A Bayesian adaptive phase 1 design to determine the optimal dose and schedule of an adoptive T-cell therapy in a mixed patient population.
We present a novel Bayesian adaptive phase 1 design to determine the optimal dosing regimen for an adoptive T-cell therapy in a mixed patient population. Our design is motivated by a B-cell Non-Hodgkin Lymphoma trial evaluating multiple dosing regimens within multiple disease subtypes. A utility score is calculated from both safety and efficacy utility functions and used to guide dose-escalation decisions. We pool safety data across disease subtypes and use a single dose-toxicity model while sharing efficacy information between disease subtypes using a hierarchical dose-response model. In addition, an adaptive randomization approach is applied to dynamically assign patients to a regimen when more than one regimen is open for enrollment. We illustrate this study design through a simulated trial example, and we investigate the operating characteristics using simulation studies.
Berry Consultants, LLC, 4301 Westbank Drive, Bldg B, Suite 140, Austin, TX 78746, USA.
Melanie
M
Quintana
Juno Therapeutics, 307 Westlake Avenue, Seattle, WA 98109, USA. Electronic address: daniel.li@junotherapeutics.com.
Daniel H
DH
Li
Juno Therapeutics, 307 Westlake Avenue, Seattle, WA 98109, USA.
Tina M
TM
Albertson
Berry Consultants, LLC, 4301 Westbank Drive, Bldg B, Suite 140, Austin, TX 78746, USA; University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, USA.
Jason T
JT
Connor
D019264:Adoptive Transfer / Q000379:methods*; D018941:Antigens, CD19 / Q000378:metabolism; D001499:Bayes Theorem; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000628:therapy*; D020522:Lymphoma, Mantle-Cell / Q000628:therapy*; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation*; D014182:Transplantation, Autologous
D018941:Antigens, CD19; C000604811:CD19 molecule, human; D015704:CD4 Antigens; D016827:CD8 Antigens
Adaptive randomization; Bayesian adaptive; Hierarchical modeling; Mixed population; Phase 1; Utility score