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Melphalan+Bortezomib as a Conditioning Regimen for Autologous and Allogeneic Stem Cell Transplants in Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT00948922
Recruitment Status : Active, not recruiting
First Posted : July 29, 2009
Results First Posted : October 12, 2018
Last Update Posted : October 12, 2018
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Brief Summary:
The purpose of this study is to evaluate the effectiveness of Bortezomib when added to standard chemotherapy medicine(s) for treatment of Multiple Myeloma.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Bortezomib Drug: Melphalan Procedure: Autologous Stem Cell Transplant Drug: Fludarabine Procedure: Allogeneic Stem Cell Transplant Phase 2

Detailed Description:

The primary objectives of this study are:

  • To determine the 2 year-progression free survival in multiple myeloma with an allogeneic transplant using a conditioning regimen of melphalan + fludarabine + Bortezomib in patients < 60 years of age and available HLA-matched donor and compare it with the 2 year-progression-free-survival after an autologous stem cell transplant with melphalan+Bortezomib conditioning in patients < 60 years.
  • To determine the 2 year-progression free survival in multiple myeloma with an autologous stem cell transplant using a conditioning regimen of melphalan + Bortezomib. for patients > 60 years of age and patients < 60 years of age who decline allogeneic stem cell transplant.

The secondary objectives of this study are:

  • To determine the overall survival in multiple myeloma with autologous or allogeneic stem cell transplants using the above conditioning regimens
  • To determine the response rates in multiple myeloma using the above regimens.
  • To determine minimal residual disease status using allele specific oligonucleotides (ASO-PCR) by PCR and flow-cytometry for multiple myeloma cells.
  • To correlate minimal residual disease status with 2 year progression free survival and overall survival.
  • To determine the incidence of acute and chronic graft-versus-host disease (GVHD) in multiple myeloma with allogeneic stem cell transplant using the above conditioning regimen.
  • To examine quality of life in patients treated with allogeneic and autologous stem cell transplants using the above conditioning regimen.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 124 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Melphalan+Bortezomib as a Conditioning Regimen for Autologous and Allogeneic Stem Cell Transplants in Multiple Myeloma After Cytoreductive Therapy
Actual Study Start Date : June 18, 2009
Actual Primary Completion Date : April 20, 2017
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
A: Allogeneic Stem Cell Transplant
Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.
Drug: Bortezomib
AUTOLOGOUS ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows Melphalan infusion). ALLOGENEIC ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows fludarabine and melphalan infusion).
Other Name: Velcade

Drug: Melphalan
AUTOLOGOUS ARM: Day -4 and Day -3 Melphalan 100 mg/m^2/day IV over 30 minutes. ALLOGENEIC ARM: Day -4, Day -3 Melphalan 70 mg/m^2/day IV over 30 minutes.
Other Name: Alkeran(R)

Drug: Fludarabine
Days -6,-5,-4,-3 Fludarabine 30 mg/m^2/day IV
Other Name: Fludara(R)

Procedure: Allogeneic Stem Cell Transplant
Allogeneic Stem Cell Transplant: Allogeneic Peripheral Blood Stem Cell Rescue. Day 0 Infusion of allogeneic peripheral blood stem cells. For the allogeneic matched-related donors peripheral blood stem cells will be harvested with GCSF mobilization and infused fresh to the recipients. Allogeneic donor stem cells may also be cryopreserved if they cannot be infused fresh.

B: Autologous Stem Cell Transplant
Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue.
Drug: Bortezomib
AUTOLOGOUS ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows Melphalan infusion). ALLOGENEIC ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows fludarabine and melphalan infusion).
Other Name: Velcade

Drug: Melphalan
AUTOLOGOUS ARM: Day -4 and Day -3 Melphalan 100 mg/m^2/day IV over 30 minutes. ALLOGENEIC ARM: Day -4, Day -3 Melphalan 70 mg/m^2/day IV over 30 minutes.
Other Name: Alkeran(R)

Procedure: Autologous Stem Cell Transplant
Autologous Stem Cell Transplant: Autologous Peripheral Blood Stem Cell Rescue. Stem cell mobilization with granulocyte colony-stimulating factor (GCSF) at a dose of 10 μg/kg/day as per institutional standards. CD34+ peripheral blood stem cells will be collected following the administration of G-CSF as per institutional standards. Day 0 Infusion of autologous stem cells.

BE: Group B Expansion
Group B Expansion on Bortezomib Maintenance: Autologous Only.
Drug: Bortezomib
AUTOLOGOUS ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows Melphalan infusion). ALLOGENEIC ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows fludarabine and melphalan infusion).
Other Name: Velcade

Drug: Melphalan
AUTOLOGOUS ARM: Day -4 and Day -3 Melphalan 100 mg/m^2/day IV over 30 minutes. ALLOGENEIC ARM: Day -4, Day -3 Melphalan 70 mg/m^2/day IV over 30 minutes.
Other Name: Alkeran(R)

Procedure: Autologous Stem Cell Transplant
Autologous Stem Cell Transplant: Autologous Peripheral Blood Stem Cell Rescue. Stem cell mobilization with granulocyte colony-stimulating factor (GCSF) at a dose of 10 μg/kg/day as per institutional standards. CD34+ peripheral blood stem cells will be collected following the administration of G-CSF as per institutional standards. Day 0 Infusion of autologous stem cells.




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: End of 2 year, post transplant follow-up ]
    PFS: Number of participants, per treatment arm with progression free survival at time of analysis. Survival time will be measured from the date of transplant to the date of progression, death or the last follow-up, whichever comes first. Progressive Disease (PD): Increase of ≥ 25% from lowest response value in any one or more of the following: Serum M-component and/or; Urine M-component and/or; Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL; Bone marrow plasma cell percentage; absolute percentage ≥ 10%; Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.


Secondary Outcome Measures :
  1. Overall Survival (OS) Rate [ Time Frame: End of 2 year, post transplant follow-up ]
    Overall survival in participants with multiple myeloma treated with Bortezomib (Velcade®) containing conditioning regimen and autologous as well as allogeneic transplantation.

  2. Molecular Complete Response (CR) Rates in Patients With Multiple Myeloma [ Time Frame: End of 2 year, post transplant follow-up ]
    Complete Response according to International Myeloma Working Group uniform response criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.


Other Outcome Measures:
  1. Incidence of Acute or Chronic Graft-versus-host Disease (GVHD) Following Transplant [ Time Frame: End of 2 year, post transplant follow-up ]
    Number of participants with Acute or Chronic GVHD following transplant, per study treatment arm.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Multiple Myeloma Criteria(International Uniform Response Criteria for Multiple Myeloma)

  • Patients with responsive disease after any line of induction therapy
  • A complete response
  • A very good partial response
  • A partial response
  • Patients greater than or equal to 18 years of age are eligible. There is upper age limit of 60 years for allogeneic transplants.
  • Patients must have a histologically confirmed diagnosis.
  • All patients should have a life expectancy of at least 12 weeks.
  • Patients must have undergone a complete psychosocial evaluation and have been considered capable of compliance.
  • Meet the following criteria for allogeneic hematopoietic cell transplant:
  • Must have an identified donor match defined as: HLA-A, HLA-B, HLA- C, DRB1 8/8 allele matched sibling, family member, or unrelated donor. [7/8 would go on separate mismatched trials] and be < 60 years of age.
  • Calculated hematopoietic cell transplantation-specific comorbidity index (HCT-CI) <3

Exclusion Criteria:

  • Patients who do not achieve at least a partial response (PR) by the criteria mentioned above with induction therapy.
  • Patient has a platelet count of <30 x 10^9/L within 14 days before enrollment.
  • Patient has >/= Grade 2 peripheral neuropathy within 30 days before enrollment.
  • Patient has an absolute neutrophil count of <1.0 x 10^9/L within 30 days before enrollment.
  • Myocardial infarction within 6 months prior to enrollment or has New York Hospital 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. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant in order for the subject to be considered eligible. Left ventricular ejection fraction (LVEF) by multiple gated acquisition (MUGA) scan < 40%.
  • Patient has hypersensitivity to bortezomib, boron or mannitol.
  • Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
  • Patient has received other investigational drugs with 30 days before enrollment
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Patients with a diffusing capacity of lung for carbon monoxide (DLCO) less than 50% (adjusted) of normal or with symptomatic obstructive or restrictive lung disease are ineligible.
  • Patients with a total bilirubin greater than 2.0 mg/dL excluding Gilbert's syndrome and serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) greater than two and a half times normal (unless due to primary malignancy), or a history of severe hepatic dysfunction are ineligible.
  • Calculated creatinine clearance </= 30 ml/min within 30 days before enrollment
  • Patients with active infections are ineligible.
  • Patients who are HIV positive are ineligible.
  • Patients with active leptomeningeal involvement are ineligible. Patients with a history of previous cerebrospinal fluid (CSF) tumor involvement without symptoms or signs are eligible provided the CSF is now free of disease on lumbar puncture, and MRI of the brain shows no tumor involvement. Patients with severe symptomatic central nervous system (CNS) disease of any etiology are ineligible.
  • Patients with uncontrolled insulin-dependent diabetes mellitus defined as a random glucose level of > 400 in the 30 days prior to initiation of study therapy; or uncompensated major thyroid or adrenal dysfunction are ineligible.
  • Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of >/= 2(Karnofsky < 50%) are ineligible.
  • Patients with an ECOG performance status of 2 to 3(Karnofsky 30-50%), secondary to bone pain, may be enrolled.
  • Patients with an ECOG performance status of 2 to 3(Karnofsky 30-50%), secondary to a potentially reversible disease-related problem, may be enrolled.
  • Patients with any previous malignancy other than non-melanoma skin cancer are ineligible, unless the patient is without evidence of disease >/= 5 years after the treatment for the cancer was completed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00948922


Locations
United States, Florida
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Melissa Alsina, MD H. Lee Moffitt Cancer Center and Research Institute
Principal Investigator: Jose Ochoa-Bayona, MD H. Lee Moffitt Cancer Center and Research Institute
  Study Documents (Full-Text)

Documents provided by H. Lee Moffitt Cancer Center and Research Institute:

Additional Information:
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT00948922     History of Changes
Other Study ID Numbers: MCC-15697
XO5271 ( Other Grant/Funding Number: Millennium )
First Posted: July 29, 2009    Key Record Dates
Results First Posted: October 12, 2018
Last Update Posted: October 12, 2018
Last Verified: September 2018

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
multiple myeloma
myeloma
myeloma proteins
autologous
allogeneic
G-CSR
granulocyte colony-stimulating factor
stem cell transplant
stem cell
stem cell mobilization

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
Fludarabine
Fludarabine phosphate
Bortezomib
Melphalan
Vidarabine
Lenograstim
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Alkylating