title: Dose escalation and dosimetry of first-in-human α radioimmunotherapy with 212Pb-TCMC-trastuzumab.
abstract: Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity, and tumor response of intraperitoneal (212)Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2)-expressing malignancy.
  
  
  METHODS
  In a standard 3 + 3 phase 1 design for dose escalation, (212)Pb-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies.
  
  
  RESULTS
  Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m(2)) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n = 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time). Non-decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5μSv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative.
  
  
  CONCLUSIONS
  Five dose levels of intraperitoneal (212)Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama lobrown@uabmc.edu.
authors.forename: Ruby
authors.initials: R
authors.lastname: Meredith
authors.affiliation: AREVA Med, Bethesda, Maryland; and.
authors.forename: Julien
authors.initials: J
authors.lastname: Torgue
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sui
authors.initials: S
authors.lastname: Shen
authors.affiliation: Dade Moeller Health Group, Richland, Washington.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.affiliation: AREVA Med, Bethesda, Maryland; and.
authors.forename: Eileen
authors.initials: E
authors.lastname: Banaga
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Patty
authors.initials: P
authors.lastname: Bunch
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Desiree
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jinda
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Straughn
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011829:Radiation Dosage; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007856:Lead Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: 212Pb-TCMC-trastuzumab; alpha; dosimetry; radioimmunotherapy; radionuclide