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

Abstract

In the current era of rapid marketing approval for promising new products in oncology, dose finding and optimization for small-molecule oncology drugs occurs throughout the development cycle and into the postmarketing setting. Many trials that support a regulatory application have high rates of dose reductions and discontinuations, which may result in postmarketing requirements (PMR) to study alternate doses or dosing schedules. Kinase inhibitors particularly have been susceptible to this problem, and among the 31 approved drugs of this class, the approvals of eight have included such PMRs and/or commitments. Thus, the current paradigm for dose finding and optimization could be improved. Newer strategies for dose finding rather than traditional 3 þ 3 designs should be considered where feasible, and dose optimization should be continued after phase I and throughout development. Such strategies will increase the likelihood of a right dose for the right drug at the time of regulatory approval.

Lessons Learned: Dose Selection of Small Molecule–Targeted Oncology Drugs

“…If the toxicities are not tolerable, then dose intensity and patient compliance may become issues and could have an impact on efficacy trial outcomes as well as the benefit-risk balance. This concept is further discussed in this CCR Focus by Nie and colleagues (4) and J€ anne and colleagues (6).…”

“…Pneumonitis, cardiac toxicity, vascular toxicity, gastrointestinal toxicity, hepatic toxicity, and other toxicities have plagued targeted agents both in development and postapproval. Some of these toxicities are often not predicted by nonclinical testing (5) and may not be observed in the first cycle of treatment, during which the MTD is determined (6). Delayed serious toxicities have limited the use of some of the targeted agents.…”

Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

“…Although this seems on the surface to be an acceptable approach, many of the small-molecule targeted therapies have late-onset and/or cumulative toxicity with toxicities surfacing after 3 or more cycles. 2,8 Obtaining samples in every cycle or in odd-or even-numbered cycles throughout treatment up to a cut point of 6 to 12 months can provide PK data that capture exposure over time to connect to these late-onset or cumulative toxicities. These later-stage samples also help to model accurate exposure parameters following dose reductions or interruptions that may occur during treatment.…”

Challenges and Opportunities in Dose Finding in Oncology and Immuno‐oncology

“…For some targeted therapies, toxicities are delayed and assessment of a tolerable dose in DLT assessment during Cycle 1 is not always feasible. This may result in identification of a dose that is tolerable in Cycle 1 but requires reduced doses or discontinuations in a large number of patients in subsequent cycles due to delayed toxicities, resulting in patients unable to derive meaningful benefit from treatment 16. Approaches have been published where a phase Ib dose expansion cohort can be better designed to inform the recommended phase II dose (RP2D) 14.…”