Similar graphs will also be produced for the BMS-986226 monotherapy. This plot supplements the information provided in Figure 3-1 . It allows for a more in-depth and focused visualization of general trend of dose-DLT relationship, as well as the magnitude and variability in the DLT rates for each pre-specified dose level. 3.1 Example of the BLRM using BMS-986226 Monotherapy Dose Escalation According to safety consideration and clinical judgement, the dose level 25 mg is recommended as the starting dose for BMS-986226 monotherapy. With the current BMS-986226 prior specified Revised Protocol No.: 04 Date: 31-May-2019 212 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS in the Section 1.2 and all available DLT information up to 80 mg, a corresponding d ecision tree illustrating various models’ recommendations under all possible scenarios (for dose levels of 200 mg and 400 mg) is provided in Figure 3.1-1. Tracing a branch of the decision tree in Figure 3.1-1 illustrates the decision making process. Taking the left-most branch of the tree as an example, starting at 25 mg, there were 0 DLT observed at 25 mg in the real clinical trial, the model recommended to escalate to 80 mg (The BLRM actually recommends escalating to dose level 400 mg, but sin ce this is a 16-fold increase of dose and this type of dose skipping is not allowed, the dose level 80 mg is selected), one level above the current treated dose level according escalation rules per protocol. Additionally, if there was 0 DLT observed at 80 mg in real data, the model recommended to escalate further one dose level to 400 mg. As illustrated in Figure 3.1-1, there are 6 potential decision paths for dose levels 80 mg and moving onwards up to 200 mg. During the actual clinical study, the tree would be narrowed or deepened based on actual DLT. The clinical team w ill be able to leverage this d ecision tree to preview decisions at each interim monitori ng step and to plan proactively. Figure 3.1-1: The BLRM Model Hypothetical Decision Tree for BMS-986226 Monotherapy during Dose Escalation (up to 400 mg) Abbreviations: DE = de-escalation; E = escalation; S = stay. 4 BLRM-COPULA MODEL SETUP FOR BMS-986226 AND NIVOLUMAB OR IPILIMUMAB COMBINATION For Parts B and C of this study, the BLRM-Copula model w ill be used to evaluate the starting dose and to guide the subsequent doses of BMS- 986226 in combination with nivolumab or ipilimumab. Revised Protocol No.: 04 Date: 31-May-2019 213 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS The BLRM-Copula model inc orporates the latest information, including monotherapy information from Part A and any available toxicity information in comp leted portion of Parts B and C, available at the time of dose recommendation. In other words, the model concept covers both the starting doses and any subsequent doses of BMS-986226 in combination with nivolumab or ipilimumab in Parts B and C. Specifically, the starting dose of BM S-986226 in Parts B and C will be guided using the BLRM-Copula model, inc orporating available single-agent toxicity profiles of BMS-986226 from the preliminary safety cohorts and Part A and nivolumab or ipilimumab. Any subsequent dose of BMS-986226 in Parts B and C w ill be evalu ated using the BLRM -Copula model, incorporating single-agent toxicity profiles of BMS-986226, nivolumab or ipilimumab and any available combination toxicity profiles from on-going Parts B and C. In any case, the dose of BMS-986226 in combination with nivolumab or ipilimumab in Parts B and C will not exceed the maximum administered dose for BMS-986226 monotherapy in Part A. In summary, the doses of BMS-986226 in Parts B and C (combination with nivolumab or ipilimumab) will be determined using all available sa fety (clinical and laboratory), PK, and target engagement data, and th e modelling reco mmendation using the BLRM-Copula model. The tox icity profiles of both BMS-986226 monot herapy and nivolumab or ipilimumab monotherapy, to be incorporated in the BLRM- Copula model, w ill be discussed in upcoming subsections. We introduce briefly th e technical background of the BLRM-Copula model in the following paragraph. A copula-type model can be used to cover all general combination cases, including additive and synergistic effects. The combination of the 2 treatments will be explored using a Bayesian hierarchical model by utilizing the toxicity profiles of the single agents as prior marginal profiles for the combination. The following copula-type model 4will be used to describe the probability ݌௜௝ of toxicity when dose level ݅of agent A and dose level ݆of agent B are administered in combination: ݌௜௝ൌ1െ݌ݔ݁ሺെ൤ ሼെ݃݋݈ሺ 1െ݌௜௠ሻሽଵఊభൗ൅൛െ݃݋݈ሺ 1െݍ௝௡ሻൟଵఊభൗ൨ఊభ ሻ, where ݌௜is the prespecified best guess toxicity probability for agent A, ݍ௝is the prespecified best guess toxicity probability for agent B, ݉and ݊characterize the individual drug effect, and ߛଵcharacterizes the drug-drug interactive effect. The joint toxicity framework models the toxicity rates of both agents as well as their interaction effects in a 7-parameter hierarchical model, where each monotherapy dose-toxicity relationship will be ch aracterized by a 2-param eter BLRM model (see Section 1.1 ). There are 3 additional parameters for the copula-type model, 1 for each agent ( ݉and ݊ )as well as 1 for the interaction term (ߛ ଵ). A dose-toxicity surface w ill be char acterized for different dose combinations of these 2 agents. As there are currently no historical d ata or prior knowledge to indicate how much i nformation is to be borrowed for each of the single agents, parameters ݉and ݊are both set to be 1, meaning borrowing 100% of the information from th e 2 agents. The above formula is then simplified into a 5-parameter model as follows: Revised Protocol No.: 04 Date: 31-May-2019 214 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS ݌௜௝ൌ1െ݌ݔ݁ሺെ൤ ሼെ݃݋݈ሺ1െ݌௜ሻሽଵఊభൗ൅൛െ݃݋݈൫1െݍ௝൯ൟଵఊభൗ൨ఊభ . In each cohort of the study, since only a fixed nivolumab dose (in Part B1) or ipilimumab dose (1 mg/kg in Part B2, 3mg/kg in Part B3) will be used in the combination with BMS- 986226, this surface will be simplified into a 2-dimensional dose-toxicity c urve. Posteriors for the corresponding 5 parameters (2 logistic regression parameters [ ߙଵ,ߚଵ] for BMS-986226 and 2 logistic regression parameters [ ߙଶ,ߚଶ] for nivolumab or ipilimumab, as well as 1 interaction parameter for the copula-type model [ ߛଵ, which will be discussed in detail in the following section]) will be fitted into the in-house deve loped model. It implements the above-described theoretical setup. 4.1 Prior Specification for Combination Therapy In this section, we illustrate the prior specification of parameters in the BLRM-copula model for combination therapies. While we give prior examples for illustration purposes, all of those specifications may be subject to change when new data of monotherapies are available. 4.1.1 Marginal Prior for BMS-986226 Posterior information on log( α1) and log( β1) from the m onotherapy part of the study will be used as marginal BMS-986226 prior for co mbination with ipilimumab. This prior information is not prespecified and will be continuously updated when additional DLT i nformation from the monotherapy is available. In the simulation (see Section 3, the prior of BMS-986226 as described in Section 1.2 (Table 1.2-1 ) is used for illustration purposes because no real-time DLT data are available at this time. 4.1.2 Marginal Prior for Nivolumab Parameters (log( α2),log(β2)) Similar to BMS-986226 monotherapy in the lead-in phase, the logistic model for nivolumab is as follows: ݐ݅݃݋݈൫ݍ௝൯ൌ݃݋݈ ሺߙଶሻ൅ߚଶ݃݋݈ሺ݀ଶ௝ ݀ଶ∗൘ሻ, where ܽଶ,ߚଶ > 0. Note that the ߙଶandߚଶparameters are assumed positive, and ݀ଶ∗is the reference dose for nivolumab. The toxicity profile of nivolumab has been studied in several studies. A bivariate normal prior for the nivolumab model parameters (log( α2), log(β2)) was obtained by extracting a posterior of nivolumab using incidence of treatment-related Grad e 3 to 4 AEs from a Phase 1 dose-escalation study and several Phase 3 nivolumab studies, which are used later as the MAP prior for nivolumab. These include a Phase 1 dose-escalation study of nivolumab (Study CA209003, N=306 in doses of 0.1, 0.3, 1, 3, and 10 mg/kg across multiple tumor types), a randomized Phase 3 study in advanced melanoma participants progressing post anti-CTLA-4 therapy (Study CA209037, N=268 in a dose of 3 mg/kg), a Phase 3 study in previously treated participants with squamous cell NSCLC (Study CA209017, N=131 in a dose of 3 mg/kg), a Phase 3 study in previously treated participants with non-squamous cell NSCLC (Study CA209057, N=287 in a dose of 3 mg/kg), and a Phase 3 Revised Protocol No.: 04 Date: 31-May-2019 215 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS study in previously treated participants with clear- cell RCC (Study CA209025, N=406 in a dose of 3 mg/kg). The results from the simulation of nivolumab flat dose exposures, the corresponding exposure-response analyses, and review of nivolumab safety support nivolumab flat dose and the overall distributions of nivolumab exposures are comparable after treatment with either 3 mg/kg Q2W or 240 mg Q2W nivolumab. The MAP prior for the model parameters (log(α 2), log(β2)) was obtained in the following steps. First, a prior distribution for nivolumab was developed: •The median DLT rate at the reference dose (3 mg/kg every 2 weeks) was assumed to be 10%, that is, mean (log( α2)) = logit(0.10) = log(0.1/0.9) = -2.197. •A doubling in dose was assumed to double odds of DLT, that is, mean(log( β2)) = 0. •The standard deviation of log( α2) was set to 2, and the standard deviation of log( β2) to 1, which allows for considerable prior uncertainty for the dose-toxicity profile. •The correlation between log(α 2),and log( β2) is assumed to be 0 (assuming independence of log(α2) and log( β2)). •In addition, heterogeneity between the historical study and current study was incorporated using a MAP by defining between-trial standard deviations τ1and τ2for log(α2) and log( β2), respectively. The between-trial variability is assumed to be moderate. Therefore, τ 1and τ 2 were set to follow a log-normal distribution wi th mean log(0.25) and l og(0.125), resp ectively, with a common standard deviation log(2)/1.96. With this prior, the clinical trial data below were used to generate the posterior for nivolumab, which is then used as the MAP prior for this study. Table 4.1.2-1: Data from Nivolumab Studies Nivolumab Flat Dose (mg), Q4WDose of Nivolumab (mg/kg) Q2WToxicitya 0.1 29% (5/17) 0.3 17% (3/18) 160 1 14% (12/86) 480 3 13% (150/1146) 10 16% (21/131) a% of participants with treatment-related Grade 3-4 AEs Abbreviation: Q2W = every 2 weeks; Q4W - every 4 weeks. Revised Protocol No.: 04 Date: 31-May-2019 216 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS Table 4.1.2-2: Marginal Prior Distribution for Model Parameters for Nivolumab (ie, Posterior from MAP Method) Parameter Means Standard Deviations Correlation log(α 2), log(β 2) (-1.856, -2.131) (0.404, 0.546) -0.009 Note: Nivolumab prior information was based on mg/kg dos ing instead of flat dosing.