Oncology Dosing Tool Kit

This tool kit is a resource intended to support stakeholders in their decision-making regarding dosage optimization, i.e., identifying the dosage(s) that maximize the benefit/risk profile of a drug. Collection and interpretation of relevant data (see table below) can provide support for the dosage(s) chosen for evaluation in a clinical trial and/or help identify gaps in the dosage optimization strategy. The tool kit can be used iteratively to support decision-making throughout clinical development and to ultimately select the dosage(s) to be evaluated in the registration trial. In this tool kit, “registrational trial(s)” refer to the trial(s) designed to evaluate safety and effectiveness in support of a marketing application.

Overarching Questions

Which dosages will be evaluated during dose escalation?
Which dosages will be chosen for further investigation; e.g., in a randomized dosage evaluation*?
What dosages will be selected for the registration trial(s)?

Key Area	Information to Support Dosage Optimization
Translational Evidence	Rationale for clinical starting dosage and dose-escalation range, including available nonclinical modeling (i.e., biomarkers, tumor size). Additional information such as: pharmacological evidence in relevant nonclinical species; dose- and exposure-response relationships from cellular systemics and animal models; and potential on- and off-target relationships.
Pharmacokinetic Characteristics	Single-dose and multiple-dose pharmacokinetics, proportionality and time-dependence. Effect of intrinsic and extrinsic factors (e.g., body size, immunogenicity, race, ethnicity, age, food intake, organ impairment, concomitant medications) on the parent drug and active metabolites. Major active metabolites and their relative contribution to activity and safety compared to that of the parent drug.
Safety	MAD and MTD, if identified Safety information for each dosage evaluated Duration of exposure Incidence of TEAEs including all grade, grade 3 to 4, serious, and fatal events. Dosage modifications for TEAEs, including time course and incidence of interruptions, reductions, and discontinuations, and most common TEAEs leading to dosage modifications. Incidence of key TEAEs of interest, including grade 1-2 TEAEs which may affect tolerability. Dose-limiting toxicities Relative dose intensity As applicable: Additional measures of safety and tolerability if applicable (e.g., laboratory data), including rationale to support utility of the measure to estimate safety or tolerability. Patient-reported outcome data regarding symptomatic TEAEs. Alternative dosages (e.g., step-up dosing, intermittent dosing) to mitigate acute or transient toxicities. Overlapping toxicities (with combination regimens).
Efficacy	Efficacy information for each dosage evaluated. Additional measures of activity if applicable, including rationale to support utility of the measure to estimate activity or efficacy.
Dose- and Exposure-Response	Dose- and exposure-response relationships for safety, tolerability, and activity, including pharmacodynamic markers and other outcomes. Exposure metrics, relevant covariates, and limitations to the models.
Other Information	Modeling & simulation approaches Biopharmaceutical considerations (e.g., pill burden, maximal feasible dose) Relevant patient factors (e.g., patient convenience, adherence, dosing interval, route of administration) Additional scientific evidence (e.g., from similar class, MOA or indication)

Abbreviations: AEs=adverse events; DLT=dose-limiting toxicity; DOR=duration of response; MAD=maximum administered dose; MOA=mechanism of action; MTD=maximum tolerated dose; ORR=overall response rate; PD=pharmacodynamic; PFS=progression-free survival; PFS=progression free survival; PK=pharmacokinetic; TEAE=treatment-emergent adverse events

*Randomized dosage evaluation refers to evaluation of the benefit-risk of two or more dosages for dosage optimization.

U.S. Food and Drug Administration

Oncology Dosing Tool Kit

Overarching Questions

Key Area

Information to Support Dosage Optimization

Translational Evidence

Rationale for clinical starting dosage and dose-escalation range, including available nonclinical modeling (i.e., biomarkers, tumor size).

Additional information such as: pharmacological evidence in relevant nonclinical species; dose- and exposure-response relationships from cellular systemics and animal models; and potential on- and off-target relationships.

Pharmacokinetic Characteristics

Single-dose and multiple-dose pharmacokinetics, proportionality and time-dependence.

Effect of intrinsic and extrinsic factors (e.g., body size, immunogenicity, race, ethnicity, age, food intake, organ impairment, concomitant medications) on the parent drug and active metabolites.

Major active metabolites and their relative contribution to activity and safety compared to that of the parent drug.

Safety

MAD and MTD, if identified

Safety information for each dosage evaluated

Duration of exposure

Incidence of TEAEs including all grade, grade 3 to 4, serious, and fatal events.

Dosage modifications for TEAEs, including time course and incidence of interruptions, reductions, and discontinuations, and most common TEAEs leading to dosage modifications.

Incidence of key TEAEs of interest, including grade 1-2 TEAEs which may affect tolerability.

Dose-limiting toxicities

Relative dose intensity

As applicable:

Additional measures of safety and tolerability if applicable (e.g., laboratory data), including rationale to support utility of the measure to estimate safety or tolerability.

Patient-reported outcome data regarding symptomatic TEAEs.

Alternative dosages (e.g., step-up dosing, intermittent dosing) to mitigate acute or transient toxicities.

Overlapping toxicities (with combination regimens).

Efficacy

Efficacy information for each dosage evaluated.

Additional measures of activity if applicable, including rationale to support utility of the measure to estimate activity or efficacy.

Dose- and Exposure-Response

Dose- and exposure-response relationships for safety, tolerability, and activity, including pharmacodynamic markers and other outcomes.

Exposure metrics, relevant covariates, and limitations to the models.

Other Information

Modeling & simulation approaches

Biopharmaceutical considerations (e.g., pill burden, maximal feasible dose)

Relevant patient factors (e.g., patient convenience, adherence, dosing interval, route of administration)

Additional scientific evidence (e.g., from similar class, MOA or indication)

Further Information