Busulfan, Melphalan, and Bortezomib Before First-Line Stem Cell Transplant in Treating Patients With Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Ira Braunschweig, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier:
NCT01605032
First received: March 7, 2012
Last updated: March 2, 2015
Last verified: March 2015
  Purpose

This phase II trial studies how well busulfan, melphalan, and bortezomib before first-line stem cell transplant works in treating patients with multiple myeloma. Giving chemotherapy before a peripheral blood stem cell transplant may stop the growth of cancer cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.


Condition Intervention Phase
DS Stage I Plasma Cell Myeloma
DS Stage II Plasma Cell Myeloma
DS Stage III Plasma Cell Myeloma
Refractory Plasma Cell Myeloma
Drug: Busulfan
Drug: Melphalan
Drug: Bortezomib
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Procedure: Peripheral Blood Stem Cell Transplantation
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study Assessing the Efficacy and Toxicity of PK--directed Intravenous Busulfan in Combination With High--Dose Melphalan and Bortezomib as Conditioning Regimen for First--Line Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Albert Einstein College of Medicine of Yeshiva University:

Primary Outcome Measures:
  • Rate of complete response as determined by the IMWG criteria [ Time Frame: Day 100 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall response rate, defined as the percentage of participants that achieve either stringent complete response, CR, very good partial response plus partial response) [ Time Frame: Up to day 360 ] [ Designated as safety issue: No ]
    Descriptive statistics and tabular representations will be used to describe and evaluate response rates.

  • Incidence of toxicity assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Descriptive statistics and tabular representations will be used to describe and evaluate toxicities.

  • Mortality [ Time Frame: Up to day 360 ] [ Designated as safety issue: No ]
  • Time-to-progression [ Time Frame: From start of treatment to disease progression with deaths, up to 5 years ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: From transplant (day 0) to time of progression, assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be performed using Kaplan-Meier methods. The log-rank test will be used to compare survival among patients based on their response.

  • Event-free survival [ Time Frame: From stem cell transplant until an event (disease progression or death from any cause) has occurred, assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be performed using Kaplan-Meier methods. The log-rank test will be used to compare survival among patients based on their response.

  • Overall survival [ Time Frame: From transplant until death of any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be performed using Kaplan-Meier methods. The log-rank test will be used to compare survival among patients based on their response.

  • Pharmacokinetic parameters of busulfan [ Time Frame: Day -6: end of infusion (EOI), EOI + 15 minutes (+/- 2 minutes), EOI + 30 minutes (+/- 2 minutes), and 240, 300 and 360 minutes (+/- 10 minutes) after the start of the infusion ] [ Designated as safety issue: No ]
    The association between gender, race and pharmacokinetic data will be explored.

  • Methylation expression profile [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Gene expression profile [ Time Frame: Baseline ] [ Designated as safety issue: No ]

Estimated Enrollment: 42
Study Start Date: February 2012
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (busulfan, melphalan, bortezomib, autologous PBSCT)

CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4.

TRANSPLANT: Patients undergo autologous PBSCT on day 0.

Drug: Busulfan
Given IV
Drug: Melphalan
Given IV
Other Name: Alkeran
Drug: Bortezomib
Given IV
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous PBSCT
Other Name: Autologous Stem Cell Transplantation
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo autologous PBSCT
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the complete response rate as defined by the International Myeloma Working Group (IMWG) criteria for patients with multiple myeloma treated with high dose chemotherapy with pharmacokinetic (PK) directed intravenous (IV) busulfan, bortezomib and melphalan (Bu/BTZ/Mel140) followed by autologous hematopoietic stem cell transplantation (ASCT) as first line therapy.

SECONDARY OBJECTIVES:

I. To determine the overall response rate of the regimen Bu/BTZ/Mel140. II. To determine the treatment related toxicity and mortality of the regimen, including 100-day mortality rates.

III. To determine the duration of response, time to progression, progression-free survival, event-free survival and overall survival for this conditioning regimen.

IV. To determine whether there is a gender or race difference in the pharmacokinetic profile of IV busulfan.

V. To determine methylation and gene expression signatures of pre-treatment bone marrow plasma cells and explore associations of these signatures with outcome.

OUTLINE:

CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4.

TRANSPLANT: Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0.

After completion of study treatment, patients are followed up for up to 5 years.

  Eligibility

Ages Eligible for Study:   18 Years to 72 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed multiple myeloma
  • Measurable disease must be present as defined by protein criteria (quantifiable M-component in serum, urine or serum free light chains) in order to evaluate response as per IMWG; non-secretory patients are eligible provided the patient has > 20% plasmacytosis OR multiple (> 3) focal plasmacytomas or focal lesions on magnetic resonance imaging (MRI)
  • Patients must have received induction chemotherapy for myeloma, but not more than 12 months of prior chemotherapy for this disease, and must be eligible for the first planned autologous transplant
  • A minimum stem cell dose of 2.0 x 10^6 cluster of differentiation 34-positive (CD34+) cells/kg has been collected
  • Life expectancy of greater than 12 months
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL (unless myeloma related)
  • Absolute neutrophil count >= 1,500/mcL (unless myeloma related)
  • Platelets >= 50,000/mcL (unless myeloma related)
  • Total bilirubin =< 2 x institutional upper limit of normal unless 2nd to Gilbert's disease
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Ejection fraction by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) >= 40% performed within 60 days prior to registration
  • Patients must have adequate pulmonary function studies: > 50% of predicted on mechanical aspects (forced expiratory volume in one second [FEV1], forced vital capacity [FVC]) and diffusion capacity (diffusing capacity of the lung for carbon monoxide [DLCO]) > 50% of predicted, within 60 days of registration; if the patients is unable to complete pulmonary function tests due to multiple myeloma (MM) related pain or condition, exception may be granted if the principal investigator (PI) documents that the patient is a candidate for high dose therapy
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least six months following the stem cell transplantation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Prior treatment history of autologous hematopoietic stem cell transplant (HSCT) or high-dose chemotherapy with stem cell rescue for any medical reason, not limited to myeloma treatment
  • Patients may not be receiving any other investigational agents
  • Patients with known brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to or other agents used in the study, such as busulfan, melphalan, bortezomib, boron, or mannitol
  • Grade 2 or greater peripheral neuropathy within 14 days prior to enrollment
  • Unresolved grade >= 3 non-hematologic toxicity from previous therapy; patients with grade 2 toxicity will be eligible at the discretion of the PI
  • Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent < 5 years will not be allowed unless approved by the PI; cancer treated with curative intent > 5 years will be allowed
  • Patients must not have significant co-morbid medical condition
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients must not have suffered recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with busulfan
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Patients found to have an active hepatitis B infection (hepatitis B surface antigen +) are not eligible unless they meet ONE of the following criteria:

    • Patient is able to start dual anti-hepatitis (Hep) B therapy prior to enrollment with adefovir and telbivudine
    • Patient is already on dual anti-hepatitis B therapy
    • Consultation and co-management with a hepatitis expert regarding hepatitis B treatment is strongly encouraged before and during the trial
  • Patients, who are positive for hepatitis B core antibody, but negative for the hepatitis B surface antigen, should be started on lamivudine 100 mg daily until at least 3 months post stem cell transplant
  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: NCT01605032

Locations
United States, New Jersey
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
NYU Cancer Institute
New York, New York, United States, 10016
Sponsors and Collaborators
Albert Einstein College of Medicine of Yeshiva University
Investigators
Principal Investigator: Ira Braunschweig Albert Einstein College of Medicine of Yeshiva University
  More Information

No publications provided

Responsible Party: Ira Braunschweig, Principal Investigator, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier: NCT01605032     History of Changes
Other Study ID Numbers: 11-12-434, NCI-2013-01207, 11-102, 11-12-434, P30CA013330
Study First Received: March 7, 2012
Last Updated: March 2, 2015
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
Bortezomib
Busulfan
Melphalan
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on July 01, 2015