A Phase I Dose-Finding Design Incorporating Intra-Patient Dose Escalation.

Area of Science:

• Clinical Trials Methodology
• Biostatistics
• Pharmacometrics

Background:

• Conventional Phase I trials require large patient cohorts to determine the maximum tolerated dose (MTD).
• Recruiting sufficient patients for dose-finding studies is challenging in pediatric or rare cancer trials.
• Existing designs may not efficiently utilize patient data for MTD determination.

Purpose of the Study:

• To propose a novel Phase I dose-finding design, IP-CRM, integrating intra-patient dose escalation with the continual reassessment method (CRM).
• To enhance the efficiency and accuracy of MTD identification in Phase I clinical trials.
• To address limitations of traditional designs in patient recruitment and data utilization.

Main Methods:

• The proposed IP-CRM design allows intra-patient dose escalation based on individual toxicity and cumulative data.
• Adaptive updating of starting doses for patient cohorts.
• Extension of IP-CRM to account for carryover effects and intra-patient correlations.

Main Results:

• The IP-CRM design significantly reduces sample size requirements compared to standard Phase I designs.
• Simulation studies demonstrate improved efficiency in identifying the MTD.
• IP-CRM shows enhanced probability of correctly identifying the MTD versus standard CRM and 3+3 designs.

Conclusions:

• The IP-CRM design offers a more efficient approach to Phase I dose-finding studies.
• This novel design is particularly beneficial for trials with limited patient populations.
• IP-CRM improves MTD identification accuracy and sample size efficiency in early-phase oncology trials.