Overall, the scenarios illustrated above demonstrate that the model performs well in the hypothetical scenarios investigated. 3 INTERIM MONITORING CASE STUDY TO ILLUSTRATE PROVISION OF DOSE RECOMMENDATIONS DURING DOSE-ESCALATION In order to provide a comprehensive view of the dynamics of the models, different hypothetical scenarios exploring all possibilities are examine d. For the simplicity of illustration purposes, a static cohort size of 3 subjects is applied for dose levels 25 mg, 80 mg, 200 mg, 400 mg, and 800 mg in the BMS-986226 monotherapy. This cohort size could vary during the actual clinical trial, and the BLRM models are designed to fit various different cohort sizes, adaptively. In general, there are 4 possible scenarios for a specific dose lev el, which are 0 DLT observed in 3 total subjects in that cohort (denoted as 0/3), 1 DLT observed in 3 subjects (1/3), 2 DLTs observed in 3 subjects (2/3), and 3 DLTs observed in 3 subjects (3/3). During interim monitoring, posterior probabilities will be updated when there is new DLT information available. The following three visualization plots w ill be produced to reflect the real time dose-DLT relationship, to quantify benefit (in the form of target dosing) and risk (in the form of overdosing and underdosing) during model’s recommendation process, and to facilitate clinical team’s interpretation of the model recomme ndations for the final decision making: Revised Protocol No.: 04 Date: 31-May-2019 208 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS •Dose-DLT profile for the doses ranging between 0 mg and 800 mg (Figure 3-1). •Stacking histograms displaying predictive probabilit ies on DLT rates classified into 3 different categories (Underdosing, Target dosing, and Overdosing) ( Figure 3-2). •Box plots summarizing the Markov Chain Monte Carlo samples of predicted DLT rates for the 5 pre-specified dose levels ( Figure 3-3 ). In the following illustrations, Figure 3-1 to Figure 3-3 are produced using a hypothetical example assuming 0/3 DLTs observed in the 25-mg cohort and 1/3 DLTs observed in the 80-mg cohort. Figure 3-1: Updated Dose-DLT Profile After Incorporating Prior Information and All Previous DLT Information up to 80 mg Abbreviations: DLT = dose-limiting toxicity; L = low boundary; U = upper boundary. Interpretation and usage of Figure 3-1: Figure 3-1 is a snapshot of an updated dose- DLT profile with DLT information available at dose level 80 mg. The dose-DLT profile is captured with a continuous dose spectrum ranging from 0 mg to 800 mg. For each dose within the range, there is a corresponding distribution of the predicted DLT rates calculated from the posterior samples of the model parameters. This figure will be updated each time when new DLT information becomes available. In Figure 3-1, there are 3 different quant iles (2.5%, 50%, and 97.5%) pl otted to char acterize the current trend of the toxicity profile (as shown by the 50% quantile), as well as the variation of the Revised Protocol No.: 04 Date: 31-May-2019 209 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS dose-DLT profile (as shown by the 2.5% percentile and the 97.5% percentile), according to the accumulation of DLT data from all previous and current dose levels. The toxicity boundaries (low boundary 0.16 and high boundary 0.33) are illustrated in two dotted horizontal lines to benchmark the way, in which the dose-DLT profile is trending. Intermediate dose levels can be identified using different boundary cutoffs. For example, using the 50% percentile curve (green highlight), which represe nts the nearly average DLT distribution for each dose level, the 100 mg could be a poten tial intermediate dose level corresponding to the lower pre-specified DLT rate boundary of 0 .16, and the 450 mg could be a fitted MTD dose level associated with the upper boundary of 0.33. Moreover, if all of the current pre-specified doses are considered intolerable (overdosing probabilities > 0.3, a case not shown on the current Figure 3-1 ), the model will recommend to stop the current dose level, and the clinical team can leverage the current updated dose-DLT curve to pinpoint a new dose, which is lower than pre-specified lowest dose (25 mg) by using the DLT rate boundaries. Figure 3-2: Updated Stacking Histogram a fter Incorporating Prior Information and All Previous DLT Information up to 80 mg Monotherapy Data to Classify Predicted DLT Rates Into 3 Categories (Under Target, Target Interval and Over Target) Interpretation and usage of Figure 3-2: Figure 3-2 is a snapshot of stacking histogram with DLT information available at dose level 80 mg for the combination studies. This figure w ill be updated each time when new DLT information Revised Protocol No.: 04 Date: 31-May-2019 210 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS becomes available in the combination setting.