Considerations on the Calculation of the Human Equivalent Dose from Toxicology Studies for Biologic Anticancer Agents

Abstract

First-in-human (FIH) clinical trials for investigational anticancer agents are often conducted in cancer patients who are resistant and/or refractory to standard therapy or have no other treatment options that would confer clinically relevant benefit. Selecting an appropriate starting dose for these studies is not only important to ensure patient safety but also to enable efficiency in reaching the therapeutically relevant dose range. Starting with a dose that is too low could lead to a lengthy dose escalation and subjecting many terminally ill cancer patients to subtherapeutic doses [1]. The International Conference on Harmonization (ICH) S9 guidance provides recommendations on non-clinical evaluation for anticancer agents, including basic guidelines on determination of the starting dose based on toxicity studies in animal species [2]. The guidance indicates that for most systemically administered small molecules, the starting dose could be determined based on scaling of an appropriate threshold ‘safe dose’ in animal studies to a human equivalent dose (HED), which is then used to determine the starting dose after applying a safety factor [2, 3]. For immune-activating biologics, toxicology studies in animal species may not fully capture the clinically expected immune-related adverse events, and thus may underpredict toxicity in humans. Differences in receptor expression pattern and/or binding affinities between animal species and humans, as well as the potential for eliciting complementdependent cytotoxicity (CDC) or antibody-dependent cellmediated cytotoxicity (ADCC), may result in exaggerated safety findings in humans that may not be observed in non-clinical toxicology studies [2–4]. Therefore, for biologics with agonistic properties (e.g. those with cellular targets that activate downstream pathways and trigger cytokine release), the starting dose is typically based on the minimally anticipated biologic effect level (MABEL) [2–4]. Data from in vitro studies (e.g. target binding affinity, in vitro cytotoxicity, or cytokine-release assays) and in vivo studies (e.g. tumor growth inhibition studies using relevant preclinical models) are used for MABEL determination [2–4]. It is important to highlight that there is no universal approach for determining MABEL and the cut-offs and assays used are dependent on the therapeutic modality and the intended pharmacological effect. For example, for immune-activating antibodies, e.g. PD-1/PD-L1 inhibitors, starting doses that correspond to 20–80% receptor occupancy (RO) could be associated with acceptable/manageable toxicities [5]. However, the RO approach is not acceptable for T-cell-engaging CD3 bispecifics because doses that correspond to as low as 10% RO were found to be above the human maximum tolerated dose (MTD) or highest human dose [6]. For T-cellengaging CD3 bispecifics, the first-in-patient starting dose corresponding to concentrations that achieve up to 50% of the maximal effect from the most sensitive in vitro activity assay was considered an acceptable approach [6]. Typically, MABEL-based starting dose is lower than that derived based on animal toxicology studies and is considered a more conservative approach for immune-activating biologics [4–6]. However, given the lack of a unified approach for determining MABEL, in some cases the MABEL dose could be similar to or higher than the starting dose calculated based on animal toxicology studies. Therefore, accurate understanding of in vitro/in vivo data, exposure–toxicity and exposure–efficacy relationships in preclinical species need to be considered to select an appropriate starting dose. Relevant factors used to convert the animal doses determined in the toxicology studies (e.g. the highest non-severely toxic dose [HNSTD] or the no-observed adverse effect level [NOAEL]) to the HED should be considered [3]. The 2005 US FDA * Mohamed Elmeliegy [email protected]