2007;405:61- 86 CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 68 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 16.2 APPENDIX 2: NEW YORK HEART ASSOCIATION (NYHA) SCALE Class I – Patients with cardiac disease but without resulting limitation of physical activity; ordinary physical activity does not cause undue dyspnoea (or fatigue, palpitation or anginal pain) . Class II – Patients with cardiac disease resulting in slight limitation of physical activity; they are comfortable at rest; ordinary physical activity results in dyspnoea (or fatigue, palpitation or anginal pain) . Class III – Patients with cardiac disease resulting in marked limitations of physical activity; they are comfortable at rest; less than ordinary physical activity causes dyspnoea (or fatigue, palpitation or anginal pain) . Class IV – Patients with cardiac disease resulting in inability to carry out physical activity without discomfort; symptoms of dyspnoea (or of angina) may be present even at rest; if any physical activity is undertaken, discomfort is increased. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 69 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 16.3 APPENDIX 3 : MEASUREMENT OF DISEASE Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumo urs: Immune -Related Response Criteria (irRC) Wolchok J. et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumour s: Immune- Related Response Criteria. Clin Cancer Res 2009;15(23):7412– 20. Introduction Investigators have relied on Response Evaluation Criteria in Solid Tumou rs (RECIST) or modified WHO criteria to evaluate anti -tumou r responses to chemotherapeutic agents. However, the responses that are seen with immunotherapeutic agents may extend beyond those of cytotoxic agents and could include responses after disease progression that are not captured by Response Evaluation Criteria in Solid Tumou rs or WHO criteria. The current report presents novel criteria, designated immune- related response criteria (irRC), which can better capture the response patterns observed with some immunotherapeutic agents. Novel to the irRC is the measurement of over all tumo ur burden as a metric of disease progression, compared to the limitation to baseline lesion measurements taken with WHO and RECIST. According to irRC, new lesions do not constitute disease progression if net tumou r burden (including new lesions) is stable or decreases. The irRC also permit disease progression prior to response and introduce the concept of confirmation of progression at a subsequent time point after first detection. This accounts for the period required for activated T -cells to infiltrate the tumou r, which may cause initial tumou r volume increase but can subsequently translate into tumou r shrinkage. The irRC also classify durable stable disease as clinical activity. Immune -related response criteria To systematically characterize additional patterns of response in patients with advanced cancer treated by immunotherapy, underlying WHO criteria were evolved into immune- related response criteria. The definitions of the irRC and guidelines on how they can be used in clinical practice are detailed below. Antitumour response based on total measurable tumo ur burden For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional WHO criteria, which do not require the measurement of new lesions, nor do they include new lesion measurements in the characterization of evolving tumo ur burden). At the baseline tumo ur assessment, the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is calculated. At each subsequent tumo ur assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to provide the total tumou r burden: Tumour Burden + SPD index lesions + SPD new, measurable lesions A comparison of the use of SPD in WHO criteria versus the use of tumou r burden in irRC is presented in Table 1. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 70 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK Table 1. Comparison between WHO criteria and the irRC WHO irRC New, measurable lesions (i.e., ≥5 × 5 mm) Always represent PD Incorporated into tumour burden New, non- measurable lesions (i.e., <5 × 5 mm) Always represent PD Do not define progression (but preclude irCR) Non- index lesions Changes contribute to defining BOR of CR, PR, SD, and PD Contribute to defining irCR (complete disappearance required) CR Disappearance of all lesions in two consecutive observations not less than 4 wk apart Disappearance of all lesions in two consecutive observations not less than 4 wk apart PR ≥50% decrease in SPD of all index lesions compared with baseline in two observat ions at least 4 wk apart, in absence of new lesions or unequivocal progression of non -index lesions ≥50% decrease in tumour burden compared with baseline in two observations at least 4 wk apart SD 50% decrease in SPD compared with baseline cannot be established nor 25% increase compared with nadir, in absence of new lesions or unequivocal progression of non -index lesions 50% decrease in tumour burden compared with baseline cannot be established nor 25% increase compared with nadir PD At least 25% inc rease in SPD compared with nadir and/or unequivocal progression of non- index lesions and/or appearance of new lesions (at any single time point) At least 25% increase in tumour burden compared with nadir (at any single time point) in two consecutive observ ations at least 4 wk apart Time -point response assessment using irRC Percentage changes in tumour burden per assessment time point describe the size and growth kinetics of both conventional and new, measurable lesions as they appear. At each tumour assessment, the response in index and new, measurable lesions is defined based on the change in tumour burden (after ruling out irPD). Decreases in tumour burden must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening). The irRC were derived from WHO criteria and, therefore, the thresholds of response remain the same (Table 2).However, the irRC response categories have been modified from those of WHO criteria as detailed in Tables 1 and 2. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 71 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK Table 2. Derivation of irRC overall responses Measurable Response Non-Measurable Response Overall Response using irRC Index and new measurable lesions (total measurable tumour burden)* Non-index lesions New, non – measurable lesions 100% decrease Absent Absent irCR† 100% decrease Stable Any irPR† 100% decrease Unequivocal progression Any irPR† ≥50%decrease Absent/Stable Any irPR† ≥50%decrease Unequivocal progression Any irPR† <50 decrease to < 25% increase Absent/Stable Any irSD <50 decrease to < 25% increase Unequivocal progression Any irSD ≥25 increase Any Any irPD† Index and non- index lesions are selected at baseline. Index lesions are measurable ( ≥5 x 5mm) and non-index lesions are non- measurable (<5 x 5mm, ascites, bone lesions, pleural/pericardial effusion etc.). *Changes are assessed relative to baseline and include measurable lesions only (> 5 x 5 mm) † Assuming response and progression are confirmed by a second, consecutive assessment at least 4 weeks apart. Overall response using irRC The overall response according to the irRC is derived from time- point response assessments (based on tumour burden) as follows: irCR , complete disappearance of all lesions (whether measurable or not, and no new lesions) confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented irPR, decrease in tumour burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 wk after first documentation irSD, not meeting criteria for irCR or irPR, in absence of irPD irPD, increase in tumour burden ≥25% relative to nadir (minimum recorded tumour burden) confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented Patients were considered to have irPR or irSD even if new lesions were present, as long as they met the respective thresholds of response as described above. Furthermore, patients were not considered to have irPD if new lesions were present and the tumour burden of all lesions did not increase by ≥25%. In contrast to irCR, irPR, and irPD, a response of irSD does not require confirmation. It is important to note that irCR, irPR, and irSD include all patients with CR, PR, or SD by WHO criteria as well as those patients that shift to these irRC categories from WHO PD. Patients with irSD, particularly those with slow-declining tumour burden ≥25% from baseline at the last tumour assessment, are considered clinically meaningful because they show an objectively measurable reduction in tumour burden without reaching the 50% threshold that defines irPR (it represented an objectively measured reduction not CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 72 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK commonly observed in the natural history of advanced melanoma patients). If a patient is classified as having irPD at a post -baseline tumour assessment, then confirmation of irPD by a second scan in the absence of rapid clinical deterioration is required. The definition of confirmation of progression represents an increase in tumour burden ≥25% compared with the nadir at two consecutive time points at least 4 wk apart. It is recommended that this be done at the discretion of the investigator because follow -up with observation alone may not be appropriate for patients with a rapid decline in performance status. Confirmation of irPD allows for the capture of all observed responses using the irRC (Table 2), as most of these late- responding patients have a trend toward response within 4 wk after initial irPD. Whereas WHO criteria consider any new measurable lesion to indicate PD, determination of immune- related best overall response (irBOR) is based on changes in total tumour burden from the baseline (nadir, for irPD) tumour assessment, regardless of any initial increase in baseline lesions or the appearance of new lesions.