Model of a Queuing Approach for Patient Accrual in Phase 1 Oncology Studies

Abstract

Importance: Phase 1 cancer studies, which guide dose selection for subsequent studies, are almost 3 times more prevalent than phase 3 studies and have a median study duration considerably longer than 2 years, which constitutes a major component of drug development time.

Objective: To discern a method to reduce the duration of phase 1 studies in adult and pediatric cancer studies without violating risk limits by better accommodating the accrual and evaluation process (or queue).

Design: The process modeled, the phase 1 queue (IQ), includes patient interarrival time, screening, and dose-limiting toxicity evaluation. For this proof of principle, the rules of the 3 + 3 and rolling 6 phase 1 designs were modified to improve patient flow through the queue without exceeding the maximum risk permitted in the parent designs. The resulting designs, the IQ 3 + 3 and the IQ rolling 6, were each compared with their parent design by simulations in 12 different scenarios.

Main outcomes and measures: (1) The time from study opening to determination of the maximum tolerated dose (MTD), (2) the number of patients treated to determine the MTD, and (3) the association of the design with the dose selected as the MTD.

Results: Based on 800 simulations, for all 12 scenarios considered, the IQ 3 + 3 and the IQ rolling 6 designs were associated with reduced expected study durations compared with the parent design. The expected IQ 3 + 3 reduction ranged from 1.6 to 10.4 months (with 3.7 months for the standard scenario), and the expected reduction associated with IQ rolling 6 ranged from 0.4 to 10.5 months (with 3.4 months for the standard scenario). The increase in the mean number of patients treated in the IQ 3 + 3 compared with the 3 + 3 ranged from 0.6 to 3.2 patients. No increase in the number of patients was associated with the IQ rolling 6 compared with the rolling 6 design. The probability of selecting a dose level as the MTD changed by less than 3% for all dose levels and scenarios in both parent designs.

Conclusions and relevance: This study found that IQ designs were associated with reduced mean duration of phase 1 studies compared with their parent designs without changing the risk limits or MTD selection operating characteristics. These approaches have been successfully implemented in both hematology and solid tumor phase 1 studies.

Figure 1.. Representations of Patient Flow Through a Typical Phase 1 Trial

A, The process accounts for 3 outcomes. Patients who receive protocol-specified minimum therapy without a dose-limiting toxicity (DLT) pass. Patients with a DLT are designated DLT. Inevaluable denotes ones who do not meet criteria for pass or DLT, often because of inadequate treatment or insufficient follow-up. Disposition is found by randomly sampling times of occurrence of inevaluable and DLT distributions. If both occur, the disposition is the first event. B, Simulation software showing patient flow. Each dose level has 2 cohorts of 3 beds, plus 2 extra beds for use in queue-based modifications during escalation. There are 2 more beds (gray) for rare instances during deescalation of the rolling 6 design and queue-based modified designs, so all consenting patients are treated without delay. Patients go to the waitlist or screening (yellow). If they exceed maximum wait time or do not meet criteria, they exit. Patients meeting criteria take a bed, are treated, and are pending (blue). Patients who pass are green; with DLTs, red. If inevaluable, they exit. A summary data dashboard for many of the same scenario and various design parameters is at right (https://www.flexsim.com/clinical-trials). MAD indicates maximum administered dose; MTD, maximum tolerated dose; TDPS, total, DLTs, pending, status (dose above closed).

Figure 2.. Box-Whisker Plots of Study Duration for the 3 + 3 and Phase 1 Queue (IQ) 3 + 3 and Rolling 6 and IQ Rolling 6 Designs

A, Study duration for the 3 + 3 and IQ 3 + 3 studies. B, Study duration for the rolling 6 and IQ rolling 6 studies. C, Number of patients who started treatment for the 3 + 3 and IQ 3 + 3 designs. D, Number of patients who started treatment for the rolling 6 and IQ rolling 6 designs. Graphs are based on 800 simulations per scenario (Table 3).