Abstract 5391: Antibody-drug conjugates in oncology drug development: Examining approaches to set the first-in-human dose

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL While many anti-neoplastic drugs have a proven ability to kill cancer cells, some possess limited selectivity and high toxic effects on normal cells, which can yield marginal therapeutic indices. Antibody-drug conjugates (ADCs) represent an alternative therapeutic option being pursued by pharmaceutical companies. These therapeutic agents, also called immuno-conjugates, combine the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules to deliver and release the anti-cancer agent inside tumor cells. ADCs consist of a cytotoxic agent, an antibody targeting an antigen expressed on tumor cells, and a linker that covalently binds these components together. They are designed to provide selective killing of target tumor cells while minimizing the cytotoxic effects on normal tissues. Human mAbs are one of the fastest-growing categories of therapeutics entering clinical studies. As technology improves, the rational design and optimization of chemical linkers have resulted in renewed interest in ADCs among pharmaceutical companies. Phase I studies are a critical step in oncology drug development, as they translate years of laboratory studies, non-clinical data, into clinical use. A Sponsor-submitted investigational new drug application (IND) contains non-clinical data to establish the maximum recommended starting dose in humans. This panel of non-clinical data includes those derived from laboratory animal studies and consists of pharmacology information, toxicologic profile of the compound, and the pharmacokinetics of the therapeutic agent, all of which are considered when determining the first-in-human dose. This dose is expected to exert some pharmacologic activity and have acceptable toxicities based on the patient population and the benefit:risk consideration. While the U.S. Food and Drug Administration (FDA) has established a guideline for identifying the first-in-human dose for small molecules for oncology indications (ICH S9), there is no specific FDA established approach currently for ADCs. A growing number of INDs submitted to the FDA include ADCs as the investigational drug. Our research consists of an examination of 46 INDs containing ADCs, submitted to the FDA between 2003 and 2011. Analysis of the data revealed that different approaches have been proposed by Sponsors of the INDs for selection of the human dose based on non-clinical data. During this research, these approaches are evaluated with the goal of ultimately identifying the best approach. The objectives of this research are to: 1) analyze approaches used to set the human start dose based on animal pharmacology and toxicology data, 2) examine the method and rationale for selecting the Phase I clinical start dose, and 3) identify the optimal approach for first-in-human dose selection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5391. doi:1538-7445.AM2012-5391