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

Bullock, Julie; Rahman, Atiqur; Liu, Qi

doi:10.1158/1078-0432.ccr-15-2646

Cited by 46 publications

(46 citation statements)

References 14 publications

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“…This is supported by research concluding that utilizing concentration-response analyses for dose justification leads to better dose selection and higher success rates for confirmatory trials. 1 Further, the European Medicines Agency notes in International Council on Harmonisation E4 that the value of concentration response extends beyond dose justification but that an established concentration-response relationship can be "useful for ascertaining the magnitude of the clinical consequences of (1) PK differences, such as those due to drug-disease (eg, renal failure) or drug-drug interactions, or (2) for assessing the effects of the altered PK of new dosage forms (eg, controlled-release formulation) or new dosage regimens without need for additional clinical data." 28 Furthermore, a firm understanding of the effect of concentration to both response and toxicity can help developers and regulators decide what to do in cases of altered PK.…”

Section: Exposure-response Analysesmentioning

confidence: 99%

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

Bullock

Lin

Bilic

2017

The Journal of Clinical Pharma

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Targeted therapies are now considered an integral component in the treatment armamentarium for many malignancies, and the approach to developing these drugs needs to be refined from the previous cytotoxic paradigm of toxicity-guided dose finding and identification of maximum tolerated dose to a paradigm driven by target activity. Moving away from the toxicity-driven dose finding and justification model requires an integrated approach in order to adequately characterize the risk-benefit of a drug. This approach starts with understanding the importance of collecting samples for pharmacokinetic and pharmacodynamic assessments in all phases of clinical development to fully characterize the pharmacokinetics and identify covariates and then correlating exposure to key markers of safety and efficacy in pharmacometric analyses to perform a robust risk-benefit assessment and establish the right dose. In addition, for oral agents, decisions on administering the drug with respect to food can impact dose among other clinical trial outcomes such as tolerability and patient compliance. Understanding the importance of model-based drug development as a decision-making tool to support drug development through incorporation of all relevant data allows for a robust risk-benefit assessment at key decision points. Utilization of clinical pharmacology tools and assessments throughout development will provide the key components of a successful oncology development program.

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Section: Exposure-response Analysesmentioning

confidence: 99%

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

Bullock

Lin

Bilic

2017

The Journal of Clinical Pharma

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“…In addition, small molecules with poor solubility frequently show high intra-and interpatient variability, making the identification of exposure-response relationships for toxicity or efficacy difficult to identify. Specific case studies are discussed by Bullock and colleagues in this CCR Focus (21).…”

Section: Dose-exposure Explorationmentioning

confidence: 99%

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

Kim

Shaw

Sridhara

et al. 2016

Clinical Cancer Research

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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.

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“…The latter can be the maximum tolerated dose (MTD) for cytotoxics or the maximum effective dose (usually lower than the MTD) for compounds affecting signaling pathways. This dose is used to determine the antitumor activity of the agent in a Phase II study [1][2][3]. In the classical drug development setting, an active compound (antitumor activity comparable to that of standard therapy), will proceed to a randomised Phase III study in which the new drug will be compared to the standard therapy or placebo.…”

Section: Introductionmentioning

confidence: 99%

“…In the classical drug development setting, an active compound (antitumor activity comparable to that of standard therapy), will proceed to a randomised Phase III study in which the new drug will be compared to the standard therapy or placebo. However, with several novel compounds in which a target is defined, a Phase I study may be expanded to include only patients with predefined biomarkers [3]. Drugs can obtain market approval from Medicines agencies such as the EMA and FDA, based on an extensive risk/benefit ratio evaluation.…”

Section: Introductionmentioning

confidence: 99%