18 3.3 Benefit/Risk Assessment Participants who have advanced solid tumors have a poor prognosis, few treatment options, and the majority will die of disease. Immunotherapy with ipilimumab or nivolumab has demonstrated clinical activity in a percentage of participants with MEL, NSCLC, RCC, HNSCC, and other tumors. Treatment-related AEs include those associated with autoimmune activation, such as colitis, pneumonitis, thyroiditis, hepatitis, and adrenal insufficiency. Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab is manageable and generally consistent across completed and ongoing clinical studies with no MTD reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) AEs with relatively few related, high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, Revised Protocol No.: 04 Date: 31-May-2019 46 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS severity, or causality of AEs with respect to nivolumab dose level. A pattern of immune-related AEs has been defined, for which management algorithms have been developed; these are provided in Appendix 6 . Most high-grade events were manageable with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these al gorithms. Additional details on the safety profile of nivolumab and ipilimumab, including results from other clinical studies, are available in the respective IBs. Preclinical Toxicology Three anti-ICOS antibodies have entered the clinic for evaluation in humans (NCT02520791, NCT02904226, and NCT02723955), however, published sa fety data are not available. Since no anti-ICOS class of compounds has been markete d, and BMS-986226 has never been administered to humans, data to inform the safe conduct of FIH studies are mainly based on the toxicology studies in monkeys.The safety of BMS-986226 has been extensively evaluated in nonclinical models. Based on nonclinical data in cynomolgus monkeys, administration of single or multiple doses of BMS-986226 is expected to be well tolerated at all the doses proposed for this FIH clinical study. Efficacy of the anti-ICOS mAb has been evaluate d as monotherapy or in combination with either anti-PD-1 or anti-CTLA-4 in multiple tumor-bearing mouse models. Based on the nonclinical data, the combination of BMS-986226 and nivolumab or ipilimumab is expected to exert anti-tumor activity across multiple tumor types. In the absence of clinical studies with BMS-986226, the evaluation of risk is based on information from nonclinical studies with BMS-986226 in cynomolgus monkeys (Section 3.2.2.2 ), and potential effects are based on the proposed mechanism of action and clinical evidence from nivolumab or ipilimumab therapy. The nonclinical GLP toxicology assessment of BMS-986226 has demonstrated a dose-related toxicity profile of immune-related AEs (irAEs) and cytokine-release potential compatible with the expected mechanism of action. Overall, there were no adverse findings observed in the nonclinical toxicology studies that identify specific safety concerns for using BMS-986226 in the proposed clinical study as a single agent. The nonclinical safety of BMS-986226 was evaluated in vitro in a human tissue cross-reactivity study and in cytoki ne-release and lymphocyte-activation assays in human cells. In vivo, BMS-986226 was evaluated in exploratory repeat-dose IV toxicity studies in rats (≤30 mg/kg) and cynomolgus monkeys ( ≤75 mg/kg; pivotal study). In addition, an exploratory single- and repeat-dose (2-week) IV toxicity study was conducted in mice us ing BMS-986246, a surrogate anti-mouse ICOS agonistic antibody with ident ical complemen tarity- determining regions (hamster-derived) as BMS-986226 with mouse Fc domains, and with comparable affinity for mouse ICOS. While toxicities associated with ADA formation limited the usefulness of this animal model, the results are not expected to be predictive of human response to ADA. As described in ICH S6, the induction of ADA formation in animals is not predictive of a potential for ADA formation in humans. A detailed explanation of the nonclinical toxicology program for BMS-986226 is described in Section 3.2.2.2 and in the IB. Revised Protocol No.: 04 Date: 31-May-2019 47 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS Overall Risk/Benefit for Combination with Nivolumab or Ipilimumab In combination therapy of BMS-986226 and nivolumab or ipilimumab, as observed in the combination of ipilimumab and nivolumab, it is possible that a higher incidence of irAEs may occur with the combination of the 2 antibodies . The safety profiles of nivolumab and ipilimumab monotherapy and the combination of ipilimumab and nivolumab are well defined based on experience with more than 12,300 patients evalu ated in clinical studies. The frequency and types of immune-mediated adve rse reactions ar e similar across multiple types of tumors and are described in the Reference Safety Inform ation in the current IBs for nivolumab17and ipilimumab18. Unanticipated side effect events may also occur. Summary The proposed clinical study of BMS-986226 has been designed to minimize the overall risk to participants; thus, measures will include: •A sentinel participant will be utilized for all dose escalation c ohorts in monotherapy (Preliminary Safety Cohorts and Part A) and all cohorts in combination therapy (Parts B and C; see Section 5.1.2 ). •Continuous safety assessments will be ut ilized by the i nvestigators and Sponsor to determine whether dose modification, additional safety measures, or termination of the study is required at any time. In addition, AEs and SAEs will be reviewed on an ongoing basis by the Bristol- Myers Squibb (BMS) Medical Monitor/Study Dir ector (or designee) and Global Pharmacovigilance and Epidemiol ogy representatives to monitor for any safety signals or trends. As BMS-986226 is an experimental agent, it is possible that unforeseen, unknown, or unanticipated reactions may occur. Howe ver, based on the nonclinical safety profile of BMS-986226 a nd the 250-fold exposure margin (based on the nonclinical HNSTD of 75 mg/kg in cynomolgus monkeys) built into the planned starting dose of 25 mg (flat dose), the potential safety risks are expected to be minimized. •The administration will occur at infusion centers wi th medical monitoring and the capability to manage infusion reactions or anaphylax is. Premedications are recommended to be administered prior to BMS-986226 infusion, as described in Section 7.1 and 7.3.6 . Participants will be observed for at least 60 minutes fo llowing the completion of BMS-986226 infusion due to the potential risk of, and to monitor for, infusion reactions. The protocol provides a treatment algorithm for i nfusion reactions (see Section 7.3.6 and Appendix 6 ). In addition to conventional safety measures for infusion of biologic agents, all par ticipants w ill undergo observation and assessment for signs of infusion reaction post-infusion after all infusions of BMS-986226. •Furthermore, to assess for potential effects of lymphocyte activation, dose- limiting toxicities (DLTs) will be recorded for all the c ohorts in monotherapy and in combination with nivolumab or ipilimumab. •Management algorithms for nivolumab- and ipilimumab-i nduced AEs involving GI, renal, pulmonary, hepatic, endocrine, skin, and neurologic systems are included in the protocol (seeSection 7.3.3 ). •Participants who develop irAEs may require prolonged treatment with high-dose corticosteroids and other immunosuppressive agents. This could increase the risk of Revised Protocol No.: 04 Date: 31-May-2019 48 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS opportunistic infections. IrAE management algor ithms in the protocol recommend antibiotic prophylaxis against opportunistic infections in such situations. •Complete blood counts and chemistry (including liver enzyme) tests w ill be carried out prior to administration of study tr eatment and on a weekly basis during the first 4 weeks of treatment in monotherapy or in combination betw een BMS-986226 and nivolumab or ipilimumab. In addition, a comp lete physical examination (PE) will be conducted on Cy cle 1 Day 1 along with weekly symptom-directed targ eted PEs during the first 5 to 6 weeks of treatment. Due to the potential risk of exaggerated inflammatory response, participants with autoimmune disorders, chronic hepatitis, or who are at risk for flare of autoimmunity will be excluded. In conclusion, there may be no direct benefit to participants treated with BMS-986226, and the potential exists for study treatment-related toxicity. However, there may be potential direct benefit to participants in this study including the follo wing: both single-agent and combined therapy with these investigational agents may result in a gr eater proportion of participants with stabilization of disease, objective response, or increased DOR than those observed with standard therapy or other investigational immunotherapy. It is also possib le that both single-agent and combined therapy may reverse T-cell exhaustion and achieve responses in 1) tumors refractory to anti-PD-1, anti- PD-L1, or anti-CTLA-4 antibody therapy; and/or 2) tumors with high Treg infiltrate. The potential benefit described above support s evaluating BMS-986226 both as single agent and in combination with nivolumab or ipilimumab in this Phase 1/2 clinical study with risk mitigation and clinical monitoring described above.4 OBJECTIVES AND ENDPOINTS Table 4-1: Objectives and Endpoints Objectives Endpoints Primary To characterize the safety and tolerability of BMS-986226 administered alone and in combination with nivolumab or ipilimumab in participants with advanced solid tumorsIncidence of AEs, SAEs, AEs meeting protocol-defined DLT criteria, AEs leading to discontinuation, and AEs resulting in death. Incidence of clinical laboratory test abnormalities Secondary To explore the preliminary efficacy of BMS-986226 administered alone and in combination with either nivolumab or ipilimumab in participants with advanced solid tumorsORR, mDOR, and PFS rate at 24 weeksa To characterize the PK of BMS-986226 when administered alone and in combination with nivolumab or ipilimumab in participants with advanced solid tumorsPK parameter estimates of BMS-986226 To characterize the immunogenicity of BMS-986226 when administered alone and in combination with nivolumab or ipilimumab in participants with advanced solid tumorsIncidence of ADAs specific for BMS-986226 Revised Protocol No.: 04 Date: 31-May-2019 49 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS Table 4-1: Objectives and Endpoints Objectives Endpoints To monitor target engagement of BMS-986226 administered alone and in combination with either nivolumab or ipilimumab in participants with advanced solid tumorsSummary measures of changes from baseline (% or absolute change) in cell surface ICOS expression on T cells and ICOS-ligand+ B cells aThese endpoints will be assessed based on RECIST v1.1 or PCWG3 (prostate only) criteria and will be determined based on tumor measurements occurring every 8 weeks ( ±1 week) during the treatment period and at least every 12 weeks ( ±2 week) in the response and survival follow-up periods . For Part A, scans will be collected centrally and may be reviewed by BICR at a later date or at any time during the study.