What is the primary role of a Phase 1 clinical trial?

Primary Role of Phase 1 Clinical Trials

Phase 1 clinical trials are designed to determine the safety, tolerability, and maximum tolerated dose (MTD) of a new therapeutic agent through systematic dose escalation, with pharmacokinetic and pharmacodynamic assessment as secondary objectives. 1, 2

Core Objectives

Safety and Dose-Limiting Toxicity Assessment

• The primary endpoint is identifying dose-limiting toxicities (DLTs) by escalating doses until the minimally intolerated dose (MID) is reached; the dose immediately below the MID defines the MTD. 2
• Phase 1 trials typically enroll small numbers of patients (20-80 individuals) spread across several dose levels to minimize risk while accumulating preliminary toxicity data. 3, 4
• Clinical dose escalation studies increase the dose until significant toxicity develops, establishing the highest tolerable dose for subsequent phase 2 efficacy studies. 1

Pharmacokinetic and Pharmacodynamic Characterization

• Phase 1 studies assess absorption, distribution, metabolism, and excretion (ADME) properties to understand drug behavior in humans. 2, 5
• Pharmacokinetic endpoints become primary when evaluating drug-drug interactions, particularly for combinations with plausible pharmacokinetic interactions requiring crossover study designs with extensive sampling. 1
• Pharmacodynamic biomarkers can assist in defining a safe and potentially effective dose range, though efficacy remains a secondary consideration. 2, 5

Design Considerations for Combination Trials

When Formal Phase 1 Evaluation is Required

• Combination therapies with overlapping DLTs or plausible pharmacodynamic interactions leading to DLTs require formal phase 1 evaluation using dose-escalation designs. 1
• The classic 3+3 cohort expansion design remains most commonly used, though model-based approaches incorporating both toxicity and efficacy can be helpful when escalating both agents. 1
• Selection of doses must be justified based on preclinical data, nature of drug interactions, and specific phase 2 development plans, with explicit criteria for success and failure defined upfront. 1

When Phase 1 Can Be Abbreviated

• Combinations without overlapping toxicities, without plausible pharmacodynamic interactions leading to DLTs, and without plausible pharmacokinetic interactions do not require formal phase 1 studies; a pilot safety run-in as part of phase 2 is sufficient. 1

Critical Pitfalls to Avoid

• Do not conduct phase 1 trials without a clearly stated hypothesis and development plan for subsequent trials; if the development plan is unclear or not feasible, it calls into question the rationale for undertaking the phase 1 trial. 1
• Phase 1 studies have inherent limitations including small sample sizes, very few patients receiving efficacious doses, and absence of controls, making extrapolation of efficacy data inappropriate. 4
• For molecularly targeted agents and immunotherapies with non-dose-dependent toxicities, toxicity-based endpoints may not appropriately determine recommended dose; alternative parameters such as pharmacokinetic or pharmacodynamic outcomes should be considered. 5
• DLTs occurring after the first cycle can prevent administration of subsequent cycles and must be factored into determination of recommended phase 2 dosing. 1