title: An FDA oncology analysis of antibody-drug conjugates.
abstract: Antibody-drug conjugates (ADCs) are complex molecules composed of monoclonal antibodies conjugated to potent cytotoxic agents through chemical linkers. Because of this complexity, sponsors have used different approaches for the design of nonclinical studies to support the safety evaluation of ADCs and first-in-human (FIH) dose selection. We analyzed this data with the goal of describing the relationship between nonclinical study results and Phase 1 study outcomes. We summarized the following data from investigational new drug applications (INDs) for ADCs: plasma stability, animal study designs and toxicities, and algorithms used for FIH dose selection. Our review found that selecting a FIH dose that is 1/6th the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys or 1/10th the STD10 in rodents scaled according to body surface area (BSA) generally resulted in the acceptable balance of safety and efficient dose-escalation in a Phase 1 trial. Other approaches may also be acceptable, e.g. 1/10th the HNSTD in monkeys using BSA or 1/10th the NOAEL in monkeys or rodents using body weight for scaling. While the animal data for the vc-MMAE platform yielded variable range of HNSTDs in cynomolgus monkeys, MTDs were in a narrow range in patients, suggesting that for ADCs sharing the same small molecule drug, linker and drug:antibody ratio, prior clinical data can inform the design of a Phase 1 clinical trial.
authors: 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: Haleh
authors: H
authors: Saber
authors: 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: john.leighton@fda.hhs.gov.
authors: John K
authors: JK
authors: Leighton
mesh_terms: D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D001830:Body Surface Area; D001835:Body Weight; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D054796:Drug Dosage Calculations; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D008252:Macaca fascicularis; D020714:Maximum Tolerated Dose; D051379:Mice; D023421:Models, Animal; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates
keywords: Antibody-drug conjugates; First-in-human start dose selection; Oncology drug development