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Table 1 Design challenges, recommendations, assumptions, and available software for early-phase trials of imunne-oncology agents

From: Design considerations for early-phase clinical trials of immune-oncology agents

Design Challenge

Design Recommendation

Endpoints

Model Assumptions

Available software

Late-onset DLTs

TITE-CRM [21]

TITE-BOIN [23]

Binary toxicity

Probability of DLT increases with increasing dose level.

R Package dfcrm

SAS macros https://sph.umich.edu/ccb/tite-resources.html

www.trialdesign.org

Additional endpoints

Wages & Tait [30]

Zang et al. [29]

Ursino et al. [55]

Binary toxicity and binary efficacy (biologic activity or clinical response)

Binary toxicity and continuous PK measures (AUC)

Probability of DLT increases with increasing dose level. Probability of efficacy increases or plateaus with increasing dose level.

Toxicity related to the PK measure & PK triggers toxicity when above a certain threshold

https://uvatrapps.shinyapps.io/wtdesign/

www.trialdesign.org

R Package dfpk

Drug combinations

POCRM [37]

BOIN [39]

PIPE [38]

Binary toxicity

Probability of DLT increases with increasing dose level of each agent for a fixed dose level of the other agent.

R Package pocrm

www.trialdesign.org

R package pipe.design

Dose and schedule

Braun et al. [52]

Wages et al. [54]

Binary toxicity

Probability of DLT increases with increasing dose level of each agent for a fixed schedule.

https://biostatistics.mdanderson.org/softwaredownload/SingleSoftware.aspx?Software_Id=75

R Package pocrm