Bortezomib Before Donor Stem Cell Transplant in Treating Patients With Multiple Myeloma

Sponsor

Mayo Clinic (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00995059

Collaborator

(none)

Enrollment

Arm

Study Details

Study Description

Brief Summary

Rationale: Giving bortezomib and low doses of chemotherapy and total-body irradiation before a donor stem cell transplant or peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving sirolimus and tacrolimus before and after transplant may stop this from happening.

Purpose: This phase I/II trial is studying the side effects and best dose of bortezomib before donor stem cell transplant in treating patients with multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma Refractory Multiple Myeloma	Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Procedure: allogeneic bone marrow transplantation Drug: bortezomib Drug: melphalan Drug: anti-thymocyte globulin Drug: sirolimus Drug: tacrolimus Radiation: total-body irradiation	Phase 1/Phase 2

Detailed Description

Objectives:

To determine the maximum tolerated dose (MTD) of bortezomib when used in a novel conditioning regimen for patients undergoing allogeneic stem cell transplantation for multiple myeloma.
To evaluate the tolerability and feasibility of this novel conditioning regimen and GVHD prophylaxis strategy incorporating several anti-myeloma agents, including bortezomib, in patients undergoing allogeneic stem cell transplantation for multiple myeloma.
To obtain an initial assessment of the efficacy of this novel conditioning regimen.

Outline: This is a phase I dose-escalation study of bortezomib followed by a phase II study.

Reduced-Intensity Conditioning: Patients receive bortezomib IV and then undergo fractionated total-body irradiation on days -5 and -2. Patients receive thymoglobulin IV over 6 hours on days -5 to -2 and melphalan IV over 30 minutes on days -4 to -3.

Allogenic Stem Cell Transplantation: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

Graft versus Host Disease Prophylaxis: Beginning on day -3, patients receive oral sirolimus and taper beginning on day 61. Beginning on day -2, patients receive oral or IV tacrolimus and taper beginning on day 101. After completion of the study treatment, patients are followed every 3 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of a Novel Reduced Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation in Patients With Multiple Myeloma

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 CONDITIONING: Patients receive bortezomib IV and then undergo fractionated total-body irradiation on days -5 and -2. Patients receive thymoglobulin IV over 6 hours on days -5 to -2 and melphalan IV over 30 minutes on days -4 to -3. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Beginning on day -3, patients receive oral sirolimus and taper beginning on day 61. Beginning on day -2, patients receive oral or IV tacrolimus and taper beginning on day 101.	Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Undergo transplantation Procedure: allogeneic bone marrow transplantation Undergo transplantation Other Names: bone marrow therapy, allogeneic bone marrow therapy, allogenic transplantation, allogeneic bone marrow transplantation, allogenic bone marrow Drug: bortezomib Given IV Other Names: LDP 341 MLN341 PS-341 VELCADE Drug: melphalan Given IV Other Names: Alkeran CB-3025 L-PAM L-phenylalanine mustard L-Sarcolysin Melfalan Drug: anti-thymocyte globulin Given IV Other Names: ATG ATGAM lymphocyte immune globulin Thymoglobulin Drug: sirolimus Given orally Other Names: AY 22989 RAPA Rapamune rapamycin SILA 9268A SLM Drug: tacrolimus Given oral or IV Other Names: Advagraf FK 506 Prograf Protopic Radiation: total-body irradiation Undergo total-body irradiation Other Names: TBI

Arm

Intervention/Treatment

Experimental: Arm 1

CONDITIONING: Patients receive bortezomib IV and then undergo fractionated total-body irradiation on days -5 and -2. Patients receive thymoglobulin IV over 6 hours on days -5 to -2 and melphalan IV over 30 minutes on days -4 to -3. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Beginning on day -3, patients receive oral sirolimus and taper beginning on day 61. Beginning on day -2, patients receive oral or IV tacrolimus and taper beginning on day 101.

Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation

Undergo transplantation

Procedure: allogeneic bone marrow transplantation

Undergo transplantation

Other Names:

bone marrow therapy, allogeneic

bone marrow therapy, allogenic

transplantation, allogeneic bone marrow

transplantation, allogenic bone marrow

Drug: bortezomib

Given IV

Other Names:

LDP 341

MLN341

PS-341

VELCADE

Drug: melphalan

Given IV

Other Names:

Alkeran

CB-3025

L-PAM

L-phenylalanine mustard

L-Sarcolysin

Melfalan

Drug: anti-thymocyte globulin

Given IV

Other Names:

ATG

ATGAM

lymphocyte immune globulin

Thymoglobulin

Drug: sirolimus

Given orally

Other Names:

AY 22989

RAPA

Rapamune

rapamycin

SILA 9268A

SLM

Drug: tacrolimus

Given oral or IV

Other Names:

Advagraf

FK 506

Prograf

Protopic

Radiation: total-body irradiation

Undergo total-body irradiation

Other Names:

TBI

Outcome Measures

Primary Outcome Measures

Tolerability as assessed by CTCAE v3.0 (Phase I) []
Assessment of toxicity (Phase I) []
Proportion of successes []
Transplant-related mortality (TRM) (Phase II) [100 days]
Rate acute graft-vs-host disease (GVHD) (Phase I) []

Secondary Outcome Measures

Rate of grades II-IV and grades III-IV acute graft-vs-host disease (GVHD) []
Cumulative rate of chronic GVHD []
Overall response []
Overall survival []
Progression-free survival []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

ECOG performance status (PS) 0, 1, or 2
Diagnosis of symptomatic multiple myeloma
High risk myeloma as defined by progressive disease =< 12 months after high dose chemotherapy and autologous HSC transplant or presences of poor prognostic features such as deletion of chromosome 13 or hypodiploidy by standard cytogenetics, or t(4;

by fluorescence in situ hybridization (FISH), or t(14;16) by FISH, or 17p- by FISH, or plasma cell labeling index >= 3%

Availability of a HLA fully-matched or 1 mismatch related donor by low-resolution HLA typing for the loci A, B, C, DRB1 and DQB1 or HLA fully-matched unrelated donor by high-resolution typing for loci A, B, C and DRB1 and at least low-resolution for loci DQB1
Recovery from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and hematological toxicity)
Physically and psychologically capable of undergoing bone marrow or PBSC transplant
Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control for the during of the study
Male subject agrees to use an acceptable method for contraception for the duration of the study

Exclusion Criteria:

Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV hear failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
NOTE: Prior to study entry, and ECG abnormality at screening has to be documented by the investigator as not medically relevant
Significant cardiac dysfunction defined as left ventricle ejection fraction < 40% or presence of symptomatic coronary artery disease
Significant pulmonary disease defined as FEV < 50% or CLCO < 50% of the predicted values
Pre existing peripheral neuropathy grade > 1
Significant renal dysfunction defined as estimated creatinine clearance < 50 ml/min
Significant liver dysfunction defined as total bilirubin >= 2 x upper limit of normal (ULN) or AST, ALT >= 3 x ULN
Seroreactive for HIV, HTLV I or II, HBV, HCV
Presence of uncontrolled bacterial, viral, or fungal infection
Known allergy to any of the component of the investigational treatment regimen or required ancillary treatments
Considered unable to tolerate the included doses of total body irradiation due to previous treatment with radiation
Female subject is pregnant or breast-feeding
Other active concurrent malignancy
Prior allogeneic bone marrow/peripheral blood stem cell transplant
Received other investigational drugs =< 14 days prior to enrollment