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 July 2016 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01503242
First received: December 30, 2011
Last updated: July 18, 2016
Last verified: July 2016
  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.

Condition Intervention Phase
Plasma Cell Myeloma
Refractory Plasma Cell Myeloma
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Cyclosporine
Drug: Fludarabine Phosphate
Drug: Mycophenolate Mofetil
Procedure: Peripheral Blood Stem Cell Transplantation
Radiation: Total-Body Irradiation
Radiation: Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • 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%.

  • Tissue localization of 111In-BC8-DOTA Ab [ Time Frame: Up to 72 hours post infusion ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Disease response [ 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 ]
  • Duration of remission [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: January 2012
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Other Names:
  • allogeneic stem cell transplantation
  • HSC
  • HSCT
Drug: Cyclosporine
Given PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Gengraf
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation
Radiation: Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8
Given IV
Other Name: 90Y Anti-CD45 MoAb BC8

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01503242

Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Damian J. Green    206-667-5398    dgreen@fhcrc.org   
Principal Investigator: Damian J. Green         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Damian Green Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01503242     History of Changes
Other Study ID Numbers: 2450.00  NCI-2010-02041  2450  2450.00  P30CA015704  R21CA155911 
Study First Received: December 30, 2011
Last Updated: July 18, 2016
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
Antibodies
Immunoglobulins
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Fludarabine phosphate
Antibodies, Monoclonal
Mycophenolic Acid
Vidarabine
Fludarabine
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Antifungal Agents

ClinicalTrials.gov processed this record on July 27, 2016