Design of a Phase I Drug Combination Study with Adaptive Allocation Based on Dose-Limiting Toxicity Attribution

Area of Science:

• Oncology
• Clinical Pharmacology
• Biostatistics

Background:

• Describes adaptation of a Phase I drug combination method for dose-limiting toxicity (DLT) attribution.
• Motivated by the Embolden trial (NCT03240211) evaluating pembrolizumab with pralatrexate or decitabine in T cell lymphomas.

Purpose of the Study:

• To adapt a dose-finding method to incorporate DLT attribution in early-phase drug combination trials.
• To guide simultaneous dose escalation of multiple agents by attributing DLTs to specific drugs.

Main Methods:

• Adapted the partial order continual reassessment method (POCRM) for DLT attribution.
• Integrated drug-specific DLT attribution to guide dosing in simultaneous escalation.
• Required software modifications for design performance evaluation via simulations.

Main Results:

• Successfully adapted the POCRM to incorporate DLT attribution for complex drug combinations.
• Ensured appropriate de-escalation of the offending agent in simultaneous dose escalation.
• Demonstrated the feasibility of the adapted method through simulations.

Conclusions:

• Novel dose-finding strategies are crucial for early-phase trials.
• The adapted POCRM enhances efficiency and transparency in dose assignment.
• Promotes broader adoption of advanced dose-finding methods in clinical research.