title: An FDA oncology analysis of immune activating products and first-in-human dose selection.
abstract: As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products.
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States. Electronic address: haleh.saber@fda.hhs.gov.
authors.forename: Haleh
authors.initials: H
authors.lastname: Saber
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Gudi
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Manning
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Wearne
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
authors.forename: John K
authors.initials: JK
authors.lastname: Leighton
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000032:analysis* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009369:Neoplasms / Q000276:immunology*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000911:Antibodies, Monoclonal
keywords: First-in-human dose; Immune oncology; MABEL