Cy cle 1 Day 1). Study day will be calculated as follows: Days pri or to fi rst dose: Study day = date –first dose date Days on or after first dose: Study day = date –first dose date + 1 First dose refer s to ei ther durvalumab or tremelimumab, whichever was administered first. Dates of progression will not be imputed. The end o f study is defined as the last expected visit/contact of the last patient undergoing the study . A pat ient is considered to have co mpleted the study when he/she has completed his/her last scheduled visit shown in the schedule of act ivities (CSP sect ion 1.1). Categorical data will be summarized by the number and percentage of patients in each category . Continuous data will be summarize d using descript ive statist ics, including n, arithmetic m ean, STD, m edian, minimum, and maximum values. Addit ionally , geom etric means and coefficient of variat ion (CV)% will be reported for PK variables (concentrations and all PK parameters. The geometric mean is cal culated as the exponential o f the arithmetic mean calculated from data on a log scale. All data will be listed . Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 50of 654.1.1 Rounding and precision For continuous data, the mean and median will be rounded to 1 addit ional decimal place compared to the ori ginal data. The standard deviat ion (STD) will be rounded to 2 additional decimal places com pared to the ori ginal data. Minimum and maximum will be displayed wi th the same accuracy as the ori ginal data. For categorical data, percentages will be rounded to 1 de cimal place. If further guidance is needed the methods described in Sect ion 5.2 of ‘Statist ical guidelines for Clinical Pharmaco logy Alliance studies’ will be applied. 4.1.2 Baseline m easurements and change from baseline Baseline will be the last non -missing value obtai ned pri or to the first dose/administration of study treatm ent (durvalumab or tremelimumab) and any information taken after first dose/administration of study treatm ent is regarded as post baseline information in the relevant phase. If two visit sare equally eligible to assess patient status at baseline (e.g., screening and baseline assessments both on the same date prior to first dose/administration with no washout or other intervent ion in the screening period) and time of assessment is not avail able, the average should be taken as the baseline value. For non -numeric laboratory tests (i .e. som e of the urinalysis parameters) where taking an average is not possible then the best value would be taken as baseline as this is the most conservative. In t he scenario where there are two assessments on the same day one wi th time recorded and the other without time recorded, the one wi th time recorded would be selected as baseline. If no value exists before the first dose/administration, then the baseline val ue will be treated as missing. For questionnaires where mult iple records are eligible to be used as the baseline value and time of assessment is not available, the best scenario will be flagged as this is the most conservative. Absolute change from baseli ne outcom e variables is com puted as (post baseline value –baseline value). Percent change fro m baseline is computed as ((post baseline value –baseline value) / baseline value) × 100%. If eit her the post -baseline value or the baseline value is missing, then the abso lute or percent change from baseline value will also be set to missing. 4.1.3 Time Windows Safety assessments Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 51of 65Time windows will need defining for any presentatio ns that summari ze values by visit. The following convent ions apply: The time w indows should be exhaust ive so that data recorded at any time po int has the potenti al to be summari zed. Inclusio n within the time window should be based on the actual date and not the intended date of the visit. All unscheduled visit data should have the potenti al to be incl uded in the summaries. The window for the visit s following baseline will be constructed in such a way that the upper limit of the interval falls halfway between the two visits (the lower limit of the first post-baseline visit will be Da y 2). If an even number of days exists between two consecut ive visits, then the upper limit will be taken as the midpo int value minus 1 day . For example, the visit windows for vital signs data in the dose -expansion phase for patients’ treatment with durval umab in co mbinat ion with tremelimumab are: -Cycle 1 Day 8 visit window day 2-11 -Cycle 1 Day 15 visit window day 12 - 21 -Cycle 2 Day 1 visit window day 22 - 35 -Cycle 2 Day 15 visit window day 36 - 49 -Cycle 3 Day 1 visit window day 50 – 63 etc The upper limit for the l ast record on treatment will consider end of treatment date and not date of di sease progressi on. For summaries showing the maximum or minimum values, the maximum/minimum value recorded on treatment will be used (regardless o f where it falls in an interval). Listings should display all values contributing to a time point for a patient. For vi sit based summaries: -If there is more than one value per patient within a time window then the closest value to the scheduled visit date should be used, or the earlier in the event the values are equidistant from the no minal visit date. The list ings should highlight the value for that patient that went into the summary table, wherever feasible. Note: in summaries of extrem e values all on -treatm ent val ues collect ed are used including those collected at unscheduled visits. -To prevent very large tabl es or pl ots being produced that contain many cells wi th meaningless data for outputs in the dose expansio n phase, for each treatment group visit data should only be summ arized if the number of observat ions is greater than the minimum o f 5 of patients dosed. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 52of 65For summaries at a patient level, all values should be included, regardless o f whether they appear in a corresponding visit -based summary , when deriving a patient leve l stati stic such as a m aximum . 4.2 Analysis methods The two phases of the study will be summarized and analyzed separately. For the dose -finding phase, summaries will be presented by dose level. For the dose -expansio n phase, summaries and analyses will be pres ented by cohort (see section 4.1). For the dose -finding phase, the arms based on patient weight (Arm A: patients ≥35 kg and Arm B: pat ients <35 kg) will be summariz ed separately, along wit h an overall summary by dose l evel. 4.2.1 Multiplicity Not applicable for this study . 4.2.2 Efficacy analysis The fo llowing tabl e (Table 9) presents the analyses planned for the efficacy endpoints. All tumor-related endpo ints will be analyzed using Investigator RECIST 1.1 assessments. The efficacy analyses will be produced for the dose -expansio n patients only. Table 9 Pre-planned statistical analysis to be conducted Endpoint analyzed Notes ORR Exact 90% 2 -sided CI (Mi d-P) DoR Median est imated from KM curve DCR Exact 90% 2 -sided CI (Mi d-P) BoR n (%) of patients in each response category PFS Median estimated from KM curve OS Median est imated from KM curve APF12 90% 2 -sided CI est imated fro m KM curve APF18 90% 2 -sided CI est imated fro m KM curve OS12 90% 2 -sided CI est imated fro m KM curve OS24 90% 2 -sided CI est imated fro m KM curve CI Confidence interval; KM Kaplan -Meier. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 53of 654.2.2.1 Objective response rate (ORR) The ORR will be based on the programmat ically derived (RECIST 1.1) outcome. The point estimate and 90% confidence interval (CI) (2 -sided) of the ORR will be presented for each if the three analysis cohorts. If the cohort is expanded after the initial DRC review, t he CI will be calculated using an exact Mid -P method ( Porcher and Desseaux 2012 ). If the cohort is not expanded an exact CI will be pres ented. 90% Mid -p confidence limits are the values that have a one -sided Mid- p value of 0.05. (A Mid-p value for a one -sided test is obtained by including in the tail only one-half o f the probabilit y of the observed sample). The exact Mi d-p confidence limits θ L (lower limi t) and θ U(upper limit) are those values which satisfy the equat ions: ()−1 2 ()= 0.95 ()−1 2 ()= 0.05 This analysis will be performed on the evaluable for response analysis set. Summaries will be produced that present the number and percentage of patients with a confirmed tumor response (CR/PR). Sensit ivity analyses will be performed for tumor response (CR/PR) on FAS and "unconfirmed CR/PR" on the evaluable for response analysis set. 4.2.2.2 Progression -free survival (PFS) KM pl ots of PFS (based on the programmat ically derived [RECIST 1.1] outcome) will be presented. Median PFS will be presented (calculated by the KM method). Summaries of the number of percentage of pat ients experienci ng a PFS event and the ty pe of event (RECIST 1.1, or death) will also be provided. The analysis will be performed on the FAS. The treatment status at the time of analysis will be summarized. This will include the number (%) of pat ients who were on treatmen t at the time of progression, the number (%) of patients Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 54of 65who discont inued study treatm ent pri or to progressio n, the number (%) of patients who have not progressed and were on treatment or discont inued treatment. 4.2.2.3 Overall survival (OS) KM pl ots as well as summaries of the number and percentage of patients who have died, those still in survival fo llow-up, those l ost to follow -up, and those who have withdrawn consent will be provided alo ng with the median OS (calculated using KM method) for each cohort. 4.2.2.4 Durati on of response (DoR) Descript ive data and KM plots of DoR will be presented. The median DoR will also be summarized, calculated by the KM method . Only patients who have a confirmed response will be included in this summary .This analysis will be performed on the evaluable for response analysis set. Swimmer pl ots that cl early show the profile of each patient who responds will also be produced. This depicts each duration of response for each patient as a separate bar (hori zontally) over time. Each cohort will appear on a separate plot. Sensit ivity analyses will be performed on FAS. 4.2.2.5 Best objective response (BoR) Overall visit response data will be listed for all pat ients in the FAS, BoR will be summarized by n (%) for each category (CR, PR, SD, PD, and NE categ ories sect ion 3.2.5 ). 4.2.2.6 Disease control rate (DCR) For DCR, the point estimate and 90% CI (2 -sided) will be presented at each timepo int (16 and 24 weeks). If the cohorts are expanded after the initial DRC, t he CI will be calculated using an exact Mid -P method , otherwi se an exact CI will be presented. This analysis will be performed on the evaluable for response analysis set. Sensit ivity analyses will be performed on FAS. 4.2.2.7 Proportion alive and progression -free at 12 and 18 months APF12, and its 90% CI will be summarized (using KM methodology ) and presented. APF18 will be summarized as for APF12. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 55of 654.2.2.8 Overall survival at 12 and 24 months OS12, and its 90% CI will be summarized (using KM methodology ) and presented. OS24 will be summarized as per OS12. 4.2.2.9 Change in tumor size The best change in TL tumor size fro m baseline, (where best change in TL size is the maximum reduct ion from baseline or the minimum increase fro m baseline in the absence of a reducti on) will be summarized using descript ive statist ics for each soli d tum or cohort (SARCOMA and STO). Tumor size will also be presented graphically using waterfall pl ots for each soli d tum or cohort, to present each subject’s best percentage change in tumor size as a separate bar, with the bars ordered from the largest increase to the largest decrease. Reference lines at the +20% and –30% change in tumor size levels will be added to the plots, which correspond with the definit ions of progressi on and ‘parti al’ response respect ively. All progressions will be marked with a ‘●’ or designated with patterns or colors for ORR categories. The scale in these plots will be fixed to be from -100 to 100 to avoid present ing extreme values. V alues that are capped as a result of this restrict ion to the scale are marked with ‘#’. Addit ionally , ‘spider’ pl ots will be produced for each solid tumor coh ort. This depicts each patient’s percentage change in TL tumor size as a line over time and progre ssion due to nontarget and/or new lesio ns will be indicated. 4.2.2.10 Overall RECIST response (Dose -finding) No formal efficacy analysis will be performed for dose -finding cohorts, however a list ing detailing overall RECIST response based on investigators assessmen t will be presented. 4.2.3 Safety analysis Data from all cycles of treatment will be co mbined in the presentation of safet y data. Safet y summaries will be descript ive only. No formal statist ical analyses will be perform ed on the safet y variables. 4.2.3.1 DLT The number and percentage of subjects with DLT during the dose finding phase will be presented by dose level based on DLT evaluable populat ion. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 56of 654.2.3.2 Adverse events AEs will be summarized separately for the periods defined in Sect ion 3.3.1 . AEs occurring pre-treatm ent or occurri ng post study treatm ent, or post- subsequent anti -cancer therapy will be listed, but not summarized separately . An overall summary tabl e will be produced showing the number and percentage of patients with at least 1 AE in any of the fo llowing categories: AEs, SAEs, deaths due to AE, AEs causing discont inuation o f study treatm ent, and AESI /AEPI . The total number of AEs in the different AE categori es in term s of AE counts will also be presented (i.e. accounting for multiple occurrences of the same event in a patient). AEs will be summarized by system organ class (SOC) and PT assigned to the event using MedDRA. For each PT, the number and pe rcentage of pati ents reporting at least one occurrence will be presented i.e. for 1 patient, multiple occurrences of an AE will only be counted once. AEs (by SOC and PT) will be summarized by causalit y and m aximum reported CTCAE grade. If a patient report s mult iple occurrences of the same AE, maximum reported CTCAE grade will be taken as the highest recorded CTCAE grade for each SOC and PT. Summary informat ion (the number and percent of patients by SOC and PT, for each phase, will be tabulated for: All AEs Most commo n AEs All AEs by maximum reported CTCAE grade AEs of CTCAE grade 3 or 4 Most commo n AEs of CTCAE grade 3 or 4 Causally related AEs (to any study treatm ent) Causally related AEs of CTCAE grade 3 or 4 AEs leading to dose interruption / di scont inuat ion Dose limit ing toxicit ies (based on DRC decisio n) Death summaries and list ings: All deaths AEs with an outcome of death AEs with an outcome of death –key patient informat ion Listing of deaths Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 57of 65SAE summaries and list ings: SAEs Causally related SAEs SAEs –listing of key informat ion AEs leading to discont inuat ion summaries and list ings: AEs leading to discont inuat ion of any study treatment Causally related AEs leading to di scont inuat ion of any study treatm ent AEs leading to discont inuat ion of study treatm ent –key patient inform ation AEs of special or possible interest summaries : AESI /AEPI list of PTs a AESI /AEPI by CTCAE grade AESI /AEPI by outcome AESI /AEPI with an outcom e of no longer present, by time of reso lution AESI /AEPI leading to dose interruptions or discontinuat ion a–AESI /AEPI PTs will be obtained from the AZ team (see section 3.3.1 ) imAE: The imAEs will be summarized in the same manner as for the summaries for AESI described above. The addit ional analyses include but not limited to, time to first onset imAE and resol ution of imAE of Grade 3 or 4.