Accelerating drug development by efficiently using emerging PK/PD data from an adaptable entry-into-human trial:...

Area of Science:

• Oncology
• Pharmacology
• Clinical Trial Design

Background:

• Investigational monoclonal antibodies require robust data for optimal dosing.
• Early clinical trials often face challenges in determining effective combination regimens.
• Pharmacokinetic (PK) and pharmacodynamic (PD) data are crucial for guiding dose selection.

Purpose of the Study:

• To evaluate the utility of early PK/PD data in guiding combination therapy regimens.
• To determine if emerging data from a dose-escalation study can inform subsequent trial phases.
• To optimize the dosing strategy for lumretuzumab in combination therapies.

Main Methods:

• Utilized emerging PK/PD data from nine patients receiving lumretuzumab monotherapy (100-400 mg q2w).
• Employed a pharmacokinetic model incorporating target-mediated drug disposition.
• Informed the selection of the starting dose for combination regimens based on PK/PD and safety data.

Main Results:

• Lumretuzumab doses up to 2000 mg q2w were investigated without reaching a maximum tolerated dose.
• The PK model predicted linear pharmacokinetics and >95% target saturation at lumretuzumab doses ≥400 mg q2w.
• These predictions supported initiating combination studies with cetuximab and erlotinib at 400 mg lumretuzumab, with subsequent data aligning with model predictions.

Conclusions:

• PK/PD modeling of early clinical data can expedite drug development programs.
• This approach allows for the commencement of later trial components before monotherapy completion.
• Optimized dosing and scheduling of lumretuzumab for combination therapy were achieved at doses below the maximum investigated.