Simple Modifications of Phase I Trial Designs Could Reduce Time Required for New Advances

Phase I queue (IQ) designs were associated with reduced expected study durations compared to their parent designs without changing the risk limits or maximum tolerated dose selection operating characteristics, according to a recent study published in JAMA Network Open.

There were also minimal changes in the number of patients treated and the determination of the maximum tolerated dose in this study’s modified designs, without altering operating characteristics or exceeding the parent design’s risk limits.

“We observed in our phase I studies that these details can dramatically affect phase 1 study duration and such imperfections are present in every study,” wrote the researchers. “We can adapt designs to these imperfections to reduce the study duration while not exceeding the risk permitted in the parent design or affecting the operating characteristics.”

Overall, the expected reduction for the IQ 3 + 3 design ranged from 1.6 to 10.4 months (with 3.7 months for the standard scenario). The expected reduction for the IQ rolling 6 design ranged from 0.4 to 10.5 months (with 3.4 months for the standard scenario).

More, there was no associated increase in the number of patients treated for the IQ rolling 6 design compared to the standard rolling 6, but there was an associated increase in treated patients for the IQ 3 + 3 compared to the standard 3 + 3 ranged from 0.6 to 3.2 patients.

The IQ process included patient interarrival time, screening, and dose-limiting toxicity evaluation, which were then compared with parent designs based on 800 simulations in 12 different scenarios. The study was based on the IQ 3 + 3 and the IQ rolling 6, a modified design to improve patient flow through the queue.

“The IQ 3 + 3 and the IQ rolling 6 designs should be considered as alternatives to the 3 + 3 and rolling 6 designs, respectively,” wrote the researchers. “The IQ designs better adapt to the patient queue to reduce study duration without exceeding the risk limits of the parent design or affecting operating characteristics.”

The researchers did not implement separate screening-time distributions for patients considered failures versus successes. More, the team did not model time to acquire data or decision time.

Moving forward, the researchers recommend examining an expansion cohort at the recommended phase 2 dose with additional monitoring rules. Even further, a randomized dose-ranging phase 2 study is warranted to evaluate candidate doses. Finally, expanding the queue-based methods beyond the maximum tolerated dose determination is a potential area of future work.

“To our knowledge, this represents the most beneficial modification of 2 of the most commonly used designs (1 for adults and 1 for pediatric populations) to reduce expected study duration without affected the operating characteristics,” wrote the researchers. “These new designs have been successfully implemented in several completed and ongoing clinical trials.”

Reference:

Frankel PH, Chung V, Tuscano J, et al. Model of a Queuing Approach for Patient Accrual in Phase 1 Oncology Studies. JAMA Network Open. doi:10.1001/jamanetworkopen.2020.4787.