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Total Body Irradiation and Astatine-211-Labeled BC8-B10 Monoclonal Antibody for the Treatment of Nonmalignant Diseases

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ClinicalTrials.gov Identifier: NCT04083183
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : December 16, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase I/II trial studies the best dose of total body irradiation with astatine-211 BC8-B10 monoclonal antibody for the treatment of patients with nonmalignant diseases undergoing hematopoietic cell transplant. Radiation therapy uses high energy gamma rays to kill cancer cells and shrink tumors. Astatine-211-labeled BC8-B10 monoclonal antibody is a monoclonal antibody, called anti-CD45 monoclonal antibody BC8-B10, linked to a radioactive/toxic agent called astatine 211. Anti-CD45 monoclonal antibody BC8-B10 is attached to CD45 antigen positive cancer cells in a targeted way and delivers astatine 211 to kill them. Giving astatine-211 BC8-B10 monoclonal antibody and total-body irradiation before a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells.

Condition or disease Intervention/treatment Phase
Non-Malignant Neoplasm Biological: Astatine At 211 Anti-CD45 Monoclonal Antibody BC8-B10 Drug: Fludarabine Drug: Cyclophosphamide Biological: Lapine T-Lymphocyte Immune Globulin Radiation: Total-Body Irradiation Procedure: Hematopoietic Cell Transplantation Drug: Mycophenolate Mofetil Drug: Sirolimus Phase 1 Phase 2

Detailed Description:

OUTLINE:

Patients receive astatine At 211 anti-CD45 monoclonal antibody BC8-B10 intravenously (IV) on any day between days -10 and -7, fludarabine IV on days -6 to -2, cyclophosphamide IV over 1 hour on days -6 to -5 and 3 to 4, and thymoglobulin IV over 4-6 hours on days -4 to -2. Patients undergo TBI on day -1 and hematopoietic cell transplant on day 0. Beginning day 5, patients also receive mycophenolate mofetil orally (PO) or IV thrice daily every 8 hours up to day 35 if no GVHD present and sirolimus PO daily until day 365.

After completion of study treatment, patients are followed up at 1 and 2 years and then periodically for up to 5 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Targeted Astatine-211-Labeled BC8-B10 Monoclonal Antibody as Reduced Intensity Conditioning for Nonmalignant Diseases
Actual Study Start Date : June 16, 2020
Estimated Primary Completion Date : January 9, 2028
Estimated Study Completion Date : January 9, 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (astatine 211,fludarabine,cyclophosphamide,TBI,HCT)
Patients receive astatine At 211 anti-CD45 monoclonal antibody BC8-B10 IV on any day between days -10 and -7, fludarabine IV on days -6 to -2, cyclophosphamide IV over 1 hour on days -6 to -5 and 3 to 4, and thymoglobulin IV over 4-6 hours on days -4 to -2. Patients undergo TBI on day -1 and hematopoietic cell transplant on day 0. Beginning day 5, patients also receive mycophenolate mofetil PO or IV thrice daily every 8 hours up to day 35 if no GVHD present and sirolimus PO daily until day 365.
Biological: Astatine At 211 Anti-CD45 Monoclonal Antibody BC8-B10
Given IV
Other Names:
  • Astatine 211-Labeled Anti-CD45 Monoclonal Antibody BC8-B10
  • Astatine At 211 MAb BC8-B10
  • At 211 Anti-CD45 Monoclonal Antibody BC8-B10
  • At 211 MAb BC8-B10

Drug: Fludarabine
Given IV
Other Names:
  • 118218
  • 2-Fluoro-9-beta-arabinofuranosyladenine
  • 2-Fluorovidarabine
  • 21679-14-1
  • 9-Beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine
  • 9-Beta-D-arabinofuranosyl-2-fluoroadenine
  • Fluradosa

Drug: Cyclophosphamide
Given IV
Other Names:
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclostin
  • Cyclostine
  • Cytoxan

Biological: Lapine T-Lymphocyte Immune Globulin
Given IV
Other Names:
  • Anti-thymocyte Globulin Rabbit
  • Grafalon
  • Rabbit Anti-Human Thymocyte Globulin (RATG)
  • Rabbit Anti-Thymocyte Globulin
  • Rabbit Antithymocyte Globulin
  • Rabbit ATG
  • rATG
  • Thymoglobulin

Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TBI
  • TOTAL BODY IRRADIATION
  • Whole Body Irradiation
  • Whole-Body Irradiation

Procedure: Hematopoietic Cell Transplantation
Undergo hematopoietic cell transplantation
Other Names:
  • HCT
  • Hematopoietic Stem Cell Transplantation
  • HSCT
  • Stem Cell Transplant

Drug: Mycophenolate Mofetil
Given PO or IV
Other Names:
  • Cellcept
  • MMF
  • 115007-34-6

Drug: Sirolimus
Given PO
Other Names:
  • 226080
  • RAPA
  • Rapamune
  • Rapamycin
  • SILA 9268A
  • WY-090217




Primary Outcome Measures :
  1. Graft rejection (arm A) [ Time Frame: Up to 5 years post-transplant ]
    Defined as establishment of < 5% donor chimerism of CD3+ T cells and <5% donor chimerism of CD33+ myeloid cells at day 80-100 after hematopoietic cell transplant (HCT) following an human leukocyte antigen (HLA)-matched related or unrelated graft or an unrelated graft with a single HLA-class 1 allele mismatch or DQB1 antigen or allele mismatch.

  2. Graft rejection (arm B) [ Time Frame: Up to 5 years post-transplant ]
    Defined as establishment of < 5% donor chimerism of CD3+ T cells and < 5% donor chimerism of CD33+ myeloid cells at day 80-100 after HCT following an HLA-haploidentical related donor or an unrelated donor mismatched for a single HLA-class 1 antigen or a single HLA-DRB1 allele.


Secondary Outcome Measures :
  1. Transplant related mortality [ Time Frame: At day 100 post-transplant ]
  2. Overall survival [ Time Frame: At 1 year post-transplant ]
  3. Rate of acute graft versus host disease (GVHD) [ Time Frame: At day 100 post-transplant ]
  4. Rate of chronic GVHD [ Time Frame: At 1 year post-transplant ]
  5. Donor chimerism [ Time Frame: At day 28, day 84, and 1 year post-transplant ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Nonmalignant disease treatable by allogeneic hematopoietic cell transplantation (HCT). Patients with a nonmalignant disease that is not clearly defined must be approved by the principal investigator (PI)
  • Lansky play performance score or Karnofsky score >= 70
  • DONOR INCLUSION
  • HLA matched related donor that is genotypically or phenotypically identical for HLA-A, -B, -C, -DRB1, -DQB1. Phenotypic identity must be confirmed by high-resolution typing. Sibling donors are preferred over other relationships
  • Unrelated donor.

    • Matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing; OR
    • Mismatched for a single HLA-class 1 allele or HLA-DQB1 antigen or allele by high-resolution typing.

Note: A donor homozygous for one allele only at HLA-A, B, C, DRB1, or DQB1 is allowed (1 antigen mismatch for graft versus host disease [GVHD], 0 antigen mismatch for graft-rejection). In the case of a recipient who is homozygous at one locus, the mismatch is not allowed to be at that locus (0 antigen mismatch for GVHD, 1 antigen mismatch for graft-rejection)

  • HLA haploidentical donor. There must be one shared HLA-haplotype based on inheritance. The noninherited haplotype is allowed to be mismatched at any or all of these loci: HLA-A, B, C, DRB1 or DQB1.
  • Donor selection guideline recommendations: in the case where there are multiple donor options, donors should be selected based on the following priority numbered below:

    • Related donor genotypically HLA-matched
    • Related donor phenotypically HLA-matched
    • Unrelated donor HLA-matched
    • Unrelated donor with single allele level mismatch at class 1 (HLA-A, -B, or -C). For example, HLA-A02:01 versus HLA-A 02:02
    • Unrelated donor with single allele level mismatch at DQB1
    • HLA-haploidentical donor Note: We require that the donor testing be performed by a United States Clinical Laboratory Improvement Amendment (CLIA) approved laboratory. In the very rare case where the donor testing is not able to be performed in a CLIA approved laboratory, or there is confirmatory testing that needs to be performed, or for any donor identified from Europe and at risk for Creutzfeldt-Jakob Disease (CJD), we note this on the donor screening form and require that the unrelated donor medical director or the attending physician approves the use of the donor HPC-A product under urgent medical need

Exclusion Criteria:

  • Patients with Fanconi Anemia
  • Impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction of < 26% may be enrolled if approved by a cardiologist. In addition, patients with poorly controlled hypertension on multiple anti-hypertensive medications, symptomatic coronary artery disease, or patients on cardiac medications for antiarrhythmic or inotropic effects are excluded
  • Impaired pulmonary function as evidenced by carbon monoxide diffusing capability test (DLCO) < 35% of predicted or receiving supplemental continuous oxygen. In addition, if patients are unable to perform pulmonary function tests, then O2 saturation < 92% on room air
  • Impaired renal function as evidenced by estimated creatinine clearance less than 50 ml/min or serum creatinine > 2 x upper normal limit or dialysis-dependent. Serum creatinine value must be within 28 days prior to start of conditioning

    * The creatinine clearance may be estimated by the Cockcroft-Gault formula

  • Impaired liver function as evidenced by abnormal hepatic function defined as a total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) > 2 times the upper limit of normal. In addition, patients with the following liver abnormalities are excluded: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced 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
  • An uncontrolled infection requiring deferral of conditioning as recommended by an infectious disease specialist. A viral upper respiratory tract infection does not constitute an uncontrolled infection in this context
  • Patients who are known to be positive for HIV (human immunodeficiency virus)
  • Women of childbearing potential who are pregnant or breast-feeding
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Allergy to murine-based monoclonal antibodies
  • Known contraindication to radiotherapy
  • DONOR EXCLUSION
  • Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. 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 hematopoietic cell transplantation (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 or class II allele or antigen mismatch or haploidentical donors, 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

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): NCT04083183


Contacts
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Contact: Phuong Vo 206-667-2749 ptvo@fredhutch.org

Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Phuong Vo    206-667-2749    ptvo@fredhutch.org   
Principal Investigator: Phuong Vo         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Phuong Vo Fred Hutch/University of Washington Cancer Consortium
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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT04083183    
Other Study ID Numbers: RG1005632
P30CA015704 ( U.S. NIH Grant/Contract )
NCI-2019-05727 ( Registry Identifier: NCI / CTRP )
9524 ( Other Identifier: Fred Hutch / University of Washington Cancer Consortium )
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: December 16, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mycophenolic Acid
Sirolimus
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Antineoplastic Agents, Immunological
Thymoglobulin
Antilymphocyte Serum
Antibodies
Immunoglobulins
Antibodies, Monoclonal
gamma-Globulins
Immunoglobulins, Intravenous
Rho(D) Immune Globulin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents