevant MeSH terms:
|
Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Antilymphocyte Serum |
Busulfan Fludarabine monophosphate Sirolimus Everolimus Tacrolimus Immunoglobulins Fludarabine Bortezomib Vidarabine Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antineoplastic Agents, Alkylating Alkylating Agents |
ClinicalTrials.gov processed this record on May 23, 2013