An FDA oncology analysis of immune activating products and first-in-human dose selection

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 comp...

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Bibliographic Details
Published in:Regulatory toxicology and pharmacology 2016-11, Vol.81, p.448-456
Main Authors: Saber, Haleh, Gudi, Ramadevi, Manning, Michael, Wearne, Emily, Leighton, John K.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - analysis
Antibodies, Monoclonal - immunology
Dose-Response Relationship, Drug
First-in-human dose
Humans
Immune oncology
MABEL
Neoplasms - immunology
United States
United States Food and Drug Administration
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Summary: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.
ISSN:0273-2300
1096-0295
DOI:10.1016/j.yrtph.2016.10.002