Study of Intravenous Busulfan in Combination With Melphalan and Bortezomib in Patients With Multiple Myeloma

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2012 by Montefiore Medical Center.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Otsuka Pharmaceutical Development & Commercialization, Inc.
Information provided by (Responsible Party):
Montefiore Medical Center
ClinicalTrials.gov Identifier:
NCT01605032
First received: March 7, 2012
Last updated: May 22, 2012
Last verified: May 2012
  Purpose

The investigators hypothesis is that this combination will lead to a 20% improved complete response rate compared with historical controls.


Condition Intervention Phase
Multiple Myeloma
Drug: Intravenous Busulfan in Combination with High-Dose Melphalan and Bortezomib
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 2 Study Assessing the Efficacy and Toxicity of Pharmacokinetic 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 Montefiore Medical Center:

Primary Outcome Measures:
  • Complete Response Rate as a Measure of Efficacy [ Time Frame: 3 months post transplant ] [ Designated as safety issue: No ]
    The complete response (CR) rate of PK-directed iv Busulfan, Bortezomib and Melphalan (Bu/BTZ/Mel140)conditioning followed by autologous hematopoietic stem cell transplantation (ASCT) will be measured at 3 months post transplant as a measure of efficacy


Secondary Outcome Measures:
  • Mortality Related to Treatment (TRM) [ Time Frame: 30 days & 100 days post transplant ] [ Designated as safety issue: Yes ]
    The mortality secondary to the treatment at 30 and 100 days post transplant will be documented as a measure for safety

  • Event-free survival [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    The definition of an event is 1) disease progression or 2) death from any cause. Event-free survival (EFS) is the time from stem cell transplant until an event as defined above has occurred and is a measure of efficacy and safety

  • Influence of Sex and Race on the PK profile of Busulfan [ Time Frame: AUC and Cmax determined by PK measures collected at time of test dose and after first 4-hour infusion ] [ Designated as safety issue: Yes ]
    Pharmacokinetic (PK) measures such as the AUC and Cmax will be correlated with sex and race to identify differences in bioavailability.

  • Gene expression and Methylation signatures [ Time Frame: Pre-transplant ] [ Designated as safety issue: No ]
    Methylation and gene expression signatures (GEP70) of pre-treatment bone marrow plasma cells will be determined and correlated with outcomes (response and survival).

  • Overall Response Rate (ORR) [ Time Frame: 3 months post ASCT. ] [ Designated as safety issue: No ]
    Response at 3 months post transplant as defined by the International Myeloma Working Group (IMWG) criteria is a measure of efficacy. ORR is defined as either complete (CR), very good partial (VGPR), or partial response (PR).

  • Overall Survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Overall survival (OS) is defined as the time from transplant until death of any cause

  • Treatment Related Toxicity [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
    The number of participants with adverse events and the type of adverse events participants experienced within 3 months post-transplant graded by CTCAE v4.0 criteria will be reported as a measure of safety and tolerability.


Estimated Enrollment: 42
Study Start Date: February 2012
Estimated Study Completion Date: February 2013
Estimated Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Intravenous Busulfan in Combination with High-Dose Melphalan and Bortezomib
    Bulsefan Dose: 0.8 mg/kg Route: IV Frequency: every six hours for Duration of Therapy: four days (a total of 16 doses) Melphalan Dose: 200mg/m2 Route: IV Frequency: 60 minutes Duration of Therapy: during the conditioning phase on day -2 Bortezomib Dose: 1.3 mg/m2 Route: IV Frequency: 3-5 second bolus injection Duration of Therapy: 2x in the conditioning phase and 2x post transplant
  Eligibility

Ages Eligible for Study:   18 Years and older
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 IMWG3. Non-secretory patients are eligible provided the patient has > 20% plasmacytosis OR multiple (>3) focal plasmacytomas or focal lesions on MRI
  • Age 18 to 72 years. Because no dosing or adverse event data are currently available on the use of Busulfan in combination with Melphalan and Bortezomib in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric phase 2 combination trials.
  • Patients must have received induction chemotherapy for myeloma, but no 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 106 CD34+ cells/kg has been collected.
  • Life expectancy of greater than 12 months
  • ECOG performance status <2 (Karnofsky >60%; see Appendix A).
  • Patients must have normal organ and marrow function as defined below:
  • 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
  • AST(SGOT)/ALT(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 m2 for patients with creatinine levels above institutional normal
  • Ejection fraction by ECHO or MUGA ≥ 40% performed within 60 days prior to registration
  • Patients must have adequate pulmonary function studies: > 50% of predicted on mechanical aspects (FEV1, FVC) and diffusion capacity (DLCO) > 50% of predicted, within 60 days of registration. If the patient is unable to complete pulmonary function tests due to 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.
  • The effects of Busulfan, Melphalan and Bortezomib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because alkylating agents as well as other therapeutic agents used in this trial are known to be teratogenic, 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 month 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 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • 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 principal investigator (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 because Busulfan, melphalan and bortezomib Class D agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agent breastfeeding should be discontinued if the mother is treated with Busulfan.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Busulfan. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • 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-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 100mg 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

Contacts
Contact: Stefan Barta, MD 718-920-4826 sbarta@montefiore.org

Locations
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467
Contact: Barta    718-920-4826      
Contact: Zaino    718-920-2006      
Sub-Investigator: Samir Parekh, MD         
Sub-Investigator: Ira Braunschweig, MD         
Sub-Investigator: Amit Verma, MD         
Principal Investigator: Stefan Barta, MD         
Sub-Investigator: Olga Derman, MD         
Sponsors and Collaborators
Montefiore Medical Center
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
Principal Investigator: Stefan Barta, MD Montefiore Medical Center
  More Information

No publications provided

Responsible Party: Montefiore Medical Center
ClinicalTrials.gov Identifier: NCT01605032     History of Changes
Other Study ID Numbers: 11-12-434
Study First Received: March 7, 2012
Last Updated: May 22, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Montefiore Medical Center:
Busulfan
High-Dose Melphalan
Bortezomib
First-line Autologous Hematopoietic Stem Cell Transplantation
Stem Cell
Transplant
Multiple Myeloma

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

ClinicalTrials.gov processed this record on September 16, 2014