iNest - BO45230

5.1 INCLUSION CRITERIA 5.1.1 Screening (Part A) Criteria Participants must meet the following criteria for inclusion in Screening Part A: • Signed Informed Consent Form • Age  18 years at the time of signing Informed Consent Form • For patients identified prior to radical surgical resection, muscle-invasive UC of the bladder identified based on computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis, abdomen, and chest as cT3-T4 or N+. Medically eligible for radical cystectomy and pelvic lymph node dissection • For patients identified at the time of surgical resection, TNM classification (UICC/AJCC 7th edition) at pathological examination of surgical resection specimen as follows: Tumor stage of (y)pT3-4a or (y)pN+ [(y)pT3-4 or (y)pN+ for patients with UTUC] and M0 regardless of whether or not prior neoadjuvant chemotherapy was administered • Submission of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen from the pretreatment tumor biopsy (i.e., TURBT [preferred]), or surgical resection specimen if patient is identified at surgical resection and TURBT samples are not available, in paraffin blocks (blocks preferred) for upstream manufacturing of autogene cevumeran including WES and RNA sequencing, and neoantigen determination. A representative FFPE specimen in a paraffin block(s) is preferred. If an intact FFPE tumor block cannot be provided, serial thin sections derived from an FFPE tumor block prepared and shipped as outlined in the laboratory manual ("tissue curls" in vials along with unstained slides for manufacturing purposes and for biomarker analysis) is allowed. Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), brushing, and lavage samples are not acceptable. Multiple samples may be collected for a given patient, on the basis of availability; however, the requirement for a block or sectioned tissue should be satisfied by a single collection procedure. If the tumor specimen is found not to be of adequate quality, additional tumor specimens may be submitted after careful consideration of the risks associated with incurring additional delay to start of adjuvant therapy compared with a potential benefit of participating in this study. Tumor tissue should be of good quality based on total and viable tumor content. • Submission of a matched blood sample for the identification of somatic mutations in tumor tissue for the upstream manufacturing of autogene cevumeran 

5.1.2 Screening (Part B) Criteria Potential participants are eligible to be included in the study only if all of the following criteria apply: • Signed Informed Consent Form • Age  18 years at the time of signing Informed Consent Form • Histologically confirmed muscle-invasive UC (also termed TCC) of the bladder or upper urinary tract (i.e., renal pelvis, or ureters) Patients with mixed or variant histologies are required to have a dominant (i.e., 50%) urothelial pattern. • TNM classification (UICC/AJCC 7th edition) at pathological examination of surgical resection specimen as follows: Tumor stage of (y)pT3-4a or (y)pN+ [(y)pT3-4 or (y)pN+ for patients with UTUC] and M0 regardless of whether or not prior neoadjuvant chemotherapy was administered • Surgical resection of muscle-invasive UC of the bladder or upper tract For patients with MIBC, radical cystectomy may be performed by the open, laparoscopic, or robotic approach. • Patients who have both received or not received prior platinum-based neoadjuvant chemotherapy (NAC) are eligible for the study. Patients who did not receive NAC should not be eligible to receive adjuvant cisplatin-based therapy either due to cisplatin ineligibility, patient refusal, or investigator decision. Patients who have received at least three cycles of a platinum-containing regimen will be considered as those who have received prior neoadjuvant chemotherapy. Cisplatin ineligibility is defined by any one of the following criteria: – Impaired renal function (glomerular filtration rate [GFR] 60 mL/min); GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetraacetate) or, if not available, by calculation from serum/plasma creatinine (CockcroftGault formula) – A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies – Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including tingling) – ECOG performance status of 2 • Availability of a surgical tumor specimen that is suitable (e.g., adequate quality and quantity) for use in determining PD-L1 expression and for exploratory biomarker research assessed by central laboratory testing. 

5.1.2 Screening (Part B)…continued • Tumor tissue from the most recently resected site of disease must be provided for PD-L1 IHC. In order to be randomized, the participant must have a PD-L1 expression level (IHC tumor cell score of 1%, 1%, indeterminate) as determined by the central laboratory. If insufficient tumor tissue content is provided for analysis (e.g., unevaluable), acquisition of additional archived tumor tissue from the most recent resection or TURBT that yielded the initial muscle invasive diagnosis is required. • Absence of residual disease and absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 28 days prior to randomization. Confirmation of disease-free status will be assessed by independent central radiologic review of imaging data. • At least 5 cancer-specific neoantigens identified from analysis of blood and tumor specimens submitted for generation of autogene cevumeran • Full recovery from cystectomy or nephroureterectomy within 120 days following surgery • ECOG performance status of 0 or 1 • Adequate hematologic and end-organ function, as defined by the following laboratory results obtained within 14 days prior to the first study treatment: – ANC  1000 cells/L – WBC>2000/L – Platelet count  100,000/L – Hemoglobin  9.0 g/dL Patients may be transfused or receive erythropoietic treatment to meet this criterion. – AST, ALT  3.0 the upper limit of normal (ULN) – Serum bilirubin  1.5 ULN Patients with known Gilbert disease who have serum bilirubin level  3 ULN may be enrolled. – PTT/PT  1.5  ULN or INR  1.7  ULN This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. – Serum creatinine 1.5 x ULN or creatinine clearance 30 mL/min (using the Cockcroft-Gault formula) 

• Negative HIV test at screening, with the following exception: individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count 200/L, and have an undetectable viral load • No evidence of active hepatitis B, defined as having a negative hepatitis B surface antigen (HbsAg) test at screening Patients with past or resolved hepatitis B infection (defined as having a negative HbsAg test and a positive total hepatitis B core antibody [HbcAb] test are eligible, however, a hepatitis B virus [HBV] DNA test must be obtained prior to initiation of study drug and must demonstrate absence of active infection). • Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test must be performed for individuals who have a positive HCV antibody test. • For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception. • For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agree to refrain from donating sperm. 

Research Nurse: Amanda Cook (x4656) Amanda.Cook@lthtr.nhs.uk

Administrator: Yecora Lecanda-Swarbrick (x3766)