Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example

Abstract

One of the key objectives of oncology first in human trials has often been to establish maximum tolerated dose ("MTD"). However, targeted therapies might not exhibit dose limiting toxicities (DLTs) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events (AEs). Thus, while MTD-based determination of recommended phase 2 dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study. One complementary strategy is to define a biologically efficacious dose (BED) using an "effect marker." An effect marker could be a target engagement (TE), pharmacodynamic (PD), or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematological tumors). While the concept of BED has been discussed extensively, we review specific examples where the approach influenced oncology clinical development. Data extracted from the literature, and the examples, will support improving dose selection strategies to benefit patient, provider, and the biopharmaceutical industry. Although the examples illustrate key contributions of effect markers in dose selection, no one-size-fits-all approach to dosing can be justified. Higher than optimal dosing can increase toxicity in later trials (and use), which can negatively impact efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multi-factorial decision process leading to a randomized, dose-ranging study.