Experiences symptoms even while at rest. Revised Protocol No.: 04 Date: 31-May-2019 203 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS APPENDIX 10 STATISTICAL METHODOLOGY STATISTICAL DETAILS FOR BAYESIAN LOGISTIC REGRESSION MODEL AND PRIORS FOR DOSE ESCALATION AND SAFETY MONITORING 1 MODEL SETUP FOR BMS-986226 MONOTHERAPY 1.1 Monotherapy Methodology Description An adaptive 2-parameter Bayesian Logistic Re gression Model (BLRM) guided by the escalation with overdose control (EWOC) principle1,2,3will be used to guide the dose escalation of BMS-986226 monotherapy in the monotherapy phase, providing dose recommendation during dose escalation. The BLRM will be fitted on the dose-limiting toxicity (DLT) d ata during the first 5 weeks of treatment accumulated throughout the dos e escalation to model the dose-toxicity relationship of BMS-986226 in the monotherapy dose escalation phase. The dose-toxicity relationships for BMS-986226 monotherapy is assumed to follow a logistic model: ݐ݅݃݋݈ሺ݌௜ሻൌ݃݋݈ ሺߙଵሻ൅ߚଵ݃݋݈ሺ݀ଵ௜݀ଵ∗൘ሻ, where ݌௜is the probability of toxicity at dose level ݀ଵ௜. Note that the ߙଵandߚଵparameters are assumed positive, and ݀ଵ∗is the reference dose for BMS-986226 (please refer to the meaning of ߙଵand ߚଵin Section 1.2 for detailed implementation). 1.2 Prior Specification for BMS-986226 Monotherapy The Bayesian approach requires the specification of prior distributions for model parameters, which include parameters ( ߙଵ,ߚଵ) for BMS-986226. The prior distributions for BMS-986226 single agent activity were derived using a weakly informative prior, as well as discussion with the Bristol-Myers Squibb (BMS) clinical team. Details are provided below. Weakly Informative Prior •The median DLT rate at the reference dose (BMS-986226 at 800 mg every 4 weeks) was assumed to be 30%, that is, mean (log( ߙଵ)) = logit (0.3) = l og(0.3/(1-0.3)) = -0.847. •A doubling in dose was assumed to double the odds of DLT, that is, mean (log( ߚଵ)) = 0. The standard deviation (sd) of log( ߙଵ) was set to 1.53 using the following steps: •If the toxicity probability range was set to be [1%, 99%], then the toxicity interval would be logit (0.99)-logit (0.01) = 9.19. •To cover 99.7% of the variance, the toxicity interval will cover 6 ×sd (log(ߙଵ)), which gives us sd (log(ߙଵ)) = 9.19/6 = 1.53. Revised Protocol No.: 04 Date: 31-May-2019 204 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS Correspondingly, the standard deviation of log( ߚଵ) was set to 1, which allows for considerably larger prior uncertainty for the dose toxicity. 1) The correlation between log( ߙଵ) and log( ߚଵ) was set to 0.