90 Y-BC8-DOTA Monoclonal Antibody, Fludarabine Phosphate, and Total-Body Irradiation Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01503242
First received: December 30, 2011
Last updated: October 20, 2014
Last verified: October 2014

December 30, 2011
October 20, 2014
January 2012
December 2014   (final data collection date for primary outcome measure)
  • Tissue localization of 111In-BC8-DOTA Ab [ Time Frame: Up to 72 hours post infusion ] [ Designated as safety issue: No ]
  • MTD of radiation delivered via 90 Y-BC8-DOTA [ Time Frame: Up to 180 days ] [ Designated as safety issue: Yes ]
    MTD is defined as the dose that is associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as a grade III/IV regimen-related toxicity (Bearman scale) occurring within 30 days post-transplant. A two-parameter logistic model will be fit to the data, thereby generating a dose-response curve based on the observed toxicity rate at the various dose levels. Based on this fitted model, the MTD is estimated to be the dose that is associated with a toxicity rate of 25%.
  • Assessment of the tissue localization of 111In-BC8-DOTA Ab to establish reproducibly favorable biodistributions [ Time Frame: At baseline and on at least 2 of the 3 days up to 72 hours post infusion ] [ Designated as safety issue: No ]
  • MTD of radiation delivered via 90 Y-BC8-DOTA when combined with FLU and 2 Gy TBI as a preparative regimen followed by HLA-matched, related or unrelated HCT for patients with multiple myeloma [ Time Frame: At the dose associated with a toxicity rate of 25%, assessed up to 180 days ] [ Designated as safety issue: Yes ]
    MTD is defined as the dose that is associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as a Grade III/IV regimen-related toxicity (Bearman scale) occurring within 30 days post-transplant. Dose modification will be conducted according to Storer's two-stage design. A two-parameter logistic model will be fit to the data, thereby generating a dose-response curve based on the observed toxicity rate at the various dose levels. Based on this fitted model, the MTD is estimated to be the dose that is associated with a toxicity rate of 25%.
Complete list of historical versions of study NCT01503242 on ClinicalTrials.gov Archive Site
  • Disease response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Duration of remission [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Disease-free survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
Potential efficacy of this approach, within the limits of a phase I study, by examining disease response, duration of remission, DFS, and OS [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
90 Y-BC8-DOTA Monoclonal Antibody, Fludarabine Phosphate, and Total-Body Irradiation Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma
A Phase I Study of 90Y-BC8-DOTA Monoclonal Antibody, Fludarabine and TBI Followed by HLA-Matched, Allogeneic Peripheral Blood Stem Cell Transplant for the Treatment of Multiple Myeloma

This phase I trial studies the side effects and best dose of yttrium Y 90 anti-CD45 monoclonal antibody BC8 when given together with fludarabine phosphate and total-body irradiation followed by donor peripheral blood stem cell transplant in treating patients with multiple myeloma. Radiolabeled monoclonal antibodies, such as yttrium Y 90 anti-CD45 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving yttrium Y 90 anti-CD45 monoclonal antibody BC8, fludarabine phosphate, and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening and may be an effective treatment for multiple myeloma.

PRIMARY OBJECTIVES:

I. To assess the tissue localization of 111In-BC8-DOTA antibody therapy (Ab) and establish reproducibly favorable biodistribution.

II. To estimate the maximum tolerated dose (MTD) of radiation delivered via 90Y-BC8-DOTA Ab when combined with fludarabine phosphate (FLU) and 2 Gy total-body irradiation (TBI) as a preparative regimen followed by human leukocyte antigen (HLA)-matched, related or unrelated hematopoietic cell transplant (HCT) for patients with multiple myeloma.

SECONDARY OBJECTIVES:

I. To assess the potential efficacy of this approach, within the limits of a phase I study, by examining disease response, duration of remission, disease free survival (DFS), and overall survival (OS).

OUTLINE: This is a dose-escalation study of yttrium Y 90 anti-CD45 monoclonal antibody BC8 (90Y-BC8 Ab).

Patients receive 90Y-BC8 Ab intravenously (IV) on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and allogeneic peripheral blood stem cell transplant on day 0. Patients also receive graft-vs-host disease prophylaxis comprising cyclosporine orally (PO) twice daily (BID) on days -3 to 56 with taper to day 180 or on days -3 to 100 with taper to 180; and mycophenolate mofetil IV or PO BID on days 0-27, or 0-40 with taper to 96.

After completion of study treatment patients are followed up every 6 months for 2 years and then annually thereafter.

Interventional
Phase 1
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Refractory Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Radiation: yttrium Y 90 anti-CD45 monoclonal antibody BC8
    Given IV
    Other Names:
    • 90Y anti-CD45 MAb BC8
    • 90Y anti-CD45 MoAb BC8
  • Drug: fludarabine phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • Beneflur
    • Fludara
  • Radiation: total-body irradiation
    Undergo TBI
    Other Name: TBI
  • Procedure: allogeneic hematopoietic stem cell transplantation
    Undergo allogeneic peripheral blood stem cell transplantation
  • Procedure: peripheral blood stem cell transplantation
    Undergo allogeneic peripheral blood stem cell transplantation
    Other Names:
    • PBPC transplantation
    • PBSC transplantation
    • peripheral blood progenitor cell transplantation
    • transplantation, peripheral blood stem cell
  • Drug: cyclosporine
    Given PO
    Other Names:
    • ciclosporin
    • cyclosporin
    • cyclosporin A
    • CYSP
    • Sandimmune
  • Drug: mycophenolate mofetil
    Given IV or PO
    Other Names:
    • Cellcept
    • MMF
Experimental: Treatment (monoclonal antibody, chemo, TBI, transplant)
Patients receive 90Y-BC8 Ab IV on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and allogeneic peripheral blood stem cell transplant on day 0. Patients also receive graft-vs-host disease prophylaxis comprising cyclosporine PO BID on days -3 to 56 with taper to day 180 or on days -3 to 100 with taper to 180; and mycophenolate mofetil IV or PO BID on days 0-27, or 0-40 with taper to 96.
Interventions:
  • Radiation: yttrium Y 90 anti-CD45 monoclonal antibody BC8
  • Drug: fludarabine phosphate
  • Radiation: total-body irradiation
  • Procedure: allogeneic hematopoietic stem cell transplantation
  • Procedure: peripheral blood stem cell transplantation
  • Drug: cyclosporine
  • Drug: mycophenolate mofetil
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
20
Not Provided
December 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have history of symptomatic myeloma requiring treatment (defined as significant anemia [hemoglobin (HgB) less than 10 gm/dl], renal dysfunction [creatinine > 2.0] not attributable to other causes, lytic bone disease on imaging, or hypercalcemia) and meet one of the following requirements:

    • Have at least 1 high risk feature at diagnosis (including deletion 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or deletion 17 by fluorescence in situ hybridization [FISH], beta 2 microglobulin > 3.5, lactate dehydrogenase [LDH] greater than 1.5 x upper limit of normal [ULN]) (prior to chemotherapy); OR
    • Have progressive disease on primary therapy with or without prior autologous stem cell transplant; OR
    • Have persistent or progressive disease following autologous transplant; it is acceptable for these patients to have a second transplant for disease reduction
  • Bone marrow cellularity of at least 50% of normal by core biopsy (25% cellularity = 50% of normal)
  • Eastern Cooperative Oncology Group (ECOG) =< 2
  • Measured creatinine clearance > 50 ml/min or estimated creatinine clearance > 50 ml/min
  • For females of childbearing potential, must have a negative pregnancy test
  • Patients must have an human leukocyte antigen (HLA)-identical sibling donor or an HLA-matched unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) and or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) donation, as follows:

    • Sibling donor: A patient and sibling donor should be matched for HLA-A, B, C, DRB1 and DQB1 by an intermediate resolution deoxyribonucleic acid (DNA)-based method
    • Unrelated donor: An unrelated donor and recipient should be typed by a high resolution DNA-based method, and ideally matched for HLA-A, B, C, DRB1 and DQB1 alleles, or if there is only a single locus disparity mismatched for an HLA-DQB1 antigen or allele; an unrelated donor may also be mismatched for any single 1) one HLA-A, B or C antigen or allele, or 2) HLA-DRB1 allele (with or without matching for HLA-DQB1)
  • Ability to provide informed consent
  • DONOR: Patients must have an HLA matched donor as well as standard Seattle Cancer Care Alliance (SCCA) and or National Marrow Donor Program (NMDP)/other donor center criteria for PBSC donation
  • DONOR: Donors must consent and be eligible to undergo granulocyte colony-stimulating factor (GCSF) mobilization and PBSC harvest; marrow is not allowed as a source of stem cells on this study

Exclusion Criteria:

  • Patients with the following organ dysfunction:

    • Left ventricular ejection fraction < 35%
    • Corrected diffusion capacity of carbon monoxide (DLCO) < 35% or receiving supplemental continuous oxygen
    • Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidences by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease
  • Pregnant or breast-feeding females
  • Circulating antibody against mouse immunoglobulin (HAMA)
  • Prior allogeneic transplant
  • Plasmacytomas > 1cm in marrow areas measured by magnetic resonance imaging (MRI) or extramedullary plasmacytomas (radiated lesions are exempt from this criteria); patients may receive cytoreductive therapy, including allogeneic stem cell transplant (ASCT) (if high risk) or second ASCT (if failed a prior ASCT) to achieve disease control
  • Prior radiation to maximally tolerated levels to any critical normal organ, or > 20 Gy prior radiation to large areas of the bone marrow (e.g., external radiation therapy to whole pelvis)
  • Patients who are known to be seropositive for human immunodeficiency virus (HIV)
  • Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant
  • Active central nervous system (CNS) disease at the time of treatment
Both
18 Years to 65 Years
No
United States
 
NCT01503242
2450.00, NCI-2010-02041, 2450.00, P30CA015704, R21CA155911
No
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Principal Investigator: William Bensinger Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP