Clinical Trials /

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

NCT01503242

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 2450.00
  • SECONDARY ID: NCI-2010-02041
  • SECONDARY ID: 2450
  • SECONDARY ID: 2450.00
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: R21CA155911
  • NCT ID: NCT01503242

Conditions

  • Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (monoclonal antibody, chemo, TBI, transplant)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (monoclonal antibody, chemo, TBI, transplant)
Mycophenolate MofetilCellcept, MMFTreatment (monoclonal antibody, chemo, TBI, transplant)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (monoclonal antibody, chemo, TBI, transplant)ExperimentalPatients 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.
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have history of symptomatic myeloma requiring treatment 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], history of
                  plasma cell leukemia) (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 >= 50% of age defined normal values by core biopsy;
             cellularity must be evaluated within 90 days of the dosimetry infusion and at least 21
             days after receiving any cytoreductive/myelosuppressive chemotherapy

          -  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 a human leukocyte antigen (HLA)‐matched related donor or an
             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, or bone marrow donation as follows:

               -  Related donor related to the patient and genotypically or phenotypically
                  identical for HLA-A, B, C, DRB1 and DQB1; phenotypic identity must be confirmed
                  by high-resolution typing

               -  Unrelated donor:

                    -  Matched for HLA‐A, B, C, DRB1 DQB1 by high resolution typing; OR

                    -  Mismatched for a single allele without antigen mismatching at HLA‐A, B, or C
                       as defined by high resolution typing but otherwise matched for HLA‐A, B, C,
                       DRB1 and DQB1 by high resolution typing

                    -  Patient and donor pairs homozygous at a mismatched allele, in the graft
                       rejection vector are considered a two‐allele mismatch, i.e., the patient is
                       A*0101 and the donor is A*0102, and this type of mismatch is not allowed

               -  Donors are excluded when preexisting immunoreactivity is identified that would
                  jeopardize donor hematopoietic cell engraftment; this determination is based on
                  the standard practice of the individual institution; the recommended procedure
                  for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain panel
                  reactive antibody (PRA) screens to class I and class II antigens for all patients
                  before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
                  cytotoxic cross matches should be obtained; the donor should be excluded if any
                  of the cytotoxic cross match assays are positive; for those patients with an HLA
                  Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches
                  should be obtained regardless of the PRA results; a positive anti‐donor cytotoxic
                  crossmatch is an absolute donor exclusion

          -  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 > 1 cm 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, but may not receive any cytoreductive therapy within 30 days of the dosimetry
             infusion and must have bone marrow cellularity meeting inclusion criteria obtained at
             least 21 days after any cytoreductive/myelosuppressive chemotherapy was last
             administered

          -  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
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of radiation delivered via 90 Y-BC8-DOTA
Time Frame:Up to 180 days
Safety Issue:
Description: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%.

Secondary Outcome Measures

Measure:Disease response
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Disease-free survival
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Duration of remission
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 3 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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