The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents

Area of Science:

• Oncology
• Clinical Trial Design
• Pharmacology

Background:

• Many new anticancer drugs target growth inhibition, posing challenges for phase II clinical trials.
• Standard endpoints like tumor shrinkage are often not met, and time to progression is difficult to predict without concurrent controls.
• Identifying patient populations who will benefit from novel agents in early development remains a significant hurdle.

Purpose of the Study:

• To introduce and evaluate the randomized discontinuation trial (RDT) design.
• To address the limitations of traditional phase II trial designs for growth inhibitory anticancer agents.
• To demonstrate how RDT can identify patient benefit and assess disease stabilization.

Main Methods:

• The RDT involves an initial treatment period for all patients.
• Patients with objective responses continue therapy.
• Non-progressing patients are randomized to continue or discontinue therapy in a double-blind, placebo-controlled manner after a run-in period.

Main Results:

• The RDT design allows for the selection of a patient cohort most likely to benefit from the investigational drug.
• It provides a rigorous method for evaluating the disease-stabilizing activity of novel anticancer agents.
• This design overcomes the challenges of unpredictable null hypothesis times and poorly defined patient populations.

Conclusions:

• The randomized discontinuation trial offers significant advantages for early-phase anticancer drug development.
• It effectively addresses challenges related to objective response and time-to-progression endpoints.
• RDT facilitates rigorous evaluation of disease stabilization and identification of patient benefit, despite certain limitations.