Bortezomib, Melphalan, and Total-Body Irradiation Before Stem Cell Transplant in Treating Patients With Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Mayo Clinic
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01936090
First received: September 1, 2013
Last updated: May 1, 2014
Last verified: May 2014
  Purpose

This phase I/II trial studies the side effects and best dose of bortezomib when given together with melphalan, and total-body irradiation before stem cell transplant and to see how well it works in treating patients with multiple myeloma . Giving chemotherapy and total-body irradiation before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. The stem cells that were collected from the patient's blood or bone marrow are returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and total-body irradiation.


Condition Intervention Phase
Refractory Multiple Myeloma
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Drug: bortezomib
Radiation: total-body irradiation
Drug: melphalan
Procedure: autologous bone marrow transplantation
Procedure: autologous hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Other: laboratory biomarker analysis
Phase 1
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: Phase I/II Bortezomib, Melphalan and Low Dose TBI Conditioning for Patients Undergoing Autologous Stem Cell Transplantation for Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • MTD defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (phase I) [ Time Frame: Up to day 5 ] [ Designated as safety issue: Yes ]
  • The number and severity of all adverse events (phase I) [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    Will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.

  • Proportion of complete responses (CR) defined as a CR noted as the objective status on two consecutive evaluations (phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.


Secondary Outcome Measures:
  • CR rate at day 100 estimated by the total number of patients who achieve a complete CR by day 100 post-transplant divided by the total number of evaluable patients [ Time Frame: At day 100 ] [ Designated as safety issue: No ]
    Exact binomial 95% confidence intervals for the true CR rate at day 100 will be calculated.

  • Time to progression [ Time Frame: Time from registration to the earliest date with documentation of disease progression, assessed at 1 year ] [ Designated as safety issue: No ]
    Will be estimated using the method of Kaplan-Meier.

  • Time to progression [ Time Frame: Time from registration to the earliest date with documentation of disease progression, assessed at 2 years ] [ Designated as safety issue: No ]
    Will be estimated using the method of Kaplan-Meier.

  • Maximum grade for each type of adverse event [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    Will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.


Other Outcome Measures:
  • Proportion of patients who achieve MRD negative status estimated by the number of patients who are MRD negative divided by the total number of evaluable patients who achieve a CR [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Exact binomial 95% confidence intervals for the true MRD negative rate will be calculated.

  • Abnormal ratio and suppressed uninvolved immunoglobulin assessed by HevyLite assay [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The correlation of these categories with whether MRD is present (yes vs. no) will be evaluated using Fisher's exact test. In addition, the relationship between these categories and time to progression will be evaluated using Kaplan-Meier methods and log-rank statistics.


Estimated Enrollment: 69
Study Start Date: September 2013
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (bortezomib, TBI, melphalan, stem cell transplant)

Conditioning regimen: Patients receive bortezomib IV on days -5 and -2, TBI BID on days -5 and -2, and melphalan IV over 1 hour on days -4 and -3.

Transplant: Patients undergo autologous bone marrow or peripheral blood stem cell transplant on day 0.

Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Procedure: autologous bone marrow transplantation
Undergo autologous bone marrow transplant
Other Names:
  • ABMT
  • bone marrow transplantation, autologous
  • transplantation, autologous bone marrow
Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous peripheral blood stem cell transplant
Procedure: peripheral blood stem cell transplantation
Undergo autologous peripheral blood stem cell transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of bortezomib that can be added to high dose melphalan and low dose total body irradiation as part of conditioning chemotherapy for myeloma. (Phase I) II. To determine the efficacy of the bortezomib added to high dose melphalan and low dose total-body irradiation (TBI) in patients with myeloma undergoing stem cell transplantation, as defined by achievement of complete response (CR).

SECONDARY OBJECTIVES:

I. To examine the toxicities associated with addition of bortezomib to high dose melphalan and TBI in patients with multiple myeloma (MM).

II. To determine the progression free rate at 1 and 2 years.

TERTIARY OBJECTIVES:

I. To determine the proportion of patients achieving a minimal residual disease (MRD) negative status.

II. To assess the HevyLite assay prior to and during treatment.

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

CONDITIONING REGIMEN: Patients receive bortezomib intravenously (IV) on days -5 and -2, TBI twice daily (BID) on days -5 and -2, and melphalan IV over 1 hour on days -4 and -3.

TRANSPLANT: Patients undergo autologous bone marrow or peripheral blood stem cell transplant on day 0.

After completion of study treatment, patients are followed up at 100 days and then every 90 days for up to 3 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Serum creatinine =< 2 mg/dL
  • Serum total bilirubin =< 1.5 X upper limit of normal (ULN)
  • Platelet count >= 30,000/μL
  • Hemoglobin >= 8.0 g/dL
  • Diagnosis of myeloma for which autologous stem cell transplant is being considered
  • Measurable disease of multiple myeloma at the time of baseline values for disease assessment as defined by at least one of the following:

    • Serum monoclonal protein >= 1.0 g/dL
    • >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
    • Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
    • Bone marrow plasma cells >= 30%
  • Note:

    • For patients with no relapse prior to transplant, measurable disease at the time of diagnosis
    • For patients who have had a disease relapse prior to transplant, measurable disease at the time of the most recent relapse immediately prior to transplant.
    • If the patient had treatment for the relapsed disease prior to transplant, the patient must have measurable disease at the time of relapse prior to this therapy
  • Patient is considered for autologous stem cell transplantation with full dose melphalan (200 mg/m^2)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Recovered from non-hematological toxicity of previous chemotherapy (excludes grade 1 neurotoxicity)
  • 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
  • Ejection fraction >= 45%
  • Corrected pulmonary diffusion capacity of greater than or equal to 50%
  • Forced expiratory volume in one second (FEV1) >= 50%
  • Forced vital capacity (FVC) >= 50%
  • Negative pregnancy test performed =< 7 days prior to registration, for women of childbearing potential only
  • Willing to return to Mayo Clinic Rochester, for treatment and follow-up

    • Note: During the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
  • Willing to provide blood and bone marrow samples for correlative research purposes

Exclusion Criteria:

  • Prior autologous or allogeneic bone marrow/peripheral blood stem cell transplant
  • More than two prior regimens for therapy of MM
  • Myocardial infarction within 6 months prior to enrollment, or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; NOTE: prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
  • Seroreactivity for human immunodeficiency virus (HIV), human T-cell lymphotrophic virus (HTLV) I or II, hepatitis B virus (HBV), hepatitis C virus (HCV)
  • Other active malignancy < 2 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy

    • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
  • Any of the following:

    • Pregnant women or women of reproductive capability who are unwilling to use effective contraception (2 effective methods of contraception, at the same time) from the time of signing the informed consent through 30 days after the last dose of study treatment, OR unwilling to agree to completely abstain from heterosexual intercourse
    • Nursing women
    • Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 30 days after stopping treatment
    • Unwilling to agree to completely abstain from heterosexual intercourse
  • Other co-morbidity, which would interfere with patient's ability to participate in the trial, e.g. uncontrolled infection, uncompensated lung disease or psychiatric illness
  • Concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
  • Known allergies to any of the components of the investigational treatment regimen or required ancillary treatments
  • Patient has >= grade 2 peripheral neuropathy
  • Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial
  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: NCT01936090

Locations
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Mayo Clinic Clinical Trials Referral Office    507-538-7623      
Principal Investigator: Shaji K. Kumar, M.D.         
Sponsors and Collaborators
Mayo Clinic
Investigators
Study Chair: Shaji Kumar, M.D. Mayo Clinic
  More Information

No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT01936090     History of Changes
Other Study ID Numbers: MC1286, NCI-2013-01646, MC1286, P30CA015083
Study First Received: September 1, 2013
Last Updated: May 1, 2014
Health Authority: United States: Food and Drug Administration

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
Melphalan
Bortezomib
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 11, 2014