Reduced-Intensity Conditioning Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00054353
First received: February 5, 2003
Last updated: December 26, 2013
Last verified: December 2013
  Purpose

This phase I/II trial studies the side effects of giving reduced-intensity conditioning followed by donor peripheral blood stem cell transplant (PBSCT) and how well it works in treating patients with multiple myeloma (MM). Giving low doses of chemotherapy, such as fludarabine phosphate and melphalan, and total-body irradiation (TBI) before a donor PBSCT helps stop the growth of cancer cells. It may also stop 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 mycophenolate mofetil and cyclosporine after transplant may stop this from happening.


Condition Intervention Phase
Refractory Multiple Myeloma
Drug: fludarabine phosphate
Drug: melphalan
Radiation: total-body irradiation
Drug: mycophenolate mofetil
Drug: cyclosporine
Procedure: nonmyeloablative allogeneic 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: Reduced-Intensity Allogeneic HSC Transplantation From HLA-Matched Related and Unrelated Donors for Patients With Multiple Myeloma - A Multi-Center Trial

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • PFS [ Time Frame: At 1 year post-transplant ] [ Designated as safety issue: No ]
    PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission.

  • Non-relapse mortality [ Time Frame: At day 100 ] [ Designated as safety issue: No ]
    Early NRM will be monitored in a sequential fashion.

  • Incidence of acute GVHD (grades III-IV) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Severe GVHD will be monitored in a sequential fashion.

  • Incidence of chronic (extensive) GVHD [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Severe GVHD will be monitored in a sequential fashion.


Secondary Outcome Measures:
  • OS [ Time Frame: At 1 year post-transplant ] [ Designated as safety issue: No ]
    OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated.

  • Engraftment [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Engraftment will be monitored in a sequential fashion.

  • Relapse rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Relapse rate will be summarized using cumulative incidence estimates. Confidence intervals will be estimated.

  • Response rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Confidence intervals will be estimated.


Estimated Enrollment: 30
Study Start Date: October 2002
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (reduced-intensity allogeneic PBSCT)

PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).

Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo reduced-intensity allogeneic PBSCT
Procedure: peripheral blood stem cell transplantation
Undergo reduced-intensity allogeneic PBSCT
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 evaluate the efficacy of this approach by determining the 1-year progression-free survival (PFS) and overall survival (OS).

II. To evaluate day 100 non-relapse mortality.

III. To determine the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or thrice daily (TID) on days 0-40 with taper to day 96 (unrelated donors).

After completion of study treatment, patients are followed up at 3, 6, 12, 18, and 24 months, and then annually thereafter for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meet Salmon and Durie criteria for initial diagnosis of MM; transplant will be offered to patients with previously treated MM who meet one of the following criteria:

    • Patient received at least one prior autologous or syngeneic hematopoietic SCT (HSCT) and now has progressive disease (PD) (greater than 25% increase in serum or urine paraprotein levels compared to best response status after autograft or appearance of new lytic bone lesions or plasmocytomas)
    • Patient is not able to collect autologous PBSC due to poor marrow reserve (insufficient HSC-mobilization: < 2.5 x 10^6 cluster of differentiation [CD]34+ cells/kg); or contraindications to undergoing HSC-mobilization; patient now has PD and has received at least 4 cycles of standard chemotherapy (e.g. vincristine sulfate, doxorubicin hydrochloride, and dexamethasone [VAD]) in the past
  • Patients must have the capacity to give informed consent
  • DONOR: Human leukocyte antigen (HLA) genotypically identical sibling or phenotypically matched relative
  • DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria)

    • Matched for serologically recognized HLA-A or B or C antigens and at least five of six HLA-A or B or C alleles
    • Matched for HLA DRB1 and DQB1 alleles (defined by high-resolution typing) at the allele level
  • DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis for PBSC collection
  • DONOR: Donor must have adequate veins for leukapheresis or agree to placement of a temporary central venous catheter

Exclusion Criteria:

  • Karnofsky score < 60%
  • Left ventricular ejection fraction < 40% or symptomatic heart failure; ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease
  • Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL,or symptomatic biliary disease
  • Diffusion capacity of carbon monoxide (DLCO) < 50% (corrected) or receiving continuous supplemental oxygen
  • Creatinine clearance < 40 mL/min
  • Patients with poorly controlled hypertension
  • Seropositive for the human immunodeficiency virus (HIV)
  • Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
  • Pregnancy or breastfeeding
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Not fully recovered from previous high-dose therapy:

    • Persistent mucositis and gastrointestinal symptoms requiring hyperalimentation and/or intravenous hydration
    • On steroids for autologous/syngeneic GVHD
    • On IV antibiotics for documented infections
    • Cytomegalovirus (CMV)-antigenemia positive
    • On ganciclovir or foscarnet for previous CMV reactivation/infection; off of this therapy for less than two weeks despite documented CMV-antigenemia- negativity (identification [ID] should be consulted if there is persistent CMV antigenemia post autograft)
    • Ongoing radiotherapy
    • Patients who meet any of these criteria may be discussed with the principal investigator for recommendations as to the timing of the allograft
  • Patients with active bacterial or fungal infections unresponsive to medical therapy
  • DONOR: Identical twin
  • DONOR: Donors unwilling to donate PBSC
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Inability to achieve adequate venous access
  • DONOR: Known allergy to G-CSF
  • DONOR: Current serious systemic illness
  • DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for stem cell donation
  • DONOR: Age < 12 years
  • DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
  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: NCT00054353

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Italy
University of Torino
Torino, Italy, 10126
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Marco Mielcarek Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00054353     History of Changes
Other Study ID Numbers: 1743.00, NCI-2011-00386, 1743.00, P30CA015704
Study First Received: February 5, 2003
Last Updated: December 26, 2013
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
Cyclosporins
Cyclosporine
Mycophenolic Acid
Melphalan
Mycophenolate mofetil
Fludarabine monophosphate
Vidarabine
Fludarabine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on July 23, 2014