Any toxicities that occur beyond the 5-week DLT period will also be considered in dose-level decisions. For the purpose of participant managemen t, any AE that meets DLT criteria (Section 7.3.2 ), regardless of the cycle in which it occurs, will lead to discontinuation of study tr eatment. Participants who withdraw from the study during the DLT evaluation period for reasons other than a DLT may be replaced with a new participant at the same dose level. The incidence of DLT(s) during the DLT evaluation period will be used in dose escalation decisions in Part A and guide dose recommendations in Parts B and C. AEs occurring after the 5-week DLT evaluation period will be considered for the purposes of defining any BLRM recommended dose upon agreement between the Sponsor, Medical Monitor/Study Directo r (or designee), and investigators, if the AEs are determined to have no clear alternative cause and are not related to disease progression. AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 27 5.1.2.2 BMS-986226 and Nivolumab Combination Therapy Cohort (Parts B1 and B2) The purpose of combin ation cohort with nivolumab is to gather safety, tolerability, PK, and PD information regarding the administration of BMS-986226 in combination with nivolumab 480 mg flat dose Q4W. Part B1 aims to determine the kinetics of ICOS receptor downmodulation and re-expression (and/or change in selected target e ngagement/PD ) following administration of BMS-986226 Q12W in combination with nivolumab 480 mg administered Q4W for a duration Revised Protocol No.: 04 Date: 31-May-2019 58 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS of 2 years. Continuous evaluation of toxicity events in the combination cohort will be performed throughout the enrollment. All participants treated with BMS-986226 in combination withnivolumab are recommended to receiv e premedications, as described in Section 7.1 , in order to reduce the risk of infusion-related reactions. Up to 3 different dose levels of BMS-986226 will be tested in Part B1, as determined by safety, PK and PD data. The starting dose level used in combination with nivolumab (Part B) will be one dose level lower than a monotherapy (Part A) dose that has cleared the DLT period. At each dose level, approximately 6 evaluable participants will be tr eated. A sentin el participant w ill be enrolled in Part B1 (BMS-986226 Q12W + ni volumab 480 mg Q4W) and observed for 5 days before additional participants in Parts B1 at the same dose level receiv e study treatment. Part B2 (BMS-986226 Q4W + nivolumab 480 mg Q4W) will be opened at dose levels evaluated in at least one participant in Part B1. Approximately 6-12 evaluable participants will be treated per cohort, if enrolled, to better characterize safety, PK, and PD of the combination. For instance, Part B2 will begin enrollment if the re-expression of ICOS on circulating T cells is observed 4 weeks after the first dose of BMS-986226 in Parts A or B1. Part B2 would therefore be utilized to provide a more granular assessment of safety and PD of BMS-986226. More than 1 dose level (no more than 3 different dose levels) may be enrolled, shoul d additional safety, PK, and PD data be needed. Once the safety (during the DLT evaluation) of a combination of BMS-986226 and nivolumab has been established and a recommended BMS-986226 dose regimen has been s elected for Part D, then additional participants (up to 6 additional e valuable participants) may be treated at the recommended dose to better characterize the safety, PK, and PD profile. 5.1.2.3 BMS-986226 and Ipilimumab Combination Therapy Cohort (Parts C1 and C2) The purpose of combination cohort wi th ipilimumab is to gather sa fety, tolerability, PK, and PD information regarding the administration of BMS-986226 in combination with ipilimumab at 3 mg/kg Q4W. Part C1 aims to d etermine the kinetics of ICOS receptor downmodulation and re- expression (and/or change in selected target e ngagement/PD ) following administration of BMS-986226 Q12W in combination with ipilimumab administered Q4W for a duration of 2 years. Continuous evaluation of toxicity events in the combination cohort w ill be performed throughout the enrollment. All participants treated with BMS-986226 in combination with ipilimumab are recommended to receive premedications, a s described in Section 7.1, in order to reduce the risk of infusion-related reactions. Up to 3 different dose levels of BMS-986226 will be tested in Parts C1, as determined by safety, PK and PD data. The starting dose level used in combination with ipilimumab (Part C) will be one dose level lower than a monotherapy (Part A) dose that has cleared the DLT period. At each dose level, approximately 6 evaluable participants will be tr eated, where a sentinel participant w ill be enrolled in Part C1 (BMS- 986226 Q12W + ipilimumab 3mg/kg Q4W and observed for 5 days before additional participants in Parts C1 at the same dose level receive study treatment. Part C2 (BMS-986226 Q4W + ipilimumab 3 mg/kg Q4W) will be opened at dose levels evaluated in at least one participant in Part C1. Approximately 6-12 evaluable par ticipants will be treated per Revised Protocol No.: 04 Date: 31-May-2019 59 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS dose cohort, if enrolled, to better characterize safe ty, PK, and PD of the combination. For instance, Part C2 will begin enrollment if the re-expression of ICOS on circulating T cells is observed 4 weeks after the first dose of BMS-986226 in Part A or C1. Part C2 would therefore be utilized to provide a more granular assessment of safety a nd PD of BMS-986226. More than 1 dose level (no more than 3 different dose levels) may be enro lled, should additional safety, PK, and PD data be needed. Once the safety (during the DLT evaluation) of a combination of BMS-986226 and ipilimumab has been established and a recommended BMS-986226 dose regimen has been selected for Part E, then additional participants (up to 6 additiona l evaluable participants) may be treated at the recommended dose to better characterize the safety, PK, and PD profile. Dose-limiting Toxicities in Combin ation Cohorts (Parts B and C) For the purpose of ensuring safety, DLTs will be defined based on the incidence, intensity, and duration of AEs for which no clear alternative cause is identified. The DLT period will be 35 days (5 weeks) in Parts B and C. For the purpose of participant managemen t, any AE that meets DLT criteria (Section 7.3.2 ), regardless of the cycle in which it occurs, will lead to temporary hold of study treatment. Participants who withdraw from the study during the DLT evaluation period for reasons other than a DLT may be replaced with a new participant at the same dose level. Re-challenge of participants experiencing a DLT will be evaluated on a case-by-case basis, once the AE returns to baseline or Grade 1, after specific consultation and agreement between the investigator and BMS Medical Monitor/Study Directo r (or desi gnee) in settings where benefit/risk justify re-administration of study treatment (see Section 7.3.5 ). AEs will be graded according to the NCI CTCAE v4.03. 27 5.1.2.4 Combination Expansion Arms (Parts D and E) The purpose of the cohort expansion is to gath er additional safety, tolerability, preliminary efficacy, PK, and PD information regarding BMS-986226 in combination with either nivolumab (Part D) or ipilimumab (Part E). Continuous evaluation of toxicity events in the cohort expansions will be performed th roughout enrollment in the expansion cohorts. All participants treated with BMS-986226 in combination with either nivolumab or ipilimumab are recommended to r eceive premedications, as described in Section 7.1 , in order to reduce the risk of infusion-related reactions. If, at any time, the aggrega te rate of treatment-related toxicities meeting DLT criteria exceeds 33% across all participants tr eated the findings will be discussed and further enrollment will be inte rrupted. Depending on the nature and grade of the toxicity, and after assessing the risk/benefit ratio, a new dose for all cohorts may be initiated at a lower dose level. The dose and schedule of BMS-986226 in Parts D and E will be determined based on all available safety, tolerability, efficacy, PK, and PD data from Parts A, B, and C. Parts D and E w ill be implemented following the revised protocol to define dose, schedule, and population. Revised Protocol No.: 04 Date: 31-May-2019 60 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS Approximately 40 participants will be enrolled in each of Parts D a nd E. Safety, efficacy, PK, and PD data will be used to determine the precise patient popu lation that will be enrolled in the expansion arms. Participants with a response of unconfirmed progressive disease, stable di sease, partial response, or complete response, at the end of a given cycle will continue to the next treatment cycle. Participants will be allowed to continue study treatment until the first o ccurrence of any of the following: •Completion of the maximum number of cycles •Confirmed progressive disease •Clinical deterioration suggesting that no further benefit from treatment is likely •Intolerability to therapy •Participant meets the criteria for discont inuation of study treatment as shown in Section 8.2 . 5.1.3 Follow-up 5.1.3.1 Safety Follow-upUpon completion of 24 weeks of study treatmen t for Part A (or up to a maximum of 48 weeks if applicable) or 2 years for Parts B, C, D, and E, once the decision is made to discontinue the participant from study treatment (e.g., at end of treatment [EOT]), all participants will enter the safety follow-up period. For participants who complete all scheduled cy cles of therapy, the EOT visit w ill be the same as the last scheduled and completed on-treatment visit and the start of the Week 1 safety follow-up visit. For participants who do not complete all scheduled cycles of study treatment, the EOT visit will be the most recent on-tr eatment visit (with all available sa fety and response data), does not need to be repeated, and will be considered the start of the safety follow-up visit. After the EOT visit, all participants will be evaluated for any new AEs for at least 100 days after the last dose of study treatment. Follow-up visits to monitor for AEs should occur at Days 30, 60, and 100 after the last dose or on the date of discontinuation ( ±7 days). All participants will be required to complete the 3 clinical safety follow-up visits regardless of whether or not they start new anti-cancer treatment, except those participan ts who withdraw consent for study participation. 5.1.3.2 Survival Follow-up After completion of the safety follow-up visits, all par ticipants treated with monotherapy and combination therapy will enter the survival follow-up period. Participants will be followed approximately every 3 months (12 weeks) until deat h, loss to follow-up, withdrawal of consent, or conclusion of the study, whichever comes first. The duration of this phase is up to 2 years from the last dose of study treatment, although a longer follow-up period could be considered in selected cases if an efficacy signal is apparent. Revised Protocol No.: 04 Date: 31-May-2019 61 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS 5.1.3.3 Response Follow-up After completion of the Safety Follow-up pe riod, participants with ongoing SD, PR, or CR at the EOT visit will enter the Response Follow-up period. This period will occur simultaneously with the Survival Follow-up period for the mentioned participants. Participants will continue to have radiologic and clinical tumor assessments approx imately every 3 months (12 weeks) until death, loss to follow-up, withdrawal of consent, or con clusion of the study, whichever comes first. Radiological tumor assessments for participants who have ongoing clinical benefit may continue to be collected after participants complete the s urvival phase of the study. Participants who have disease progression following in itial course of st udy treatment w ill not be evaluated for response beyond the EOT visit and will be allowed to receive other tumor-dir ected therapy as required. If the participant discontinues treatment for any reas on other than progressive disease, radiological follow-up will continue until the participant receives additional treatment. 5.1.4 Treatment with Additional Cycles All participants will be treated for 24 weeks of monotherapy or for 2 years for combination therapy unless criteria for study treatment discontinuation are met earlier. Only participants completing treatment in the monotherapy (Part A) cohort, with ongoing disease control (CR, PR, or SD), or unconfirmed progressive disease, may be eligib le for an additional 24 weeks of study tr eatment on a case-by-case basis after careful evaluation an d discussion with the BMS Medical Monitor/Study Director (or designee) to determine whether the risk/b enefit ratio supports administration of further study treatment. Upon completion of the additional study treatment period all par ticipants will enter safety follow-up period. 5.1.5 Treatment Beyond Progression Treatment beyond progression may be allowed in s elect participants with initial RECIST v1.1 or PCWG3 (prostate only) defined progressive disease after discussion and agreement with the BMS Medical Monitor/Study Director (or designee) that the benefit/risk assessment favors continued administration of study treatment (e g, participants are continuing to experience clinical benefit as assessed by the investigator, tolerating treatment, and meeting other criter ia specified in (Section 8.1.2 ). Participants must be re-consented with an informed consent form (ICF) addendum to continue treatment be yond progression. Treatment beyond progression w ill require continued tumor assessments. 5.1.6 Data Monitoring Committee and Other External Committees As this is an early stage, first-in-human study, a data monitoring committee will not be used. BMS has developed a multi-layered process to ensure safety monitoring through close collaboration of study site investigators, the BMS study team, and the BMS Global Pharmacovigilance and Epidemiology (GPVE)-led Medical Surveillance Team. Study safety will be evaluated continuously in real time by representatives of BMS GPVE, who operate independently from th e clinical team and monitor safety across all BMS protocols. AEs w ill be monitored continuously by th e medical monitor(s ) and GPVE. Safety, PK, and PD data are Revised Protocol No.: 04 Date: 31-May-2019 62 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS reviewed during teleconferences between investig ators and the BMS clinical team, which will be held regularly. The decision to escalate or expa nd the dose will be base d on the aforementioned review with investigators.