5.3 End of Study Definition The start of the study is defined as the firs t visit for the first participant screened. The end of study is defined as the last visit or scheduled procedure shown in the Schedule of Activities ( Section 2 ) for the last participant. Study completion is defined as the final date on which data for the primary endpoint were or are expected to be collected if they are not the same. 5.4 Scientific Rationale for Study Design 5.4.1 Rationale for BMS-986226 First-in-Human Dose (Preliminary Safety Cohorts and Part A Monotherapy) The selection of the BMS-986226 starting dose is based on the pivotal repeat-dose IV toxicology study in cynomolgus monkeys and the mouse CT26 colon adenocarcinoma tumor efficacy model. These approaches reflect the goal of adequately ensuring patient safety while limiting the number of advanced-stage cancer patients from receiving sub-pharmacologically active doses. In the pivotal repeat-dose (5 doses/week) IV toxicity study, the dose of 75 mg/kg (AUC[0-168h] ≤452,000 μg•h/mL) was considered to be the NOAEL and was also considered the HNSTD to determine potential MRSD as per ICH S9. 28Using a standard milligram per kilogram conversion to the human equivalent dose and a safety factor of 6-fold, the potential MRSD was calculated to be 12.5 mg/kg. The anti-tumor efficacy of hamster anti-mouse ICOS agonist mAb (BMS-986246) was studied in the mouse CT26 colon adenocarcinoma model as a single agent or in combination with an anti- mouse PD-1 mAb.29In this study, improved anti-tumor efficacy of BMS-986246 was noted in combination with an anti-murine PD-1 mAb relative to single-agent treatment. The AUC and percent tumor growth inhibition (%TGI) relationship in this study was used to project human starting and efficacious doses. Peak %TGI was reached at 3 mg/kg dose of BMS-986246 in combination with anti-mPD1 (corresponding Cmax at first week of 84 μg/mL and AUC from 0 to 1 week of 450 μgday/mL). Accordingly, the 4.6-mg/kg dose of BMS-986226 (368 mg assuming Revised Protocol No.: 04 Date: 31-May-2019 63 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS 80 kg human body weight) is projected to achiev e these targeted exposures in humans and is considered the targeted efficacious dose. Negligible anti-tumor activity (no im provement over anti-murine PD-1 mAb alone) in mice was noted at 0.3 mg/kg. To achieve comp arable systemic exposures as the 0.3 mg/kg dose in mice, 25 mg was selected as the first dose level for Part A. The projected expos ures (eg, AUCs) following administration of 25 mg are 102-fold lower than the exposures observed in cynomolgus monkeys at the NOAEL dose. Other considerations to select the starting dose included ICOS expression in humans and comparisons of the projected concentrations relati ve to those used in the in vitro cytokine-release assay. Unlike high-risk targets, eg, CD28 receptor, which is constitutively expressed, normal ICOS expression is limited, with the majority of high-expressing cells found to be activated T cells.30 The dose of BMS-986226 that is projected to result in approximately 80% to 85% ICOS binding to activated T cells at Cm ax is 2 mg. This dose would be expected to engage ICOS in activated T cells, but not expected to have appreciable clinical activity and thus will be used as the starting dose in the Prelimina ry Safety Cohorts. Collectively, these data support using a starting dose of 2 mg BMS-986226 in the Preliminary Safety Cohorts to allow safe administration of BMS-986226 at a dose pro jected to not have appreciable clinical activity. The first dose level in Part A is 25 mg BMS- 986226, as it is expected to have pharmacologic activity and reasonable safety in the cancer patient population. 5.4.2 Rationale For Treatment Duration 5.4.2.1 Rationale for 24-week Duration of BMS-986226 MonotherapyWhile immunotherapies are rapidly making great st rides in the treatment of cancer, the optimal duration of treatment to obtain and maintain deep and durable responses is a matter of ongoing clinical investigation. Emerging clinical data on time to response with immunotherapies in cancer suggest that a majority of participants who responded did so within the first 24 weeks on tr eatment. 5.4.2.2 Rationale for 2-year Duration of BMS-986226 in Combination with Nivolumab or Ipilimumab The optimal duration of immunotherapy is an important question and continues to be investigated. In study CA209153, patients with previously treat ed advanced NSCLC who completed 1 year of nivolumab therapy were randomized to either c ontinue or stop treatment, with the option of retreatment upon progression. Among 163 patients still on tr eatment at 1 year and without progression, those who were randomized to continue nivolumab had significant improvement in progression-free survival (PFS) compared to those who were randomized to stop treatment, with median PFS (post-ra ndomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, the PFS curves in both groups plateau approximately 1 y ear after rando mization (i.e ., 2 years after treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond a total of 2 years. 31Moreover, accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient for long term benefit. In st udy CA 209003, a dose-escalation cohort expansion trial evaluating the safe ty and clinical activity of nivolumab in patients with previously Revised Protocol No.: 04 Date: 31-May-2019 64 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS treated advanced solid tumors (including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. Am ong 16 par ticipants with NSCLC who discontinued nivolumab after completing 2 years of treatment, 12 participants were alive > 5 years and remained progression-free without any subsequent ther apy. In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.32These survival outcomes are similar to phase 3 studies in previously treated NSCLC, in which nivolumab treatment was continued until progre ssion or unacceptable toxicity (2 year OS rates of 23% and 29% and 3 year OS rates of 16% - 18% for squamous and non-squamous NSCLC, respectively).33 Taken together, the data suggest shorter duration of nivolumab of only 1 year was associated with increased risk of progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year is likely needed. Also, treatment beyond 2 years is unlikely to confer additional clinically meaningful benefit and that the risk of progression after discontinuing treatment at 2 years is low. Although there is no data available for 2 year treatment regimen of ipilimumab, the mechanism of action of the negative regulators of T c ell activation is s imilar to that of nivolumab. Therefore, CA021002 will evaluate the safety and tolerability of ipilimumab (Q4W) in combination with BMS-986226 for up to 2 years. Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O treatment beyond two years in advanced tumors. However, even though immunotherapy is well tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore in study CA021002, treatment with BMS-986226 in combination with nivolumab or ipilimumab will not be extended beyond 2 years. 5.4.3 Rationale for Treatment Beyond Progression Immunotherapeutic agents produce atypical clinical re sponse patterns that are not usually observed in conventional chemotherapy. Accumulating clinical evidence indicates that some participants treated with immune system-stimulating ag ents may develop disease progression by the conventional response criteria before demonstrating clinical objective responses and/or SD. Two distinct nonconventional patterns have been reported: 1) a reduction in target tumor burden despite the appearance of new lesion(s) and 2) a transient increase in target tumor burden in an initial phase followed by subsequent tumor shrinkage. This phenomenon was observed in the Phase 2 study of nivolumab (Study CA209003) in solid tumor patients. Two hypotheses explain this phe nomenon. First, enhanced inflammation within tumors could lead to an increase in tumor size, which would appear as enlarged index lesions and as newly visible small non-index lesions. Over time, both the malignant and inflammatory portions of the mass may then decrease, leading to overt signs of clinical improvement. Alternatively, in some individuals, the kinetics of tumor growth may initially outpace anti-tumor immune activity. With sufficient time, the anti-tumor activity will domin ate and become clinically apparent. Therefore, it is important to avoid premature di scontinuation of the study treatment that might induce a nonconventional response pattern in some participants. Revised Protocol No.: 04 Date: 31-May-2019 65 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS The decision to continue treatment beyond investigator-assessed progression should be discussed with the BMS Medical Monitor/Study Director (or designee) and documented in the study records. The assessment of clinical benefit s hould take into acc ount whether the participant is clinically deteriorating and unlikely to receive further benefit from continued treatment. Revised Protocol No.: 04 Date: 31-May-2019 66 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS 5.5 Justification for Dose and Schedules for BMS-986226, Nivolumab, and Ipilimumab 5.5.1 Rationale for BMS-986226 Flat Dosing and Schedule Therapeutic mAb doses have been routinely calculated on a body size basis with a perception that this approach may reduce inter-participant var iability in drug exposure compared with a f lat dose approach. However, recent analyses of marketed experimental mAbs have demonstrated that body weight-based dosing did not always offer advan tages over flat dosing in reducing exposure variability. Because the magnitude of the impact of body weight on the human PK of BMS-986226 is not yet determined and it is unknown if body size-based dosing would increase or decrease inter-participant variability, this study w ill ut ilize a flat dose in the escalation and combination phases as a more convenient approach and which is more likely to reduce the potential for dosing errors. The starting dose of BMS-986226 in combination with either nivolumab 480 mg Q4W or ipilimumab 3 mg/kg Q4W will be determined based on the expected activity at this dose range and the expected tolerability and s afety profile of BMS- 986226 in the monothera py dose escalation (Part A). At no point will the dose of BMS-986226 ad ministered in combination with nivolumab or ipilimumab- exceed doses of BMS-986226 that have been demonstrated previously to be tolerated in the monotherapy dose escalation arm (Part A). A ccordingly, additi onal intermediate Revised Protocol No.: 04 Date: 31-May-2019 67 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS or lower doses or less frequent dosing of BMS- 986226 may be tested, if none of th e planned doses/schedule is found to be tolerated when combined with nivolumab or ipilimumab. The BMS-986226 dose for Parts B and C will be based on evaluating the most up-to-date data available in all dosed participants, including clinical and laboratory safety assessments as well as PK, PD, and efficacy data from all treated participants at each dose level up to the MAD. For the Preliminary Safety Cohorts and Parts A, B2 and C2, BMS-986226 will be administered at a dose schedule of Q4W. This schedule is ba sed on predicted human PK using nonclinical data. The projected T-HALF for BMS-986226 in humans is 25 days ( Section 3.2.2.5 ), allowing for dosing at an interval of 4 weeks. Parts B1 and C1 will be conducted to help inform safety and possible alternative dosing schedules by utilizing PK and target engagement/PD markers, including but not limited to ICOS downregulation and re-expression. In Parts B1 and C1, participants will be administered BMS-986226 Q12W at the dose that induces or is pre dicted to induce near-complete receptor downregulation (and/or change in selected target engagement/PD ) in the presence of nivolumab Q4W or ipilimumab Q4W. PK and PD data will be generated and analyzed to understand the duration of effect of BMS-986266 on the kinetics of ICOS downregulation and re- expression, and/or the kinetics of other appropriate PD markers. 5.5.2 Rationale for Nivolumab Dose Selection Currently, nivolumab 240 mg Q2W or nivolumab 3 mg/kg Q2W are approved in various regions for the treatment of melanoma, NSCLC, RCC, classical Hodgkin’s lymphoma, and UCC. The safety and efficacy of the nivolumab 480 mg Q4W flat dose are expected to be similar to the approved nivolumab dose of 240 mg or nivolumab 3 mg/kg Q2W. The nivolumab dose of 480 mg Q4W was selected based on clinical data and modeling and simulation approaches using PPK and exposure-response analyses of data from studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight-normalized dosing (mg/kg) has been used. The PPK analyses have shown that exposure to nivolumab increased dos e proportionally over the dose range of 0.1 to 10 mg/kg administered Q2W, and no clinically mean ingful differences in PK across ethnicities and tumor types were observed. Nivolumab clearan ce and volume of distribution were found to increase as body weight in creases but less than proportionally with increasing weight, ind icating that milligram-per-kilogram dosing represents an ove r-adjustment for the effect of body weight on nivolumab PK. Using the PPK model, the overall distributions of average nivolumab steadystate exposures are comparable after treatment with either nivolumab 3 mg/kg Q2W or nivolumab 480 mg Q4W, although the flat dose regimen of 480 mg Q4W is predicted to result in approximately 40% higher steadystate peak co ncentration (-Cmaxss-) and approximately 20% lower steady-state trough concentr ations compared to the reference regimen of 3 mg/kg Q2W. Across the various tumor types in the clinical program, nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, an d the relationship between nivolumab exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively flat. Although nivolumab Cmaxss is predicted to be higher following 480 mg Q4W, these exposures are predicted to be lower than or within the exposure ranges observed at doses up to 10 mg/kg Q2W used in the Revised Protocol No.: 04 Date: 31-May-2019 68 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS nivolumab clinical program and are not co nsidered to put participants at increased risk. The exposures predicted following administration of ni volumab 480 mg Q4W are on the flat part of the exposure response curves for previously investigated tumors (melanoma and NSCLC) and are not predicted to affect efficacy. Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and safety profiles to nivolumab- 3 mg/kg Q2W. 5.5.3 Rationale for Ipilimumab Dose Schedule Ipilimumab 3 mg/kg Q4W will be tested in comb ination with BMS- 986226 during the study in Parts C1 and C2. Ipilimumab is currently approve d in the US for administration in unresectable or metastatic melanoma following monotherapy administration and in combination with nivolumab at a dose of 3 mg/kg Q3W for a total of 4 doses. Ipilimumab is also approved in the US for the treatment of adjuvant melanoma at a dose of 10 mg/kg Q3W for 4 doses, followed by 10 mg/kg Q12W for up to 3 years or until documented disease recurrence or unacceptable toxicity.37Finally, ipilimumab is being studied in combination with nivolumab at various doses, including 1 and 3 mg/kg, and at dosing intervals up to Q12W. Benefit may be gained from dosing ipilimumab for a longer duration than the dosing interval of Q3W dosing for a total of 4 doses. Further, in the combination setting, less frequent dosing has shown to be beneficial to the tolerability and response profile of ipilimumab. 38While ipilimumab Q4W dosing has not been tested previously, it may offer benefit to enhance the tolerability of ipilimumab versus Q3W dosing, and to allow for prolonged dosing dur ation versus the 4-dose schedule when administered in combin ation with BMS-986226. 5.5.4 Rationale for Dose-escalation Phase Design The BLRM with an overdose control princip le escalation was selected as an appropriate design for this study. It offers more accuracy and efficiency in determining the true MTD/MAD compared to rule-based methods (such as 3 + 3 design) by incorporating external information from nonclinical studies as well as historical clinical studies. The escalation with overdose control (EWOC) principle limits the risk of e xposing participants in the next cohort to an unsafe or toxic dose. Hence, it ensures that safety is not compromised during dose escalation. Simulation results demonstrate that BLRM allows fast escalation when the expected toxicity is very low and with participants treated at sub-therapeutic doses, which is attributed to the adaptive Bayesian learning from previous doses. In addition, BLRM has gr eater applicability to the combination therapy setting compared to other model-based methods. All available tr eatment r elated adverse events obtained from the monotherapy phase (P reliminary Safety Cohorts and Part A) w ill be characterized and incorporated as prior knowledge into the drug combination phase of the study (Parts B, C, D, and E) or used in future studies. 6 STUDY POPULATION For entry into the study, the following criteria MUST be met prior to dosing on Day 1.