The dose levels assessed in B2 and C2 will not exceed those evaluated in Part A, B1, or C1. Revised Protocol No.: 04 Date: 31-May-2019 51 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS 5.1 Overall Design This is a Phase 1/2, open-label study of BMS-986226 administered as a monotherapy or in combination with either nivolumab or ipilimumab in participants with advanced solid tumors. The study will be c onducted in 3 parts: 1) dose-escalation monotherapy (P reliminary Safe ty Cohorts and Part A); 2) dose-escalation combination ther apy with either nivolumab (Part B) or ipilimumab (Part C); 3) a dose expansion phase with either nivolumab (Part D) or ipilimumab (Part E). Monotherapy consists of 2 different parts as follows: •Preliminary Safety Cohorts with BMS- 986226 administered as monotherapy at 2 mg and 8 mg once every 4 weeks (Q4W) for 24 weeks •Part A, with BMS-986226 administered at 25 m g, 80 mg, 200 mg, 400 mg, and 800 mg Q4W for 24 weeks Parts B and C consist of different combination cohorts comprising: •B1: BMS-986226 administered every 12 weeks (Q12W) + nivolumab 480 mg Q4W at a starting dose level of BMS-986226 one dose level lower than a monotherapy dose (Part A) that has cleared the DLT period. •B2: BMS-986226 Q4W + nivolumab 480 mg Q4W at a starting dose level of BMS-986226 tested in part B1. •C1: BMS-986226 Q12W + ipilimumab 3 mg/kg Q 4W at a starting dose level of BMS-986226 one dose level lower than a monotherapy dos e (Part A) that has cleared the DLT period. •C2: BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W at a starting dose level of BMS-986226 tested in Part C1. Parts B1 and C1 will enroll concurrently. Parts B2 and C2 will enroll if preliminary data from Part A or Parts B1 and C1 suggest a more frequent dose re gimen than Q12W and if additional safety, PK, or PD data are required to optimize dose and/or schedule selection (see Section 5.1.2.2 [Parts B1 and B2] and Section 5.1.2.3 [Parts C1 and C2]). Parts B1/C1 a nd B2/C2 can enroll concurrently and participants will be alternately assigned to all open cohorts. The doses of BMS-986226 for Parts B and C (combination with nivolumab or ipilimumab) will be determined using all available safety (clinical and laboratory), PK, a nd target engagement/PD data, as well as modeling recommendati ons within the Bayesian hierarchical modeling framework, ie, the BLRM-Copula model, by inc orporating single-agent toxicity profiles of both BMS-986226 (Preliminary Safety Cohorts and Part A) and nivolumab or ipilimumab18and any available combination toxicity data from Parts B and C (for subsequent doses of BMS-986226 in Parts B and C), PK/PD modeling, and will not exceed the maximum administered dose (MAD) of BMS-986226 monotherapy in the Preliminary Safety Cohorts and Part A (see Section 5.1.2.1 ). At no point will the dose of BMS-986226 administered in combination with nivolumab or ipilimumab (Parts B and C) exceed the dose of BMS-986226 that has been demonstrated previously to be safe in the monotherapy dose-escalation arm (Part A), nor at any point during Revised Protocol No.: 04 Date: 31-May-2019 52 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS combination therapy in Parts B and C will the BMS-986226 dose exceed the highest dose determined to be tolerated in the monotherapy dose-escalation arm (Part A). In addition, the starting dose level of BMS-986226 used in combin ation with nivolumab or ipilimumab (Parts B and C) will be one dose level lower than a monotherapy (Part A) dose that has cleared the DLT period. Parts B and C will consist of combination dose escalation cohorts aimed to e xplore the kinetics of ICOS-receptor downm odulation and re-e xpression (and/or change in selected target engagement/PD ) following administratio n of BMS-986226 in the presence of multiple doses of nivolumab Q4W (Part B) or ipilimumab (Q 4W) (Part C). Up to 3 different doses of BMS- 986226 w ill be administered in each of Parts B1 and C1 and an additional 6-12 par ticipants will be enrolled in up to 3 different dose cohorts in Parts B2 and C2: •Doses that induce or are predicted to induce different levels of ICOS r eceptor downmodulation, including at least one dose that induces n ear-complete receptor downmodulation (and/or change in selected target engagement/PD ) for a duration of at least 4 weeks. These dose levels will allow characteri zation of the ICOS receptor re-e xpression kinetics after near- complete downmodulation for a pe riod of time equal to, less than, and/or exceeding the dosing intervals used in Part A. Understanding ICOS receptor kinetics will help inform testing BMS- 986226 dosing intervals in future study(ies). S ubsequent doses will also be evaluated by BLRM-Copula for toxicity. Dose levels will be determined based on all available safety (clinical and laboratory) and PK data, as well as changes in peripheral target enga gement markers (eg, ICOS down regulation on T cells and ICOS + B cells) from previous and co mpleted portions of current cohorts and/or the BLRM/BLRM-Copula model whenever applicable. Table 5.1-1: Study Cohorts per Part Study Part Study Treatment Cohorts Preliminary Safety Cohorts and Part ABMS-986226 monotherapy•CC •CRC •HNSCC •MEL •NSCLC •PRC •RCC •TNBC •UCC •Other Advanced Epithelial Solid Tumors Parts B and C BMS-986226 + nivolumab or ipilimumab•CC •CRC •HNSCC •MEL Revised Protocol No.: 04 Date: 31-May-2019 53 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS Table 5.1-1: Study Cohorts per Part Study Part Study Treatment Cohorts •NSCLC •PRC •RCC •TNBC •UCC •Other Advanced Epithelial Solid Tumors Parts D and E BMS-986226 + nivolumab or ipilimumab•To be determined based on safety, tolerability, PK, and PD data from Parts A, B, and C For Parts A, scans will be co llected centrally and may be revi ewed by BICR at a later date or at any time during the study. For Parts B, C, D and E s cans will be collected centrally to be reviewed in real time by BICR.