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 the maximum tolerated dose (MTD). However, targeted therapies might not exhibit doselimiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) 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, pharmacodynamic, or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematologic tumors). Although the concept of BED has been discussed extensively, we review specific examples in which the approach influenced oncology clinical development. Data extracted from the literature and the examples support improving dose selection strategies to benefit patients, providers, 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 in clinical use), which can have a negative impact on efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multifactorial decision process leading to a randomized, dose-ranging study instead of a single phase II dose.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

“…However, tolerability is essential for adherence to therapy especially if long‐term administration is anticipated. Recently, dosing selection based on exposure‐response relationship considering both efficacy and tolerability has drawn attention by both regulatory agency and industry in oncology drug development 30, 31. The purpose of this research was to select the sorafenib dosing regimen in patients with AML for further clinical trials by characterizing the exposure‐response relationship for inhibition of FLT3 by sorafenib and its active N‐oxide metabolite in patients with AML.…”

Effective implementation of novel MET pharmacodynamic assays in translational studies

“…However, many selective targeted agents may not reach MTD (36,37), or such doses may be significantly higher than those required for the optimal target suppression (36,38), also known as a BED. A recent review of cancer drug monotherapies found that >60% of approved drugs have doses lower than the MTD (36). For targeted therapies such as highly selective TKIs or monoclonal antibodies, BED provides a safe and effective alternative strategy.…”

Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle

“…For solid tumors, the RECIST classification of tumor measurement is the most commonly employed to define response and progression; however, this classification uses a binary system (response vs. no response) in assessing an exposure-response relationship. The proposal to use a measurement of change in tumor size, which is a continuous data element, may provide more information in an exposure-response relationship and ultimately require fewer patients in a randomized, phase II, dose-comparison trial, thus increasing efficiency in the dose-finding endeavor (12,13). This approach may be more difficult in phase I trials in which patients frequently are heavily pretreated, and overall response rates typically are low.…”