Table 2.

Phase 1 trial designs.

Trial design	Description	Comments
Rule‐Based Designs: Dose toxicity curve not assumedDecision to escalate based on pre‐defined rules and observed toxicities in the specified DLT period of current dose level
3 + 3	3 patients treated per dose level. Depending on the number of DLTs, the dose is either escalated (0 DLTs) or de‐escalated (≥2 DLTs), or the cohort is expanded with 3 extra patients (1 DLT). Dose increments are pre‐determined eg. modified Fibonacci. RP2D is the highest dose with a pre‐specified DLT rate	• Commonly used design • Easy to implement • More patients may be treated at subtherapeutic doses • May not accurately define RP2D
Accelerated titration	Various designs proposed with fixed dose escalation increments EG:•3 + 3 design but with 40% dose increments•Single patient cohorts until a DLT or second intermediate toxicity occurs (trigger), then cohort expanded and reverted to design 1•Single patient cohorts with 80% dose increments. Revert to design 1 with the same trigger as design 2•As for design 3 but trigger to revert to design 1 is an anytime DLT or second anytime intermediate toxicity	• Acceleration and escalation in one design • Fewer patients may treated at subtherapeutic doses • Potentially faster • Delayed or cumulative toxicities masked if intrapatient dose‐escalation permitted
Model‐Based Design: Dose‐toxicity curve established a priori and then modified as toxicity data is collected on studyBiostatistical expertise required to construct and modify dose‐toxicity estimates
CRM	A target level of toxicity and the probabilities of observing a DLT at certain dose levels are pre‐defined at baseline for a fixed sample size. Initially doses for single patient cohorts are increased based on this model however with successive patients the model is re‐calculated according to Bayesian principles, which guides subsequent dose escalation. The RP2D is the dose associated with the target DLT rate consistent with the final dose‐toxicity model	• May overestimate RP2D • Limited data may exist to model initial dose‐toxicity curve • Intrapatient dose escalation may be permitted
Modified CRM	Similar to CRM except that a conservative starting dose is used with single dose level escalations per cohort. The next patient dose may not be escalated following a DLT. Cohorts may be larger than one and stopping rules are defined rather than using a fixed sample size	• Safety and efficiency improved compared to CRM
EWOC	Dose‐toxicity curve modeled to minimize the probability a patient will be treated at an unacceptably high dose	• Dose‐toxicity curve constantly remodeled requiring significant statistical support
TITE‐CRM	Data from all treated patients, including partial data, is incorporated into dose‐toxicity curve and subsequent dose calculationsPatients who have experienced DLT are fully weighted and those who have not experienced toxicity are weighted by the proportion of time observed on study	• Allows toxicity information of patients to contribute to RP2D determination • May account for chronic toxicities
Pharmacokinetically guided dose escalation (PGDE): Requires real time PK measurement and analysis for dose‐modificationAssumes DLT can be predicted by plasma drug concentration
PGDE	AUC measured for first cohort and dose escalation occurs according to distance to target AUC. This may occur initially by a factor equal to the square root of target AUC/initial AUC and then subsequently by a modified Fibonacci scheme. Another escalation strategy is to increase by a factor of 2 until 40% of target AUC is reached and then by a modified Fibonacci method	• Interpatient variability may limit dose escalation • May be suitable to estimate an ODB

MTD, maximum tolerated dose; DLT, dose‐limiting toxicity; PK, pharmacokinetic; PD, pharmacodynamic; AUC, area under the curve; CRM, continuous reassessment method; EWOC, escalation with overdose control; TITE, time to event; RP2D, recommended phase II dose; MTAs, molecularly targeted agents; OBD, optimal biological dose.