A narrative review of adaptive Phase I/II clinical trial designs for drug combinations in oncology.

BACKGROUND

Adaptive Phase I/II designs can jointly use toxicity and efficacy information to guide dose allocation and regimen selection. These designs are particularly relevant for oncology drug-combination trials, where the optimal regimen may not coincide with the maximum tolerated dose.

METHODS

We conducted a structured narrative review of adaptive Phase I/II designs for oncology drug combinations that use both toxicity and efficacy information for adaptive allocation or final regimen selection. PubMed was searched through April 16, 2026 using terms related to Phase I/II, seamless design, drug combinations, dose-finding and efficacy, optimal biological dose, dual-agent, efficacy-toxicity trade-off, utility-based dose-finding, and adaptive randomization. Google Scholar and reference lists were used for supplementary citation chasing, and ClinicalTrials.gov was searched for illustrative real-trial applications.

RESULTS

Adaptive Phase I/II designs for drug combinations were identified across model-based, model-assisted, utility-based, and response-adaptive randomization frameworks for both discrete and continuous dose settings. Across designs, the main trade-offs involved assumptions on monotonicity and ordering, the ability to handle delayed outcomes, transparency of decision rules, computational burden, and software availability. Our targeted search identified few published real-world implementations, and software directly tailored to seamless Phase I/II combination trials remained limited.

CONCLUSIONS

Adaptive Phase I/II designs for drug combinations are methodologically well developed but remain difficult to implement routinely. Broader use will require clearer design-selection guidance, accessible software, robust delayed-outcome extensions, and protocol templates that communicate operating characteristics to clinical and regulatory stakeholders.