A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual...

Area of Science:

• Oncology
• Pharmacology
• Clinical Trial Design

Background:

• Monopolar spindle 1 (MPS1) kinase inhibitor BAY 1217389 (BAY) shows synergy with paclitaxel.
• Combination therapy requires careful dose determination, especially with overlapping toxicities.

Purpose of the Study:

• To assess the safety and establish the maximum tolerated dose (MTD) of BAY 1217389 in combination with paclitaxel.
• To evaluate the pharmacokinetic profiles of both agents.
• To explore the utility of a novel randomized continuous reassessment method (rCRM) for dose determination.

Main Methods:

• Phase I clinical trial enrolling patients with solid tumors.
• Randomized design comparing BAY 1217389 plus paclitaxel against paclitaxel monotherapy in cycle 1.
• Dose escalation guided by CRM modeling, with simulations to assess rCRM contribution.

Main Results:

• Seventy-five patients were enrolled; main dose-limiting toxicities were hematologic (55.6%).
• The MTD of BAY was established at 64 mg twice daily with paclitaxel.
• rCRM design facilitated attribution of neutropenia to BAY exposure and outperformed traditional designs in MTD determination.

Conclusions:

• The combination of BAY and paclitaxel exhibited significant toxicity.
• The rCRM design proved effective in elucidating the exposure-toxicity relationship for BAY.
• rCRM is proposed as a valuable tool for optimizing dose determination in phase I trials of combination therapies.