An FDA oncology analysis of antibody-drug conjugates.
Regul Toxicol Pharmacol
; 71(3): 444-52, 2015 Apr.
Article
in En
| MEDLINE
| ID: mdl-25661711
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 drugantibody ratio, prior clinical data can inform the design of a Phase 1 clinical trial.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
United States Food and Drug Administration
/
Drug Approval
/
Toxicity Tests
/
Immunoconjugates
/
Antineoplastic Agents
Type of study:
Clinical_trials
/
Etiology_studies
/
Prognostic_studies
Limits:
Animals
/
Humans
Country/Region as subject:
America do norte
Language:
En
Journal:
Regul Toxicol Pharmacol
Year:
2015
Document type:
Article
Affiliation country:
United States