Late phase 1 studies: concepts and outcomes

Area of Science:

• Oncology
• Clinical Pharmacology
• Drug Development

Background:

• Targeted therapies are crucial for cancers with oncogene addiction, but patient relapse within 12 months is common.
• Drug resistance mechanisms and insufficient drug concentration contribute to treatment failure.
• Current dosing strategies may not achieve optimal drug concentrations, impacting efficacy.

Purpose of the Study:

• To introduce and define the concept of a late phase 1 study in clinical drug development.
• To propose intrapatient dose escalation as a strategy to overcome treatment failure in specific patient populations.
• To investigate alternative maximum tolerated doses (MTD) in patients with acquired resistance to targeted therapies.

Main Methods:

• The proposed late phase 1 study involves dose escalation within individual patients.
• Focuses on patients with initial benefit from targeted therapy who subsequently progressed without identified resistance alterations.
• Aims to define an alternative MTD based on chronic exposure and subsequent progression.

Main Results:

• Insufficient drug concentration is a frequent, yet underexplored, cause of targeted therapy failure.
• The recommended phase 2 dose may not always represent the optimal therapeutic concentration.
• Intrapatient dose escalation has the potential to increase drug concentration and restore efficacy.

Conclusions:

• A late phase 1 study offers a novel approach to optimize targeted therapy dosing.
• Addressing suboptimal drug concentrations through dose escalation may re-sensitize tumors to treatment.
• This strategy could improve outcomes for patients experiencing treatment failure due to acquired resistance.