1. 4 E x pl or at or y o bjecti ves E x pl or at or y O bjecti ve: O utc o me Me as ure: 1. 2 St u d y desi g n T his is a n o pe n -la bel, n o n -ra n d o mize d, i nter nat i o n al , m ul ti ce nter st u d y i n vesti gati n g d ur val u ma b i n c o m bi nat i o n wi t h tr e m eli m u ma b ( q 4 w f or 4 c y cles o nl y) f o ll o we d b y d ur val u ma b m o n ot hera p y ( q 4 w) i n pe diatric patie nts fr o m birt h t o < 1 8 y ears of a ge wit h r el a pse d or refract or y m ali g na nt s oli d t u m ors. Eac h treat me nt c ycle is 2 8 da ys. C CI Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 13of 65The study will be conducted in 2 sequential phases; a dose-finding phase (Phase I) fo llowed by a disease specific dose- expansio n phase (Phase II). The purpose of this study is to i dentify the recommended Phase II dose (RP2D) that will be taken forward to determine preliminary antitumor activit y of durvalumab in combinat ion with trem elimumab in so lid malignant tumors, using disease specific response criteria. Dose- finding phase The dose -finding phase of the study will be conducted using a 3 + 3 design to determine whether durvalumab and trem elimumab can be administered safely in children and if adult exposures can be achieved. Pediatric pat ients with relapsed or refractory solid malignant tumors including osteosarcoma and Ewing sarcoma (SARC -1), rhabdo myosarcom a, non - rhabdo myosarco ma, and other sarcomas (SARC -2), neurobl astom a (NB), and other solid tumors (STO), will be enro lled in 2 arms based on patient weight: Arm A: pat ients wei ghing ≥35kg Arm B: pat ients wei ghing <35kg Three dose levels may be explored in each of the arms as outlined in Figure 1. Dose level 1 will be 100% of the recommended adult dose of both durvalumab and tremelimumab administered as weight -adjusted doses. The doses and schedules are as follows: 1Cycle 1 (durval umab m onotherapy ): durvalumab 20 m g/kg 2Cycles 2 to 5 (durvalumab in co mbinat ion with tremelimumab): durvalumab 20 mg/kg and tremelimumab 1 mg/kg [4 cy cles administered every 28 days]) 3From Cycle 6 onwards, treatm ent will continue until a discont inuation criterion is m et, with durvalumab mo notherapy administered at 20 mg/kg q4w. At least one day between fi rst pati ent and subsequent patients dosed at each dose -level is requi red. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 14of 65Figure 1 Dose levels –Dose -finding phase This figure shows the maximum doses for durvalumab at DLs 2 and 3 (40 mg/kg) and tremelimumab at DL 3 (2 mg/kg). Lower doses may be tested, depending on the obtained PK modeling data. DL Dose level; NB Neu roblastoma; SARC -1 Osteosarcoma and Ewing sarcoma; SARC -2 Rhabdomyosarcoma, non-rhabdomyosarcoma, and other sarcomas; STO Solid tumor other. A Data Review Co mmittee (DRC) will be established prior to the init iation of the study to make decisio ns on dose e scalat ions and determinatio n of a recommended phase 2 dose (RP2D) to be further explored in the dose -expansion phase. Dose escalat ion decisio ns will aim to ident ify the RP2D for durvalumab and tremelimumab in combinat ion. Dose escalat ion decisio ns and dete rminat ion of RP2D will mainly consider safet y and PK informat ion obtained from Cycle 1 (durvalumab monotherapy ) and Cycle 2 (first administration of durvalumab and tremelimumab co mbined). This includes assessment of pre-defined dose -limit ing toxicit ies (DL Ts) in the first 2 cycles. A de- escalat ion step m ay occur f or durval umab or/and trem elimumab, wi th reduced doses of 15 m g/kg and 0.75 m g/kg, respect ively, if dose level 1 is considered not tolerated. Furtherm ore, if exposure of durvalumab or/and tremelimum ab proves inadequate, intermediate dose levels may also be tested. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 15of 65At least 1 patient represent ing each of the fo llowing pedi atric age subsets will be enrolled: birth to 5 y ears, 6 to 11 y ears and 12 to <18 y ears. In addit ion, 3 pati ents ol der than 2 y ears of age m ust be treated wi th durvalumab in co mbinat ion with tremelimumab and clear the DLT period and have been evaluated by the DRC before children less than 2 years old may be enrolled in the dose -finding phase. The key consi derati ons to be followed by the DRC during the dose -finding phase of the study are outlined in Table 1: Table 1 Key co nsiderations for DRC #DLTs PK Decision/Outcome 0out of 3 - 5 OR 1out of 6Equivalent to adult exposure (5 out of 6 patients) <80% of adult exposure (≤2 pati ents)Declare tol erated and observed for 4 cycles, and if <2 pat ients with DLTs are observed during the first 4 cycles o f study drug, enter dose - expansio n stage Declare tol erated and m ove to next dose l evel. 1 out of 3 Increase number of patients to 6. ≥2 Declare not tolerated; if observed on dose l evel 1, m ove to dose level -1 (see Figure 2). DLT dose limiting toxicity; DRC data review committee; PK pharmacokinetics. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 16of 65Figure 2 Dose- finding: de -escalation schema DL dose level. A separate document (a DRC charter) will be created to detail all key tasks, working rules and timing of meet ings of the DRC committee. Dose- expansion phase Once the RP2D has been established, recruit ment into the dose -expansio n study will be conducted using a Simo n 2-stage optimal design wit h an addit ional provisio n to include 1 mixed disease cohort (other malignant solid tumors). Patients will be recruited into the cohorts outlined in Table 2. During dose -expansio n, pati ents will be m onitored f or saf ety according to the same criteria employed during the dose -finding phase (although events will not be considered DLTs during dose-expansio n). Addit ionally, 4 cy cles of safet y informat ion are requi red prior to opening the initial dose -expansio n cohorts. If during the treatment period, ≥33% of patients experience safet y events m eeting the DLT criteria defined for the dose -finding phase (see CSP section 4.1.2), even if outside of the DLT evaluat ion peri od, enrollment may be paused, and study data will be reviewed to determine whether addit ional monitoring or alternat ive dose levels or schedules should be evaluated prior to further enrollment. Table 2 Malignant solid tumor cohorts Dose- finding phase Cohort Type of cancer SARC -1 Osteo sarcoma or Ewing sarco ma Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 17of 65SARC -2 Rhabdomyo sarco ma, non -rhabdo myosarco ma soft -tissue sarcoma, other sarcomas NB Neurobl astom a STO Other solid tumors (not represented in the other solid tumor cohorts) Dose- expansion phase Cohort Type of cancer SARCOMA bone sarco mas: osteosarcoma or Ewing Sarco ma; soft -tissue sarcomas [≥ 40% of enro llment]: Rhabdo myosarco ma, non -rhabdo myosarcom a and other sarcom as STO Other solid tumors (not represented in the other solid tumor cohorts) STO Solid tumors other. Disease specific cohorts will not be separated into weight -based arms, but patients within the expansio n cohorts will be dosed according to the appropriate weight-based RP2D determined in the arms of dose -finding cohorts. For the SARCOMA cohort, the init ial stage will allow 11 evaluable pat ients, to be dosed in this disease -specific cohort. If 2 or more responses are observed, addit ional patients will be accrued, as part of the second stage, into the corresponding expansio n cohort; 15 patients will be accrued into the SARCOMA expansio n cohort for a total of 26 evaluable pat ients. If there has been ≤1 obj ective response in either cohort, at the time that ev aluable patients (11 patients) dosed in the init ial stage who have been followed for at least 3 cy cles and have been assessed, the cohort will be discontinued for lack of benefit. For the STO cohort, 10 evaluable pat ients will be enro lled into this mixed -disease cohort; Simon rules are not applicable for this cohort. Duration of treatment and criteria for restarting treatment with durvalumab in combination with tremelimumab All treatment will be administered beginning on Day 1 unt il clinical progression or confirmed radiological progressi on (refer to CSP Appendix E for solid tumors, CSP Appendix F for NB,; other m alignancies will be analyzed based on the best response assessed by the Investigator) unless there is unacceptable toxicit y, withdrawal of consent, or another discont inuat ion criterion is met. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 18of 65If during the durvalumab mo notherapy com ponent of the treatment (after the 4 cycles of durvalumab + tremelimumab, where applicable), a patient’s disease progresses, re-administration of tremelimumab (in co mbina tion wi th durvalumab) for another 4 cy cles may be considered, fo llowing the condi tions bel ow: Patients who com plete the 4 dosing cy cles of the combinat ion of durvalumab and tremelimumab porti on of the regimen (with clinical benefit as per Invest igator judgement) but subsequent ly have evidence of defined PD, with or without confirmat ion, during the durvalumab monotherapy portion of the combinat ion regimen may restart treatment with the combinat ion once (4 cy cles only ). Af ter this, durvalumab monotherapy will resume, if the Investigator judges there is clinical benefit to the patient. 1.3 Number of patients Dose- finding phase The final sample size in the dose -finding phase will depend on the number of DLTs and on the number of dose levels to be explored. In addit ion, any pat ients not evaluable (NE) will be replaced in order to have the required number of patients evaluable at each dose level. A minimum o f 12 pati ents is anticipated to be dosed, to enable exploration of 1 dose level in both patients weighing 35 kg a nd greater, and patients weighing under 35 kg. If all 3 dose levels are used at both weight -based arms, then 36 evaluable pat ients woul d be necessary to complete the dose -finding phase. If approximately 20% of patients need to be replaced due to non-evalua bility, then a m aximum of 45 pati ents will be enrolled on the dose -finding cohorts. Dose- expansion phase For the dose -expansio n phase, the SARCOMA cohort will follow a Simo n 2-stage optimal design. An ORR ≤10% will not be considered clinically meaningful. In the SARCOMA cohort, the Simo n 2-stage desi gn will have a ty pe I error rate set at 0.1 (1-sided) and power of at least 85%. Based on the assumpt ion that the ORR for the null hypothesis is 10% and the true ORR for the SARCOMA cohort is 30%, then the SARCO MA cohort will require a total of 26 evaluable patients (with the requirement that ≥ 40% of the patients enrolled m ust have so ft-tissue sarcomas), with 11 evaluable pat ients requi red in the first stage. If fewer than 2 confirmed responses are observed in t he first 11 evaluable pat ients, then the cohort will be closed for lack of benefit. If 2 or more responses are observed out of the first 11 evaluable patients, then an addit ional 15 evaluable patients will be enrolled, for a total of 26 evaluable pat ients. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 19of 65For a cohort that enrolls the maximum evaluable patients for that particular cohort (26 in the SARCOMA cohort ), if fewer than 5 responses are observed out of the maximum total of evaluable pat ients, then no further investigation of that cohort will be don e; if 5 or m ore responses are observed out of the maximum total of evaluable patients, then the null hypothesis will be rejected for this cohort and further invest igation will be warranted. The STO cohort is planned to recruit 10 evaluable patients. This sample size is based on practi cal, rather than formal considerat ions, as no formal hypothesis testing is planned for this cohort. With the above considerations, the sample size for evaluable pat ients in the dose -expansio n phase is expected to range from 21to 36. Assuming that about 20% of patients may not be evaluable for ORR, the total number of patients dosed in the dose -expansio n phase may range from approximately 25 to 43. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 20of 652 ANALYSIS SETS 2.1 Definition of analysis sets Details o f the analysis sets are presented in Table 3and Table 4. Table 3 Analysis sets Analysis Set Definition Phase derived for Full analysis set (FAS) The FAS will include all pat ients who were assigned to treatment and received at least 1 dose of study treatm ent. The FAS (or subset of the FAS specified below) will be used for all efficacy analyses.Dose -finding and Dose -expansio n Evaluable for response analysis setThe subset of patients in the FAS who had measurable disease (per RECIST 1.1) at baseline oand had at least one fo llow-up scan measuring all required target lesions oand have been fo llowed for at least 3 cy cles (to allow for a confirmatory scan at 4 weeks after the first assessment scan) OR measurable disease (per RECIST 1.1) at baseline oand progressed or di ed in the absence of a follow-up scan.Dose -expansio n Safety analysis set (SAS)The SAS will consist of all pat ients who received any amount of study treatm ent. Safet y data will be summarized using the SAS according to the treatment received.Dose -finding and Dose -expansio n Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 21of 65Table 3 Analysis sets Analysis Set Definition Phase derived for Dose-limit ing toxicit y (DLT) evaluable analysis setThe DLT evaluable analysis set is a subset of the SAS for the dose -finding phase of the study. It includes all pat ients enrolled in the dose -finding phase of the study who receive the protocol - assigned trea tment wi th durvalumab + tremelimumab and co mplete the safet y follow-up through the DLT evaluation period (Cy cle 1 + Cycle 2) or experience a DLT during the DLT evaluat ion peri od.Dose -finding PK analysis set All patients who receive at least 1 dose of study treatm ent per the CSP for whom any post dose data are available and who do not vio late or deviate fro m the CSP in ways that would significant ly affect the PK analyses will be included in the PK analysis set. The populat ion will be defined by the Stud y Physician, Pharmacokinet icist, and Statist ician pri or to any analyses being performed.Dose -finding and Dose -expansio n ADA analysis set All patients who receive at least 1 dose of study treatm ent per the CSP for whom baseline, and any post dose data are available will be included in the ADA analysis set.Dose -finding and Dose -expansio n Table 4 Summary outcome variables and analysis sets Outcome variable Analysis set Efficacy Data ORR (primary for dose- expansion phase [confirmed responses] )Evaluable for response analysis set (Sensit ivity analysis on FAS) ORR (unconfirmed responses) (Sensit ivity analysis on Evaluable for response analysis set ) PFS, OS, BoR (confirmed responses) , APF12, APF18, OS12, OS24FAS DoR Evaluable for response analysis set (restricted to confirmed responders only) DCR Evaluable for response analysis set (Sensit ivity analysis on FAS) Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 22of 65Table 4 Summary outcome variables and analysis sets Outcome variable Analysis set Dem ography FAS PK data PK analysis set ADA data ADA analysis set Safety Data Exposure SAS AEs SAS Laboratory measurements SAS Vital Signs SAS DLTs (primary for dose -finding phase) DLT evaluable analysis set AE Adverse event; APF12 / APF18 Proportion of patients alive and progression -free at 12 / 18 months from first dose of study treatment; BoR Bes t objective response; DCR Disease control rate; DLT Dose -limiting toxicity; DoR Duration of response; FAS Full analysis set; OS Overall survival; ORR Objective response rate; OS12 / OS24 Proportion of patients alive at 12 / 24 months from first dose of stu dy treatment; PFS Progression -free survival; PK Pharmacokinetics; SAS Safety analysis set. 2.2 Violations and deviations The fo llowing general categories will be considered important protocol deviat ionsand will be raised in the Clinical Trial Management Sy stem (CTMS) l og.. These will be listed and discussed in the clinical study report (CSR) as appropriate: Dose- finding phase Deviat ion 1: Pati ents who received a dose of study treatment other than the dose that was intended 1.1Patient ei ther did not receive any dose of planned study treatment or di d not receive the correct dose of planned study treatm ent (i .e. less than 75% of the planned dose at the time of infusion) (as per Figure 1 in the CSP). Deviat ion 2: Pati ents who dev iate from key entry criteria as per the CSP. These are inclusio n criteria 2, 3, and 8 and exclusio n criteria 2, 3, 5, 6, 7 and 11: 2.1Patient, ol der than 18 y ears, received study treatm ent (inclusio n criteria 2) Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 23of 652.2Patient received study treatm ent wi thout a hi stopatho logic confirmat ion of a malignancy or/and have not progressed or were refractory to standard therapies or/and have not explored standard of care treatments before participat ion on this protocol . (inclusio n criteria 3) 2.3Patient wi th a hematol ogical condi tion listed in the protocol received treatment 2.4Inadequate organ and marrow function, defined as any of the fo llowing (inclusio n criteria 8): -Hem oglobin < 9.0 g/dL -Absolute neutrophil count < 1.0 × 109/L -Platelet coun t < 75 × 109/L -Serum bilirubin > 1.5 × the ULN -Creatinine clearance ≤ 60 mL/min - Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 × upper limit of normal (ULN) (for patients without liver metastases) -ALT or AST > 5 × ULN (for patients with liver metastases) 2.5Patients wi th a history of primary immunodeficiency an uncontrolled intercurrent illness that would limit compliance with study requi rements, substant ially increase risk of incurring AEs fro m IP, or com promise the abilit y of the pati ent to give written inform ed consent received study treatment. 2.6Patients wi th unreso lved toxicit ies wit h a severit y of grade ≥2 (as determined by NCI CTCAE versio n 5.0) from previous ant icancer therapy (excluding alopecia, vitiligo, lymphopenia, the laboratory values defined in the inclusio n criteria and toxicities not reasonably expected to be exacerbated by treatm ent wi th durvalumab or trem elimumab) received study treatm ent. (excl uding cri teria 6). 2.7Patients wi th known or clinically suspected acti ve brain metastases or spinal cord compressi on that have not been treated or/and were considered unstable or/and were dependent on steroids above physio logic replacement dose, received study treatm ent (excl usion criteria 7). 2.8Hypothy roidism before the start of treatment and worsening at any stage bef ore the start of cycle 3. (inclusio n criteria 2) 2.9Received the last dose of an ant icancer therapy (chem otherapy , immunotherapy , endocrine therapy , targeted therapy , biologic therapy , tum or embo lization, or Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 24of 65mAbs) ≤28 days or l ess than 5 half -lives of the dr ug, whi chever i s shorter (and minimum o f 7 day s), pri or to the first dose of study treatm ent (exclusio n criteria 11). 2.10Received any anti-cancer therapy (chemotherapy , immunotherapy , endocrine therapy , targeted therapy , biologic therapy , tum or embo lization,or mAbs) between Cycle 1, Day 1 and Cycle 3, Day 1 (excl usion cri teria 11). Patient was dosed wi th study treatm ent, but fulfilled any of the f ollowing criteria: 2.11 Have or have had documented autoimmune or inflammatory disorders (exclusio n criteria 2) excl uding: -Patients wi th hypothy roidism not controlled by endocrine therapy , where ‘controlled’ is defined as having a thy roid stimulating hormone (TSH) measurement within normal range at baseline -Known psori asis that requires systemic therapy -Celiac disease, not controlled by diet alone. 2.12 Have an act ive infect ion (exclusio n criteria 3). 2.13 Have tuberculosis (defined by clinical diagnosis or radiographic findings and/or a positive skin test), hepatit is B (defined by a posit ive surface antigen result), active hepat itis C (defined by a posit ive po lymerase chain reaction (PCR) for hepatit is C virus (HCV) ribonucleic acid (RNA)) or human immunodeficiency virus (HIV) (defined as positive HIV 1/2 ant ibodies) (exclusio n criteria 5). Deviat ion 3: Received prohibited conco mitant m edicat ions (including other anticancer agents). Please refer to the CSP section 6.4 for those medicat ions that are detailed as being ‘excluded’ from permitted use during the study . This will be used as a guiding principle for the physician re view o f all medicat ions prior to database lock to ident ify those likely have an impact on efficacy . 3.1Prior treatm ent wi th immune -mediated therapy of any of the fo llowing -Anti-PD-L1 -Anti-PD-1 -Anti-Programmed cell death ligand 2(PD -L2) -Anti-Cytotoxi c T-lymphocy te-associ ated anti gen 4 (CTLA -4) -Antibodies o f chimeric antigen receptor T -cell therapy (CAR -T) or other cell therapies Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 25of 653.2Receive a live attenuated vaccine wit hin 30 days prior to the first dose of study treatm ent 3.3Receive an immunosuppressive medicat ion within 14 day s prior to the first dose of study excluding; -Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra - articular inject ion).