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Abbreviated Title: Durvalumab & Vicineum for NMIBC NIH Protocol \#: 17-C-0157 Version Date: 01/10/2023 NCT \#: NCT03258593 Title: A Phase I Single-Arm Study of the Combination of Durvalumab (MEDI4736) and Vicineum (oportuzumab monatox, VB4-845) in Subjects with High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated with Bacillus Calmette-Guérin (BCG) NCI Principal Investigator: Vladimir Valera Romero, M.D.  
Urologic Oncology Branch National Cancer Institute 10 Center Drive, Room 1-5940 Bethesda, MD 20892 Phone: 240-858-3947 E-mail: vladimir.valeraromero@nih.gov  
| Drug Name:    | Durvalumab (MEDI4736)            | Vicineum™ (oportuzumab monatox,  VB4-845)   |
|---------------|----------------------------------|---------------------------------------------|
| IND Number:   | 136199                           | 136199                                      |
| Sponsor:      | Center for Cancer Research (CCR) | Center for Cancer Research (CCR)            |
| Manufacturer: | AstraZeneca                      | Sesen Biotherapeutics                       |
| Supplier:     | AstraZeneca                      | Sesen Biotherapeutics                       |
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precis background

In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390 deaths associated with bladder cancer.1 Bladder cancer is associated with the highest costs among all types of cancer, due to the need for lifelong routine monitoring and treatment.2 Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high grade disease, these therapies can become ineffective over time in up to two-thirds of patients and disease progression to muscle invasive bladder cancer (MIBC) can occur.3 In patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%.4 Progression to MIBC
portends a poor outcome as only 50% of patients will survive five years despite undergoing radical cystectomy.5 Clearly, there is a large unmet need in therapeutic options for NMIBC that recurs or progresses. Vicineum™ is a recombinant fusion protein, VB4-845, that contains a humanized single-chain antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on the surface of urothelial carcinoma cells and therefore represents a good target for Vicineum™ to bind to. In a previous phase II study in BCG refractory or BCG intolerant patients with high grade bladder cancer, 16% of patients treated with induction and maintenance therapy with Vicineum™ remained disease-free at 1 year. As a result, Vicineum™ is currently being evaluated as a single agent in a phase III trial. Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum™, demonstrated an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it was done in a NSCLC model, the results were impressive in causing tumor shrinkage. Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one standard platinum-based regimen in a phase I trial. Therefore, this trial will take two agents with single agent activity against urothelial cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously Treated with BCG.
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objectives primary objectives

To evaluate the safety and tolerability of durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC
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eligibility

Subjects must have a histologically-confirmed high-grade non-muscle invasive urothelial carcinoma (transitional cell carcinoma) of the bladder as follows:  
o Carcinoma-in-situ (CIS) with or without papillary tumors o High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm eligibility, the timing of the last bladder biopsy to the initial dose of study treatment must be within 12 weeks.  
Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the FDA6,7: Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course). See exception below for persistent T1 disease below. There is no upper limit on the amount of prior BCG a subject may have received.  
Patients with persistent T1 high grade disease on TURBT following a single induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is surgically unfit for cystectomy as deemed by the investigator or the patient declines cystectomy
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design

This is a Phase I, open-label study of the combination of durvalumab and Vicineum in subjects with high-grade NMIBC previously treated with BCG.  
All subjects will receive Vicineum intravesically and durvalumab systemically at the standard doses for both drugs as determined by Phase II trials for each drug, as no synergy or additive effect is expected for adverse events.  
Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.  
Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.  
Vicineum will be given as monotherapy for 1 week followed by treatment with the combination of Vicineum and durvalumab starting week 2.  
In the initial six patients, three subjects at a time will enroll at these doses and schedules.  
Dose-liming toxicity (DLT) for each subject will be determined during the initial 6-week
period that the subject is on treatment (i.e., the DLT period). When all subjects in the initial cohort have been on treatment through the DLT period, all available safety data will be considered in decisions to enroll additional subjects at this dose level, or to de-escalate the dose(s) of study drug(s), based on a standard "3 + 3" design. There will be no doseescalations in this study. The dose of durvalumab will remain at 1500 mg every 4 weeks, and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the initial doses in combination induce DLTs.  
After the first six patients, an additional 18 subjects will be enrolled at the initial doses or at the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain additional safety data, biomarker data and preliminary anti-tumor activity.  
Each subject's course will consist of the following periods:
o Screening/Baseline Period: The subject is consented and undergoes screening assessments to determine eligibility for the study.  
o Treatment Period: The subject is treated and monitored for safety. Biomarker data will be obtained prior to treatment and at periodic intervals during treatment. Subjects who remain free of high-grade NMIBC after 12 months of study treatment may continue to receive treatment for an additional 12 months until they develop recurrent high-grade disease, disease progression, or intolerable toxicity, or meet another withdrawal criterion (e.g., consent withdrawal, pregnancy).  
o Post-Treatment. The subject will return to the study site monthly for up to 90 days after the last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing clinically-significant related AEs or SAEs will have additional follow-up after the initial post-treatment visit.
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schema

Please note, at the end of each maintenance cycle there is a 2 week window in order to allow the patients sufficient time to recover from biopies prior to continuing treatment.
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induction

| Week                | Wee   |
|---------------------|-------|
| 1                   | k 2   |
| Durvalumab Vicineum |       |  
Week  
1  
Wee  
k 2  
Wee  
k 3  
Wee  
k 4  
Wee  
k 5  
Wee  
k 6  
Wee  
k 7  
Wee  
k 8  
Wee  
k 9  
Wee  
k 10  
Wee  
k 11  
Wee  
k 12  
Wee  
k 13  
Wee  
k 14
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maintenance #1

= each symbol indicates the number of treatments for that week
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maintenance #2

| Wee                                 | Wee   | Wee   | Wee   |
|-------------------------------------|-------|-------|-------|
| k 11                                | k 12  | k 13  | k 14  |
| 3                                   |       |       |       |
| Month                               |       |       |       |
| Evaluation (Cysto,  Cytol,  Biopsy) |       |       |       |  
| Wee         | Wee                      | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   |
|-------------|--------------------------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|
| k 15        | k 16                     | k 17  | k 18  | k 19  | k 20  | k 21  | k 22  | k 23  | k 24  | k 25  | k 26  | k 27  |
| Durvaluma b | 6                        |       |       |       |       |       |       |       |       |       |       |       |
| Month       |                          |       |       |       |       |       |       |       |       |       |       |       |
| Evaluation  |                          |       |       |       |       |       |       |       |       |       |       |       |
| Vicineum    | (Cysto,  Cytol,  Biopsy) |       |       |       |       |       |       |       |       |       |       |       |  
| Wee         | Wee                      | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   |
|-------------|--------------------------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|
| k 28        | k 29                     | k 30  | k 31  | k 32  | k 33  | k 34  | k 35  | k 36  | k 37  | k 38  | k 39  | k 40  |
| Durvaluma b | 9                        |       |       |       |       |       |       |       |       |       |       |       |
| Month       |                          |       |       |       |       |       |       |       |       |       |       |       |
| Evaluation  |                          |       |       |       |       |       |       |       |       |       |       |       |
| Vicineum    | (Cysto,  Cytol,  Biopsy) |       |       |       |       |       |       |       |       |       |       |       |  
| Wee         | Wee                      | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   |
|-------------|--------------------------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|
| k 41        | k 42                     | k 43  | k 44  | k 45  | k 46  | k 47  | k 48  | k 49  | k 50  | k 51  | k 52  | k 53  |
| Durvaluma b | 12                       |       |       |       |       |       |       |       |       |       |       |       |
| Month       |                          |       |       |       |       |       |       |       |       |       |       |       |
| Evaluation  |                          |       |       |       |       |       |       |       |       |       |       |       |
| Vicineum    | (Cysto,  Cytol,  Biopsy) |       |       |       |       |       |       |       |       |       |       |       |
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maintenance #3

= each symbol indicates the number of treatments for that week OPTIONAL MAINTENANCE \#4  
| Wee         | Wee                      | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   |
|-------------|--------------------------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|
| k 54        | k 55                     | k 56  | k 57  | k 58  | k 59  | k 60  | k 61  | k 62  | k 63  | k 64  | k 65  | k 66  |
| Durvaluma b | 15                       |       |       |       |       |       |       |       |       |       |       |       |
| Month       |                          |       |       |       |       |       |       |       |       |       |       |       |
| Evaluation  |                          |       |       |       |       |       |       |       |       |       |       |       |
| Vicineum    | (Cysto,  Cytol,  Biopsy) |       |       |       |       |       |       |       |       |       |       |       |  
= each symbol indicates the number of treatments for that week  
| Wee         | Wee                      | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   |
|-------------|--------------------------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|
| k 67        | k 68                     | k 69  | k 70  | k 71  | k 72  | k 73  | k 74  | k 75  | k 76  | k 77  | k 78  | k 79  |
| Durvaluma b | 18                       |       |       |       |       |       |       |       |       |       |       |       |
| Month       |                          |       |       |       |       |       |       |       |       |       |       |       |
| Evaluation  |                          |       |       |       |       |       |       |       |       |       |       |       |
| Vicineum    | (Cysto,  Cytol,  Biopsy) |       |       |       |       |       |       |       |       |       |       |       |
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optional maintenance #5

| Wee         | Wee                      | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   | Wee   |
|-------------|--------------------------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|-------|
| k 80        | k 81                     | k 82  | k 83  | k 84  | k 85  | k 86  | k 87  | k 88  | k 89  | k 90  | k 91  | k 92  |
| Durvaluma b | 21                       |       |       |       |       |       |       |       |       |       |       |       |
| Month       |                          |       |       |       |       |       |       |       |       |       |       |       |
| Evaluation  |                          |       |       |       |       |       |       |       |       |       |       |       |
| Vicineum    | (Cysto,  Cytol,  Biopsy) |       |       |       |       |       |       |       |       |       |       |       |  
= each symbol indicates the number of treatments for that week..  
| Week       | Week                                | Week   | Week   | Week   | Week   | Week   | Week   | Week   | Week   | Week   | Week   | Week   |
|------------|-------------------------------------|--------|--------|--------|--------|--------|--------|--------|--------|--------|--------|--------|
| 93         | 94                                  | 95     | 96     | 97     | 98     | 99     | 100    | 101    | 102    | 103    | 104    | 105    |
| Durvalumab | 24                                  |        |        |        |        |        |        |        |        |        |        |        |
| Month      |                                     |        |        |        |        |        |        |        |        |        |        |        |
| Vicineum   | Evaluation (Cysto,  Cytol,  Biopsy) |        |        |        |        |        |        |        |        |        |        |        |
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optional maintenance #7

Version Date: 01/10/2023  
| TABLE OF CONTENTS                                                                                                                                                 |                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS                                                                                                                                                            |                                                                                                                                                          |
| SCHEMA                                                                                                                                                            |                                                                                                                                                          |
| TABLE OF CONTENTS ..............................................................................................................................................8 |                                                                                                                                                          |
| STATEMENT OF COMPLIANCE ......................................................................................................................14                  |                                                                                                                                                          |
| l                                                                                                                                                                 | INTRODUCTION .........................................................................................................................................15 |
| 1.1                                                                                                                                                               | Study Objectives ...............................................................................................................................15       |
| Primary Objective                                                                                                                                                 |                                                                                                                                                          |
| 1.1.1                                                                                                                                                             |                                                                                                                                                          |
| 1.1.2                                                                                                                                                             | Secondary Objectives ....................................................................................................................15              |
| 1.2                                                                                                                                                               | Background and Rationale ...........................................................................................................15                   |
| 1.2.1                                                                                                                                                             | Durvalumab Background.....................................................................................................18                             |
| 1.2.2                                                                                                                                                             | Vicineum Background                                                                                                                                      |
| 1.2.3                                                                                                                                                             | US FDA withdrawal of metastatic Urothelial Carcinoma (mUC) indication for                                                                                |
| Imfinzi (durvalumab) granted under the accelerated approval pathway .................................24                                                           |                                                                                                                                                          |
| 2                                                                                                                                                                 | ELIGIBILITY ASSESSMENT AND ENROLLMENT ..................................................................25                                               |
| 2.1                                                                                                                                                               | Eligibility Criteria .                                                                                                                                   |
| Inclusion Criteria ............................................................................................................................25                 |                                                                                                                                                          |
| 2.1.1                                                                                                                                                             |                                                                                                                                                          |
| 2.1.2                                                                                                                                                             | Exclusion Criteria ..................................................................................................................................27  |
| 2.1.3                                                                                                                                                             | Recruitment Strategies                                                                                                                                   |
| 2.2                                                                                                                                                               | Screening Evaluation ..................................................................................................................30                |
| 2.3                                                                                                                                                               | Participant Registration and Status Update Procedures ........................................................31                                         |
| 2.3.1                                                                                                                                                             | Treatment Assignment Procedures ...................................................................................32                                    |
| 2.4                                                                                                                                                               | Baseline Evaluation                                                                                                                                      |
| Baseline studies ...................................................................................................................32                            |                                                                                                                                                          |
| 2.4.1                                                                                                                                                             |                                                                                                                                                          |
| 2.4.2                                                                                                                                                             | Urine studies (within 7 days prior to initiation of study therapy)                                                                                       |
| 2.4.3                                                                                                                                                             | Research Assessments at Baseline (within 7 days prior to initiation of study                                                                             |
| therapy) 33                                                                                                                                                       |                                                                                                                                                          |
| 2.4.4                                                                                                                                                             | O O THE THE PO                                                                                                                                           |
| 3                                                                                                                                                                 | STUDY IMPLEMENTATION .                                                                                                                                   |
| Study Design                                                                                                                                                      |                                                                                                                                                          |
| 3.1                                                                                                                                                               | Dose Limiting Toxicity (DLT) ..................................................................................................33                        |
| 3.1.1                                                                                                                                                             |                                                                                                                                                          |
| 3.1.2                                                                                                                                                             | Dose De-Escalation / Cohort Expansion ...........................................................................34                                      |
| 3.2                                                                                                                                                               | Drug Administration .................................................................................................................35                  |
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abbreviated title durvalumab & vicineum

| Version Date: 01/10/2023                                                                                                                |                                                                                                                                                  |               |
|-----------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| D Durvalumab                                                                                                                            |                                                                                                                                                  |               |
| 3.2.1                                                                                                                                   |                                                                                                                                                  |               |
| 3.2.2                                                                                                                                   | V1                                                                                                                                               |               |
| 3.3                                                                                                                                     | Dose Modifications ........................................................................................................................38    |               |
| 3.3.1                                                                                                                                   | D DURVALUMAB                                                                                                                                     |               |
| 3.3.2                                                                                                                                   | Vicineum                                                                                                                                         |               |
| 3.4                                                                                                                                     | Study Calendar                                                                                                                                   |               |
| 3.5                                                                                                                                     | Cost and Compensation                                                                                                                            |               |
| COSTS                                                                                                                                   |                                                                                                                                                  |               |
| 3.5.1                                                                                                                                   |                                                                                                                                                  |               |
| 3.5.2                                                                                                                                   | COMPENSATION .                                                                                                                                   |               |
| 3.5.3                                                                                                                                   | Reimbursement                                                                                                                                    |               |
| Criteria for Removal from Protocol Therapy and Off Study Criteria                                                                       |                                                                                                                                                  |               |
| 3.6                                                                                                                                     |                                                                                                                                                  |               |
| 3.6.1                                                                                                                                   | Criteria for Removal from Protocol Therapy .......................................................................53                             |               |
| 3.6.2                                                                                                                                   | OFF-Study Criteria                                                                                                                               |               |
| 3.6.3                                                                                                                                   | Lost to Follow-up                                                                                                                                |               |
| 4                                                                                                                                       | CONCOMITANT MEDICATIONS/MEASURES                                                                                                                 |               |
| Permitted Concomitant Medications                                                                                                       |                                                                                                                                                  |               |
| 4.1                                                                                                                                     |                                                                                                                                                  |               |
| 4.2                                                                                                                                     | Excluded Concomitant Medications .                                                                                                               |               |
| S                                                                                                                                       | CORRELATIVE STUDIES FOR RESEARCH .................................................................................56                             |               |
| Biospecimen Collection .                                                                                                                |                                                                                                                                                  |               |
| 5.1                                                                                                                                     | 5.1.1                                                                                                                                            | Blood studies |
| 5.1.2                                                                                                                                   | Research urine studies .......................................................................................................................57 |               |
| Tissue studies                                                                                                                          |                                                                                                                                                  |               |
| 5.1.3                                                                                                                                   |                                                                                                                                                  |               |
| Sample Collection Schedule .........................................................................................................63  |                                                                                                                                                  |               |
| 5.2                                                                                                                                     |                                                                                                                                                  |               |
| 5.3                                                                                                                                     | Sample Storage, Tracking and Disposition...............................................................................64                        |               |
| UOB Research Laboratory ....................................................................................................65          |                                                                                                                                                  |               |
| 5.3.1                                                                                                                                   | Samples (serum samples for cytokines) Stored with Clinical Pharmacology                                                                          |               |
| 5.3.2                                                                                                                                   |                                                                                                                                                  |               |
| Program (Figg Laboratory)                                                                                                               |                                                                                                                                                  |               |
| Clinical Services Program .......................................................................................................66     |                                                                                                                                                  |               |
| 5.3.3                                                                                                                                   |                                                                                                                                                  |               |
| 5.3.4                                                                                                                                   | Protocol Completion/Sample Destruction .........................................................................67                               |               |
| 5.4                                                                                                                                     | Samples for Genetic/Genomic Analysis ....................................................................................67                      |               |
| 5.4.1                                                                                                                                   | Proposed Genetic Analysis ......................................................................................................67               |               |
| 5.4.2                                                                                                                                   | Description of how privacy and confidentiality of medical information/biological                                                                 |               |
| specimens will be maximized .........................................................................................................68 |                                                                                                                                                  |               |  
| Version Date: 01/10/2023                                                                                                                                |                                                                                                                                                         |             |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Management of Results ........................................................................................................68                        |                                                                                                                                                         |             |
| 5.4.3                                                                                                                                                   |                                                                                                                                                         |             |
| 5.4.4                                                                                                                                                   | Genetic counseling                                                                                                                                      |             |
| 6                                                                                                                                                       | DATA COLLECTION AND EVALUATION ..............................................................................69                                         |             |
| DATA COLLECTION .....................................................................................................................................69 |                                                                                                                                                         |             |
| 6.1                                                                                                                                                     |                                                                                                                                                         |             |
| 6.2                                                                                                                                                     | DATA SHARING Plans                                                                                                                                      |             |
| 6.2.1                                                                                                                                                   | Human Data Sharing Plan ..................................................................................................69                            |             |
| 6.2.2                                                                                                                                                   | Genomic Data Sharing Plan                                                                                                                               |             |
| Response Criteria                                                                                                                                       |                                                                                                                                                         |             |
| 6.2.3                                                                                                                                                   |                                                                                                                                                         |             |
| 6.2.4                                                                                                                                                   | Evaluable for Objective Secondary Endpoints/Response............................................70                                                      |             |
| 6.3                                                                                                                                                     | TOXICITY Criteria                                                                                                                                       |             |
| NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....71                                                                                       |                                                                                                                                                         |             |
| 7                                                                                                                                                       | 7.1                                                                                                                                                     | Definitions |
| 7.2                                                                                                                                                     | OHSRP Office of Compliance and Training/IRB Reporting..............................................71                                                   |             |
| 7.2.1                                                                                                                                                   | Expedited Reporting ........................................................................................................................71          |             |
| 7.2.2                                                                                                                                                   | IRB Requirements for PI Reporting at Continuing Review ..........................................71                                                     |             |
| NCI Clinical Director Reporting                                                                                                                         |                                                                                                                                                         |             |
| 7.3                                                                                                                                                     |                                                                                                                                                         |             |
| 7.4                                                                                                                                                     | NIH Required Data and Safety Monitoring Plan .......................................................................72                                  |             |
| Principal Investigator/Research Team                                                                                                                    |                                                                                                                                                         |             |
| 7.4.1                                                                                                                                                   |                                                                                                                                                         |             |
| 8                                                                                                                                                       | SPONSOR SAFETY REPORTING                                                                                                                                |             |
| 8.1                                                                                                                                                     | Definitions                                                                                                                                             |             |
| 8.1.1                                                                                                                                                   | Adverse Event...........................................................................................................................72              |             |
| Serious Adverse Event (SAE) ................................................................................................72                          |                                                                                                                                                         |             |
| 8.1.2                                                                                                                                                   | Life-threatening ....................................................................................................................................73 |             |
| 8.1.3                                                                                                                                                   |                                                                                                                                                         |             |
| 8.1.4                                                                                                                                                   | Severity .                                                                                                                                              |             |
| 8.1.5                                                                                                                                                   | Relationship to Study Product .......................................................................................................73                 |             |
| Adverse Events of Special Interest (AESI) ......................................................................73                                      |                                                                                                                                                         |             |
| 8.1.6                                                                                                                                                   |                                                                                                                                                         |             |
| 8.2                                                                                                                                                     | Assessment of Safety Events ...................................................................................................................75       |             |
| 8.3                                                                                                                                                     | Reporting of Serious Adverse Events .............................................................................................75                     |             |
| Safety Reporting Criteria to the Pharmaceutical Collaborators                                                                                           |                                                                                                                                                         |             |
| 8.4                                                                                                                                                     | Safety Reporting Criteria to AstraZeneca                                                                                                                |             |
| 8.4.1                                                                                                                                                   |                                                                                                                                                         |             |
| 8.4.2                                                                                                                                                   | Safety Reporting Criteria to Sesen Biotherapeutics ........................................................77                                           |             |
| 8.5                                                                                                                                                     | Reporting Pregnancy                                                                                                                                     |             |  
| Version Date: 01/10/2023                                                                                                                             |                                                                                                                                                         |                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|
| Maternal exposure ................................................................................................................................77 |                                                                                                                                                         |                                                        |
| 8.5.1                                                                                                                                                |                                                                                                                                                         |                                                        |
| 8.5.2                                                                                                                                                | Paternal exposure                                                                                                                                       |                                                        |
| 8.6                                                                                                                                                  | Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND....................78                                                                |                                                        |
| Sponsor Protocol Deviation Reporting .......................................................................................78                       |                                                                                                                                                         |                                                        |
| 8.7                                                                                                                                                  |                                                                                                                                                         |                                                        |
| 9                                                                                                                                                    | CLINICAL MONITORING PLAN ............................................................................................................78                 |                                                        |
| 10                                                                                                                                                   | STATISTICAL CONSIDERATIONS ..........................................................................................................79                 |                                                        |
| 10.1                                                                                                                                                 | Statistical Hypotheses ..............................................................................................................................79 |                                                        |
| Sample Size Determination                                                                                                                            |                                                                                                                                                         |                                                        |
| 10.2                                                                                                                                                 |                                                                                                                                                         |                                                        |
| 10.3                                                                                                                                                 | Populations for Analysis .....................................................................................................................81        |                                                        |
| 10.4                                                                                                                                                 | Statistical Analyses .............................................................................................................................81    |                                                        |
| General Approach                                                                                                                                     |                                                                                                                                                         |                                                        |
| 10.4.1                                                                                                                                               |                                                                                                                                                         |                                                        |
| 10.4.2                                                                                                                                               | Analysis of the Primary Endpoint                                                                                                                        |                                                        |
| 10.4.3                                                                                                                                               | Analysis of the Secondary Endpoints ...................................................................................81                               |                                                        |
| 10.4.4                                                                                                                                               | Se                                                                                                                                                      |                                                        |
| Baseline Descriptive Statistics                                                                                                                      |                                                                                                                                                         |                                                        |
| 10.4.5                                                                                                                                               |                                                                                                                                                         |                                                        |
| 10.4.6                                                                                                                                               | Planned Interim Analyses .........................................................................................................82                    |                                                        |
| 10.4.7                                                                                                                                               | Subgroup Analyses .......................................................................................................................82             |                                                        |
| Tabulation of Individual Participant Data ............................................................................82                             |                                                                                                                                                         |                                                        |
| 10.4.8                                                                                                                                               |                                                                                                                                                         |                                                        |
| COLLABORATIVE AGREEMENTS ........................................................................................................82                  |                                                                                                                                                         |                                                        |
| 11                                                                                                                                                   | 11.1                                                                                                                                                    | Cooperative Research and Development Agreement (CRADA) |
| 12                                                                                                                                                   | HUMAN SUBJECTS PROTECTIONS ..................................................................................................83                         |                                                        |
| Rationale For Subject Selection                                                                                                                      |                                                                                                                                                         |                                                        |
| 12.1                                                                                                                                                 | Participation of Children ....................................................................................................................83        |                                                        |
| 12.2                                                                                                                                                 |                                                                                                                                                         |                                                        |
| 12.3                                                                                                                                                 | Participation of Subjects Unable to Give Consent ....................................................................83                                 |                                                        |
| Evaluation of Benefits and Risks/Discomforts ......................................................................83                                |                                                                                                                                                         |                                                        |
| 12.4                                                                                                                                                 | Study Agents Risks                                                                                                                                      |                                                        |
| 12.4.1                                                                                                                                               |                                                                                                                                                         |                                                        |
| 12.4.2                                                                                                                                               | Research Blood Sampling Risks                                                                                                                           |                                                        |
| 12.4.3                                                                                                                                               | Risks from Bladder Procedures ..............................................................................................84                          |                                                        |
| Non-Physical Risks of Genetic Research ...........................................................................84                                 |                                                                                                                                                         |                                                        |
| 12.4.4                                                                                                                                               |                                                                                                                                                         |                                                        |
| 12.4.5                                                                                                                                               | Radiation Risks                                                                                                                                         |                                                        |
| 12.4.6                                                                                                                                               | CT Contrast Risks                                                                                                                                       |                                                        |
| 12.4.7                                                                                                                                               | Electrocardiogram Risks                                                                                                                                 |                                                        |
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abbreviated title durvalumab & vicineum

| Version Date: 01/10/2023                                                                                                                                             |                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|
| Consent Process and Documentation ........................................................................................84                                         |                                                                                                                                             |
| 12.5                                                                                                                                                                 |                                                                                                                                             |
| 12.5.1                                                                                                                                                               | Consent Process for Adults Who Lack Capacity to Consent to Research                                                                         |
| Participation                                                                                                                                                        |                                                                                                                                             |
| 13                                                                                                                                                                   | REGULATORY AND OPERATIONAL CONSIDERATIONS ................................................85                                                |
| 13.1                                                                                                                                                                 | Study Discontinuation and Closure                                                                                                           |
| Quality Assurance and Quality Control ......................................................................................86                                       |                                                                                                                                             |
| 13.2                                                                                                                                                                 |                                                                                                                                             |
| 13.3                                                                                                                                                                 | Conflict of Interest Policy .............................................................................................................86 |
| 13.4                                                                                                                                                                 | Confidentiality and Privacy ........................................................................................................87      |
| PHARMACEUTICAL INFORMATION ............................................................................................87                                            |                                                                                                                                             |
| 14                                                                                                                                                                   | D Durvalumab (IND #: 136199)                                                                                                                |
| 14.1                                                                                                                                                                 | SOURCE                                                                                                                                      |
| 14.1.1                                                                                                                                                               |                                                                                                                                             |
| 14.1.2                                                                                                                                                               | Toxicity                                                                                                                                    |
| Formulation, packaging and storage..............................................................................92                                                   |                                                                                                                                             |
| 14.1.3                                                                                                                                                               |                                                                                                                                             |
| 14.1.4                                                                                                                                                               | Study Drug Preparation .....................................................................................................93              |
| 14.1.5                                                                                                                                                               | Study Drug Administration                                                                                                                   |
| 14.1.6                                                                                                                                                               | Incompatibilities ....................................................................................................................93    |
| 14.1.7                                                                                                                                                               | Accountability and dispensation                                                                                                             |
| 14.1.8                                                                                                                                                               | Disposition of unused investigational study drug........................................................93                                  |
| 14.2                                                                                                                                                                 | Vicineum (IND #: 136199) ...........................................................................................................93      |
| SOURCE ..............................................................................................................................................93              |                                                                                                                                             |
| 14.2.1                                                                                                                                                               | TOXICITY                                                                                                                                    |
| 14.2.2                                                                                                                                                               |                                                                                                                                             |
| 14.2.3                                                                                                                                                               | Formulation, packaging and storage                                                                                                          |
| 14.2.4                                                                                                                                                               | Product preparation                                                                                                                         |
| Administration procedures                                                                                                                                            |                                                                                                                                             |
| 14.2.5                                                                                                                                                               |                                                                                                                                             |
| 14.2.6                                                                                                                                                               | Incompatibilities ..............................................................................................................96          |
| 14.2.7                                                                                                                                                               | Accountability and dispensation                                                                                                             |
| 14.2.8                                                                                                                                                               | Disposition of unused investigational study drug........................................................96                                  |
| REFERENCES .......................................................................................................................................................97 |                                                                                                                                             |
| 15                                                                                                                                                                   |                                                                                                                                             |
| 16                                                                                                                                                                   | APPENDICES .                                                                                                                                |
| 16.1                                                                                                                                                                 | Appendix A: Performance Status Criteria ............................................................................100                     |
| Appendix B: Durvalumab Dose Calculations .........................................................................101                                                |                                                                                                                                             |
| 16.2                                                                                                                                                                 |                                                                                                                                             |
| 16.3                                                                                                                                                                 | Appendix C: Durvalumab Dosing Modification and Toxicity Management Guidelines                                                               |
| 102                                                                                                                                                                  |                                                                                                                                             |  
| 16.4   | Appendix D: Complete List of Peripheral Immune Cell Subsets31 134   |
|--------|---------------------------------------------------------------------|
| 16.5   | Appendix E: Urine Collection 135                                    |
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statement of compliance

The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and the following:
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP Training. The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the changes are implemented to the study. In addition, all changes to the consent form will be IRB-approved; an IRB determination will be made regarding whether a new consent needs to be obtained from participants who provided consent, using a previously approved consent form.
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1 introduction 1.1 study objectives

To evaluate the safety and tolerability of durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC
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1.1.2 secondary objectives

To assess potential predictive biomarkers and biomarkers of the immune response in bladder tissue, urine, and peripheral blood to durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC
To assess the pharmacokinetics of Vicineum with urine samples To assess if urinary EpCAM correlates with response to therapy To assess the preliminary antitumor activity of durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC  
Assess PD-L1 expression and PD-1 expressing T cells in paired bladder biopsies pre and post treatment with durvalumab and Vicineum as a marker of response/benefit
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1.2 background and rationale

Bladder cancer is the 6th most common cancer in the United States, affecting more men than women. It is the 3rd most common cancer in men and the 11th most common in women.  
(Bladder cancer treatment (PDQ® 2015) Approximately 75% of bladder cancers are of the nonmuscle invasive type.8 Non-muscle invasive bladder cancers (NMIBCs) can be categorized as Ta (non-invasive papillary carcinoma), T1 (tumor invades lamina propria or subepithelial connective tissue), and Tis (carcinoma in situ). Ta tumors are the most common, representing about 70% of NMIBCs, but only about 7% of these are categorized as high-grade.9 About 20%
of NMIBCs are T1 tumors.10 T1 tumors are more aggressive than Ta tumors, and considered high-risk.8 Flat, high-grade tumors confined to the mucosa (non-invasive) are characterized as carcinoma in situ (CIS),8 and these represent approximately 10% of the NMIBCs.10 The usual first treatment for NMIBC (Ta, T1, and CIS) is transurethral resection of the bladder tumors (TURBT), followed by intravesical immunotherapy, most commonly with bacillus Calmette-Guérin (BCG).8 In patients with T1 tumors, a second TURBT is recommended.8 Induction therapy with BCG is usually dosed as 6 once-weekly instillations.8 In patients with high-grade Ta, T1, and CIS, maintenance therapy with BCG of at least 1 year is recommended,8,10 although the optimal dose, dosing schedule, and duration of treatment are unknown. Local and systemic side effects are common with intravesical BCG therapy, causing discontinuation of treatment in approximately 20% of patients.11 Approximately 75% of patients experience local side effects (including cystitis, irritative voiding symptoms, and hematuria),
while 40% report systemic side effects, including general malaise and fever.11 Intravesical BCG failure occurs in up to 40% of patients.11 In ~20-35% of cases that failed an initial induction course of BCG, a second course of induction BCG may be beneficial, but patients who fail two courses are often best served by radical cystectomy.3,12,13 Therefore, cystectomy is recommended for CIS and high-grade Ta and T1 patients who experience disease recurrence following intravesical therapy.8 However, Shabsigh et al. reported that 64% of patients who undergo cystectomy suffer at least one complication within the first 90 days after surgery14 and the operation has been reported to have at least a 2.5% perioperative mortality rate even at a highvolume center.5 For patients unable or unwilling to undergo cystectomy, treatment options are limited. High grade non-muscle invasive bladder cancer tends to respond well to BCG and when it does not, there is evidence to suggest an incomplete or inefficient immune response. Immune responses directed against tumors are one of the body's natural defenses against the growth and proliferation of cancer cells. However, over time and under pressure from immune attack, cancers develop strategies to evade immune-mediated killing allowing them to develop unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and is upregulated in a broad range of cancers with a high frequency, with up to 88% expression in some tumor types. In a number of these cancers, including lung,15 renal,16-18 pancreatic,19-21 ovarian cancer,22 and hematologic malignancies,23,24 tumor cell expression of PD-L1 is associated with reduced survival and an unfavorable prognosis. Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate normal immune responses and is utilized by tumors to help evade detection and elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory signal to the T cell.25,26 This results in reduced T-cell activation and fewer activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers an inhibitory signal to those T cells, preventing them from killing target cancer cells and protecting the tumor from immune elimination.27 Therefore, targeting the PD-1/PD-L1 protein has emerged as an interesting strategy in bladder cancer especially given recent FDA approval of atezolizumab in the treatment of metastatic urothelial cancer. Durvalumab, a novel PD-L1 inhibitor, has not been investigated in NMIBC but has demonstrated activity in metastatic urothelial cancer as well.  
Limited agents have demonstrated response in the setting of BCG-refractory disease. One such agent is Vicineum™. Vicineum™ consists of a recombinant fusion protein, VB4-845, that contains a humanized single-chain antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). In 135 bladder cancer patients with CIS, TaG2-3, or T1G2-3 screened for trial enrollment for BCG-refractory disease, EpCAM staining was performed and revealed that 132 (98%) patients had some EpCAM staining. In fact, two of the 3 patients with negative staining, did not actually have tumor on the specimen analyzed. Ninety-four percent of all tumors had 2+ or 3+ staining. Therefore, EpCAM appears to be a good target in BCG-refractory bladder cancer. In a previous phase II study in patients with high grade bladder cancer previously treated with BCG, the 3-month complete response rate was 40% and 16% of patients treated with induction and maintenance therapy with Vicineum™ remained disease-free at 1 year. Given activity of Vicineum™ in such patients and activity of durvalumab in metastatic urothelial cancer, the combination of both drugs may be more effective than either drug alone. PD-1/PDL1 checkpoint inhibitors do not directly induce anti-tumor immune responses. Instead they function by taking the breaks off of existing T cell clones with a specificity for antigens expressed on the surface of tumor T cells. Therefore, in order for checkpoint inhibitor therapy to be effective, the checkpoint inhibitors should be used in conjunction with agents that are capable of inducing a cellular anti-tumor immune response. It is generally accepted that a type of cell death known as immunogenic cell death (ICD) is associated with effective stimulation of these cellular host immune responses. ICD can be identified by the presence of damage associated molecular patterns or DAMPS - these are characterized by distinct signals such as the release of ATP and HMGB1 (High Mobility Group Box 1) and cell surface translocation of calreticulin, an endoplasmic reticulum chaperone protein. Preclinical work demonstrates that Vicineum (VB4845) mediated killing of tumor cells results in the presence of these DAMPS, thereby suggesting that it could promote the desired anti-tumor cellular immune responses. Additionally, as bladder cancer is one of the cancers associated with higher levels of somatic mutations, it follows that targeted killing of EpCAM positive cancer cells should present these antigens to the immune system, thereby providing targets for the cellular immune response. Therefore, use of both agents may lead to synergistic killing of tumors. Based on the thoughts of synergy, an in vivo study was performed with a drug called Proxinium,  
 an earlier version of Vicineum™, demonstrating an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it was done in a NSCLC model, the results were impressive in causing tumor shrinkage. In this experiment, a humanized mouse model was used with an engrafted immune system (myeloablated and engrafted with human bone marrow stem cells) and a human EpCAM-expressing NSCLC PDX tumor placed in the flanks bilaterally. The mice had circulating human T cells and B cells. Four treatment groups were used. In group 1, vehicle alone was given to serve as a control group. Group 2 was treated with direct injection of VB4-845 (Proxinium/Vicineum) unilaterally into only one of the flank-bearing tumors. Group 3 was treated with PD-1 checkpoint inhibitor alone (nivolumab) and finally group 4 was treated with the combination of VB4-845 and the PD-1 checkpoint inhibitor. The left graph shows the tumor size of the injected tumor in the four groups while the right graph shows the tumor size of the uninjected tumor in the four groups. As can be seen in the left graph, intratumoral treatment of the EpCAM positive subcutaneous PDX tumor with VB4-845 led to cessation of tumor growth. PD-1 inhibitor by itself or in combination with VB4-845 was not that effective in reducing the size of the injected tumor. However, intratumoral treatment of the EpCAM positive subcutaneous PDX tumor with VB4-845 increased the ability of a PD-1 checkpoint inhibitor to decrease the growth rate of an uninjected contralateral PDX tumor as compared to treatment with the checkpoint inhibitor alone as shown on the right graph. The small number of animals per cohort and the use of a rapidly growing PDX model decreased the impact of the combination but interestingly the flattening of the growth rate of the uninjected tumors in the combination group was not observed until a sufficient period of time passed to allow for the induction of a cellular immune response. The preclinical study was performed with Vicineum in combination with a PD-1 inhibitor targeting the receptor, rather than durvalumab which is a PD-L1 inhibitor that targets the ligand of the PD-1/PD-L1 interaction. However, there is no reason to believe that durvalumab would act differently. It would be difficult to truly predict the safety of the combination of the two drugs in a preclinical model as neither antibody cross reacts with mouse homologues. Therefore, this trial is evaluating the safety and tolerability of the combination of Vicineum and durvalumab in BCG-refractory NMIBC. A secondary endpoint would be 12month recurrence-free survival (RFS) with the combination. Historical data suggests that the 12month recurrence-free survival (RFS) rate is approximately 20-35% for patients who failed one previous induction course of BCG and are treated again with BCG alone.
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1.2.1 durvalumab background

Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid tumors. Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function.
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1.2.1.1 summary of non-clinical experience

The non-clinical experience is fully described in the current version of the durvalumab Investigator's Brochure. Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction with PD-1 and CD80. *In vitro* studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release of interferon gamma (IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based functional assays. In vivo studies show that durvalumab inhibits tumor growth in a xenograft model using pancreatic and melanoma human cancer cell lines via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when given as monotherapy and resulted in complete tumor regression in > 50% of treated mice when given in combination with chemotherapy. Combination therapy (dual targeting of PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) resulted in tumor regression in a mouse model of colorectal cancer. 1.2.1.2 Summary of clinical experience Clinical experience with durvalumab is fully described in the current version of the durvalumab Investigator's Brochure. As of the DCO date (12 July 2016), across the entire clinical development program, an estimated 5225 patients have been exposed to 1 or more doses of durvalumab in AstraZeneca- or MedImmune-sponsored studies, either as monotherapy or in combination, including 2878 patients in open label trials, and 2347 patients as an estimate based on the random scheme in studies where the treatment arm is blinded. Additionally, more than 1700 patients have been exposed to 1 or more doses of durvalumab in ESR/IITs. Of the 2878 patients exposed to durvalumab in ongoing AstraZeneca- or MedImmune-sponsored open label studies, 1744 patients received durvalumab monotherapy, 808 patients received durvalumab in combination with tremelimumab, 140 patients received durvalumab in combination with other investigational products and 186 patients received durvalumab in combination with approved products. No studies have been completed and no study has terminated prematurely due to toxicity. For a summary of the different studies including study design, dosing regimen, study populations and exposure, please see IB.
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pharmacokinetics and product metabolism study

As of 24 July 2016, PK data were available for 977 patients who have been treated with durvalumab 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W (dose escalation), 10 mg/kg Q2W (dose expansion), and 20 mg/kg Q4W (dose-exploration) durvalumab administered as an iv infusion over 60 minutes. Following the first iv dose, durvalumab exhibited nonlinear PK at doses <3 mg/kg Q2W likely due to saturable target-mediated CL and exhibited linear PK at doses ≥3 mg/kg Q2W. The AUC0-14 increased dose-proportionally at doses of 3 to 20 mg/kg and more than dose proportionally at doses of <3 mg/kg, likely due to saturable target-mediated CL. Cmax increased in a dose proportional manner within the dose range examined. The steady state was achieved at approximately Week 16. Accumulation of durvalumab was observed following repeated dosing. As of 24 July 2016, a total of 790 patients provided samples for ADA analysis. Only 25 of 790 patients (1 patient each in 0.1 and 3 mg/kg cohorts, 17 patients from 10 mg/kg cohort) were ADA positive. Based on population PK covariate analysis, ADA positive status was not associated with a clinically relevant reduction of exposure to durvalumab. At the 10 mg/kg Q2W dose, sPD-L1 suppression in ADA positive patients was similar to that observed in ADA negative patients. The relevance of ADA on safety and efficacy is unknown given the small number of ADA positive patients.
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safety

The safety profile of durvalumab as monotherapy and combined with other anticancer agents was consistent with the pharmacology of the target and other agents in the immune checkpoint inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, have been observed with durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important potential risk particularly with durvalumab and tremelimumab combination therapy. These events are manageable by available/established treatment guidelines as described in the study protocols. Safety data have been pooled for 4 durvalumab monotherapy studies (CD-ON-MEDI4736-1108, D4190C00002, ATLANTIC and D4193C00001 [HAWK]) for patients who received a durvalumab dose of 10 mg/kg Q2W; a total of 1645 patients are included in this pooled data set.  
Overall, AEs reported in ≥10% of patients were fatigue (31.1%), decreased appetite
(22.5%), nausea (20.5%), dyspnoea (17.9%), constipation (17.8%), cough (17.4%), diarrhoea (16.0%), anaemia (15.3%), pyrexia (15.0%), vomiting (13.4%), back pain (12.5%), pruritus (11.0%), arthralgia (10.6%) and abdominal pain (10.2%).  
AEs that were considered by the investigator as related to durvalumab in ≥5% of patients were fatigue (14.5%); nausea (7.3%); diarrhoea (6.9%); hypothyroidism (6.6%); pruritus (6.4%); decreased appetite (6.0%) and rash (5.2%).  
A total of 820 patients (49.8%) reported AEs of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher: of these, 487 patients (29.6%) had events of Grade 3, 63 patients (3.8%) had events of Grade 4 and 270 patients (16.4%) had Grade 5 (fatal) events. AEs of Grade 3 or higher considered related to durvalumab were reported in 164 patients (10.0%): of these, 144 patients (8.8%) had events of Grade 3, 12 patients (0.7%) had events of Grade 4 and 8 patients (0.5%) had Grade 5 (fatal) events.
Grade 3 events occurring in ≥1% of patients were: anaemia (5.5%); dyspnoea (4.4%);
hyponatraemia (4.1%); fatigue (2.9%); gamma-glutamyltransferase (GGT) increased (2.7%); abdominal pain (2.0%); decreased appetite and back pain (1.9% each); pneumonia (1.8%); aspartate aminotransferase (AST) increased and dehydration (1.6% each); hypertension (1.3%); blood alkaline phosphatase (ALP) increased, hypokalaemia, urinary tract infection and vomiting (1.2% each); alanine aminotransferase (ALT) increased and pleural effusion (1.1% each); bilirubin increased, asthenia, nausea and pulmonary embolism (1.0% each). Grade 3 events considered related to durvalumab occurring in ≥0.5% patients were fatigue (1.2%), GGT increased (0.8%) and AST
increased (0.6%).  
The most commonly reported Grade 4 event was sepsis (15 patients [0.9%]). Other commonly reported Grade 4 events were: GGT increased (9 patients [0.5%]); dyspnoea, hypercalcaemia and respiratory failure (7 patients each [0.4%]) and pneumonia (5 patients [0.3%]). All other Grade 4 events were reported in less than 5 patients each. Grade 4 events considered related to durvalumab occurring in ≥2 patients were GGT increased and pneumonitis (0.1% each).  
Grade 5 events occurred in the system organ class (SOC) of 'neoplasms benign, malignant and unspecified (including cysts and polyps)' for 172 of the 270 patients with Grade 5 events (63.7%), with the highest number of events occurring for NSCLC (40 patients). Amongst the other SOCs, the most common Grade 5 events were general physical health deterioration (12 patients), respiratory failure (8 patients); Grade 5 events of pneumonia and sepsis occurred in 5 patients each with the remainder of the Grade 5
events occurring in ≤4 patients for each event. The only Grade 5 event considered related to durvalumab occurring in ≥2 patients was pneumonitis (0.1%).  
A total of 134 patients (8.1%) discontinued from study treatment due to an AE. The most common events leading to treatment discontinuation were: general physical health deterioration (10 patients); pneumonitis (7 patients); pneumonia (6 patients); dyspnoea and NSCLC (5 patients each); all other discontinuation events occurred in ≤4 patients.
A total of 89 patients (5.4%) had serious treatment-emergent AEs (TEAEs) that were considered by the investigator as related to durvalumab. The most common were: pneumonitis (12 patients [0.7%]); fatigue (5 patients [0.3%]); colitis, infusion related reaction and ILD (4 patients each [0.2%]); dehydration, diarrhoea, nausea and nervous system disorder (3 patients each [0.2%]); abdominal pain, acute kidney injury, adrenal insufficiency, AST increased, bilirubin increased, dyspnoea, hepatic function abnormal, nephritis, transaminases increased, tumor haemorrhage and vomiting (2 patients each [0.1%]).  
A total of 854 patients (51.9%) experienced an AESI during the study. The most common grouped term AESI was diarrhoea (263 patients [16.0%]; of whom 12 patients [0.7%] had events of Grade ≥3). Other common AESIs (grouped term) were: selected hepatic events (248 patients [15.1%]; of whom 113 patients [6.9%] had events of Grade ≥3); dermatitis (237 patients [14.4%]; of whom 3 patients [0.2%] had events of Grade ≥3); rash (199 patients [12.1%]; of whom 7 patients [0.4%] had events of Grade ≥3); hypothyroidism (170 patients [10.3%]; of whom 2 patients [0.1%] had events of Grade ≥3); hyperthyroidism (93 patients [5.7%]; of whom 1 patient [<0.1%] had events of Grade ≥3); and select renal events (87 patients [5.3%]; of whom 16 patients [1.0%] had events of Grade ≥3). There were 6 patients who had AESIs of CTCAE Grade 5 (fatal events): three patients had hepatic events (autoimmune hepatitis; hepatic failure and hyperbilirubinemia); two patients had pneumonitis and 1 patient had immune thrombocytopenic purpura.
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efficacy study cd-on-durvalumab-1108

Urothelial carcinoma A phase 1/2 multicenter, open-label study conducted in patients with inoperable or metastatic solid tumors, reported the results a urothelial carcinoma expansion cohort.28 Durvalumab (10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary endpoint was safety, and objective response rate (ORR, confirmed) was a key secondary end point.  
A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).
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1.2.2 vicineum background

Vicineum™ (Vicineum) contains the active pharmaceutical ingredient VB4-845, which is a recombinant fusion protein produced in Escherichia coli (E. coli) that expresses a humanized single-chain antibody fragment (scFv) specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA(252-608). ETA(252-608), which is a truncated form of Pseudomonas exotoxin A (ETA) that lacks the cell binding domain, is a single polypeptide fusion protein produced by continuous translation of a single construct. The mechanism of action is dependent upon the 2 components of Vicineum. Once bound to the EpCAM antigen on the surface of carcinoma cells, Vicineum is internalized through an endocytic pathway. Furin contained within the endosomal compartment cleaves a proteolytic site on the surface of ETA(252-608), releasing ETA(252-608). The ETA(252-608) induces cell death by irreversibly blocking protein synthesis through adenosine diphosphate (ADP)-ribosylation of a post-translationally modified histidine residue of elongation factor-2 (EF-2), called diphthamide. (Oppenheimer 1981) The truncated version of ETA, ETA(252-608), has been engineered to retain the active domains necessary to induce cell death, but the cell binding domain has been eliminated thereby preventing the ETA(252-608) moiety from entering the cell in the absence of some alternate vehicle, such as via antibody-mediated internalization. Binding to EpCAM must occur to result in ETA(252-608)-mediated effects. The ETA(252-608) component of the Vicineum fusion protein can cause an immunogenic response when administered systemically to humans. Therefore, Vicineum is being developed as a locally targeted therapeutic in order to limit its systemic exposure and to maximize the concentration of the drug in its target cells. By administering Vicineum via intravesical instillation, the probability of systemic exposure and subsequent generation of neutralizing antibodies is decreased. Furthermore, the high local concentrations of Vicineum maximize the likelihood of achieving a therapeutic benefit. Clinical experience with Vicineum is fully described in the current version of the Vicineum Investigator's Brochure (Version 8.0).
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1.2.2.1 preclinical studies

Preclinical study data have shown that Vicineum exhibits potent activity [inhibitory concentration 50% (IC50) = 0.001 - 10 pM] against numerous EpCAM-positive cell lines, with selectivity for EpCAM-expressing tumors. In vivo pharmacology demonstrated that Vicineum effectively inhibits tumor growth in several human xenograft animal models. Studies in rats found that the toxicological effects of Vicineum occur at doses 1,000-fold greater than the IC50 for activity on tumor cells, with a safety margin of at least 5- to 100-fold. 1.2.2.2 Clinical Studies
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vb4-845-02-i

A Phase 1 trial (VB4-845-02-I) of Vicineum evaluated doses up to 30.16 mg administered intravesically to 64 subjects with Grade 2 or 3, stage Ta or T1 transitional cell carcinoma (TCC)
or CIS, either refractory to or intolerant of BCG therapy.29 No dose-limiting toxicities (DLTs)
were observed. Vicineum was well tolerated, and the majority of adverse events (AEs) were mild. The most frequently reported treatment-related AEs were renal and urinary disorders, with dysuria (14.1%) and hematuria (10.9%) most commonly reported. Of the systemic AEs, fatigue was reported by 7.8% of subjects, while fever/chills and loss of appetite were each reported by 6.2% of subjects. The frequency of treatment-related AEs did not increase with increasing doses of Vicineum. There was 1 serious adverse event reported (death due to cardiac failure), which occurred 3 weeks after stopping study drug; the Investigator assessed the event to be unrelated to Vicineum treatment, attributing it to the subject's long-standing history of cardiovascular disease. Exploratory efficacy assessment at 3 months showed that of 61 evaluable subjects, a complete response (defined as non-positive urinary cytology and either normal cystoscopy or abnormal cystoscopy with negative biopsy) was achieved by 24 subjects (39%). Of the 17 subjects with Tis, 29% achieved a complete response, while complete responses were observed in 44% and 43% of the subjects with T1 and Ta, respectively.  
Blood samples for assessing humoral immune reactivity to Vicineum were taken prior to dosing on days 1, 8, 15, 22, 29, 36, and at the final study visit. Antibody titers to the scFv and ETA252–
608 portions of the fusion protein (human antihuman antibodies (HAHA) and human antiPseudomonas antibodies (HAPA)) were measured using an enzyme-linked immunosorbent assay. HAPA response was more vigorous, as patients developed a measurable titer earlier; the majority of patients exhibited HAPA by day 29, with 77% (47/61) having a measurable titer at final visit. In contrast, only 16% (10/61) of patients had HAHA by the end of the study. HAPA titers were also generally higher, with a mean maximum titer of 20,512 versus 3373 for HAHA responses. A comparison of mean titers of the HAPA and HAHA responses measured in samples taken on the final visit showed no significant difference between responders and nonresponders.
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vb4-845-02-iia

A Phase 2 study (VB4-845-02-IIA) evaluated once-weekly instillations of Vicineum 30 mg in two different induction schedules: weekly x 6 weeks or weekly x 12 weeks, followed by up to 3 maintenance cycles (3 once-weekly instillations followed by a 9-week drug-free period) in 46 subjects with histologically-confirmed TCC of the bladder and residual CIS with or without concurrent Ta or T1 who were refractory or intolerant to BCG.30 Some subjects in the 6-weekly induction arm received a second induction cycle. Forty-six subjects were considered evaluable for response. A complete response (defined as no histological evidence of disease and negative urine cytology at the 3-monthly evaluations) was achieved by 44% (20/45) of subjects, and 16%
(7/45) of subjects remained disease-free at the 1-year end-of-study (EOS) assessment. A poststudy assessment found that these subjects were still disease-free at 18-25 months. The median time to recurrence was 134 days longer in subjects who received 12 weeks of induction therapy compared to 6 weeks (408 vs 274 days, respectively; log rank test p=0.1708). The most frequently reported treatment-related AEs were renal and urinary disorders, including 50% with dysuria (61% of these were of mild intensity) and 13% with hematuria. Overall, most AEs were of mild severity. There were 3 severe events, all of which resolved without sequelae. No subject discontinued from the study due to AEs and there were no deaths or other serious AEs. Based on the preliminary positive therapeutic results and favorable tolerability profile, the present Phase 3 trial will evaluate the efficacy of Vicineum induction therapy administered for 12 weeks, and the long-term effectiveness of Vicineum maintenance therapy (up to 24 months treatment in total) in preventing disease recurrence.
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vb4-845-02-iiia

An open-label, single–arm Phase 3 trial of Vicineum (VB4-845-02-IIIA) is evaluating Vicineum in subjects who have received a least 2 courses of BCG and whose disease is considered BCGunresponsive. One hundred thirty-three subjects will enroll of whom 77 will have CIS with relapsed/refractory disease within 6 months of their last dose of BCG. Based on data in the database as of 03 October 2016, the most frequent adverse events regardless of causality were UTIs, dysuria, hematuria, fatigue, micturition, urgency, pollakiuria, diarrhea, and arthralgia. Two subjects were reported to have suspected unexpected serious adverse reactions (SUSARs). A 90 year-old patient with an elevated lipase developed acute renal failure and LFT elevations. The patient required dialysis. Cholestatic hepatitis progressed. The investigator judged these events as possibly related to study treatment. After a few weeks of dialysis, the patient elected to stop further dialysis and go to hospice care. After stopping dialysis, the patient passed away. A 74-year-old patient also developed acute kidney injury with LFT elevations. The LFT elevations resolved quickly upon stopping Vicineum treatment. The kidney function improved with hospitalization and intravenous fluids.
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trial update - investigator brochure

Vicineum demonstrated efficacy in CR rate at 3 months with sustained CR and duration of response, as well as CR rate at 6, 9, and 12 months, cystectomy free days, event-free survival, progression-free survival, overall survival, recurrence-free rates in papillary disease subjects, and time to disease recurrence in papillary disease subjects, for the treatment of BCG-unresponsive subjects who are resistant to currently available therapy. Subjects that responded to Vicineum (CIS subjects with CR and papillary subjects who were recurrence-free at 3 months) were 5 times more likely to remain cystectomy-free at 2 years than those who did not respond. The CR rate at 3 months was 39% and 40% for the primary efficacy population (mITT) and all evaluable CIS subjects, respectively. Of those mITT subjects with a CR at post-induction phase (3 months), 69%, 53%, and 42% continued to have a complete response at 6, 9, and 12 months, respectively. All CIS subjects with fewer BCG cycles had a higher CR rate than those CIS subjects treated with more courses of BCG.
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1.2.3 us fda withdrawal of

On 5/1/17, the FDA had granted accelerated approval to durvalumab for the treatment of locally advanced or metastatic urothelial carcinoma with disease progression after failing platinumbased chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy. As of February 2021, AstraZeneca has voluntarily withdrawn the indication for Imfinzi (durvalumab) in the US for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who: - Have disease progression during or following platinum-containing chemotherapy, or  
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This decision was made in consultation with the US Food and Drug Administration (FDA) based on their broad evaluation of accelerated approvals. The voluntary withdrawal was for lack of efficacy and not for safety concerns. The urothelial carcinoma indication was granted Accelerated Approval from the US FDA, based on tumor response rate and duration of response from Study 1108 and the significant unmet needs of patients.2 Accelerated approval is a specific regulatory path whereby confirmatory data is required to convert an accelerated approval to full approval. In this case, continued approval for this indication in the US was contingent upon positive results from the Phase III DANUBE trial of Imfinzi or Imfinzi plus tremelimumab versus chemotherapy as first-line therapy for patients with unresectable, locally advanced or metastatic urothelial carcinoma. The DANUBE
trial did not meet either of its co-primary endpoints of improving overall survival versus standard of care chemotherapy for Imfinzi monotherapy in patients whose tumor cells and/or tumorinfiltrating immune cells express high levels (≥25%) of programmed cell death ligand-1 (PD-L1)
or for Imfinzi plus tremelimumab in patients regardless of their PD-L1 expression. We would like to continue the drug-combination trial since our preliminary interim data analysis shows a 40% 12 week response rate (5/12 patients) with half of them showing a >12 month sustained response. We hypothesize that the prolonged response might be related to the systemic therapy (Durvalumab) administration. Also, most of the treatment related AEs are irritative voiding symptoms and most of them are grade 3 or lower, suggesting that the treatment is tolerated well thus far.Combination Therapy Dose Justification In the single-agent phase I Vicineum study, there were no dose-limiting toxicities (DLTs) and no MTD was determined. Only 2 subjects of 64 had detectable plasma Vicineum levels and these were very near the lower level of quantitation. Durvalumab has been extensively studied in Phase I and Phase II and the recommended dose and safety profile has been established. For these reasons, the initial dose level for the combination will be the standard doses for both drugs. The FDA approved dose for durvalumab is currently 10mg/kg every 2 weeks and this amounts to 750 mg every 2 weeks for an average 75 kg individual. Based on pre-clinical data, there is no difference in exposure between weight based Q2W dosing and fixed dose Q4W dosing. Therefore, we are administering 1500 mg every 4 weeks instead of 750 mg every 2 weeks for ease and dosing convenience.
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2 eligibility assessment and enrollment

2.1.1.1 Patients must have histologically or cytologically confirmed by NCI Laboratory of Pathology as high grade non-muscle invasive urothelial (transitional cell carcinoma) of the bladder as follows:
Carcinoma-in-situ (CIS) with or without papillary tumors  
High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm eligibility, the timing of the last bladder biopsy to the initial dose of study treatment must be within 12 weeks.  
Patients with persistent T1 high grade disease on TURBT following a single induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is surgically unfit for cystectomy as deemed by the investigator or the patient declines cystectomy.  
2.1.1.2 Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the FDA6,7: Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course). Please note exception above for persistent T1 disease. There is no upper limit on the amount of prior BCG a subject may have received.  
2.1.1.3 Patients who have met eligibility criterion **2.1.1.2** must have received last BCG dose within a year of enrollment.  
2.1.1.4 The investigator must document that he/she believes the subject would not benefit from additional BCG treatment at the time of study entry.  
2.1.1.5 Age ≥ 18 years at time of signing the informed consent form (ICF). Because no dosing or adverse event data are currently available on the use of Vicineum in combination with durvalumab in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Furthermore, NMIBC does not occur in children.  
2.1.1.6 Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 ( Appendix A)
2.1.1.7 Adequate organ and marrow function as defined below:
o Hemoglobin ≥ 9.0 g/dL
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
o Platelet count ≥ 75 x 109/L (>75,000 per mm3)
o Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  
o AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN  
o Creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
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males

Creatinine CL (mL/min)
= Weight (kg) x (140 - Age)
72 x serum creatinine (mg/dL)  
Creatinine CL (mL/min)  
= Weight (kg) x (140 - Age) x 0.85  
72 x serum creatinine (mg/dL)  
| Females:   |
|------------|  
2.1.1.8 Female subjects must either be of non-reproductive potential (i.e., post-menopausal as described below) OR history of surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.  
Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, or had chemotherapy-induced menopause with last menses >1 year ago 2.1.1.9 The effects of Vicineum and durvalumab on the developing human fetus are unknown.  
Females of childbearing potential and and men who are sexually active must use a highly effective method of contraception (including abstinence, intrauterine system or intrauterine device contraceptive implant, hormonal, female or partner sterilization or menopause as defined in **2.1.1.8**) and a second form of barrier contraception during study treatment and for 120 days after the last dose of study drug. Note: partner's use of the same methods of contraception (barrier, hormonal, intrauterine device [IUD], surgical sterilization) is also acceptable. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.  
2.1.1.10 Written informed consent obtained from the subject prior to performing any protocolrelated procedures 2.1.1.11 Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.  
2.1.1.12 Body weight > 30 kg
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2.1.2 exclusion criteria

2.1.2.1 Patients who are receiving any other investigational agents. 2.1.2.2 QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms. [Any clinically significant abnormalities detected require triplicate ECG results and a mean
QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs.]  
2.1.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic composition to Vicineum or durvalumab or other agents used in the study.  
2.1.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Urinary tract infections (UTIs) are excluded from being an exclusion criterion for treatment unless they are grade 3 or higher.  
2.1.2.5 Pregnant women are excluded from this study because it is unknown whether Vicineum and/or durvalumab have any teratogenic effects. In nursing mothers, breastfeeding should be discontinued as these medications may have the potential risk for adverse events in nursing infants secondary to treatment of the mother.  
2.1.2.6 Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab 2.1.2.7 Evidence of non-bladder urothelial (transitional cell) carcinoma by biopsy, cytology, or radiological imaging within the past 2 years of treatment (e.g. upper tract transitional cell carcinoma, urethral urothelial carcinoma).  
2.1.2.8 Subjects with hydronephrosis, except for those subjects where hydronephrosis has been longstanding (i.e., predates the diagnosis of the CIS, Ta, or T1 by more than 2 years) and diagnostic evaluation at screening shows no evidence of tumor causing the hydronephrosis.  
2.1.2.9 Any other anticancer therapy (e.g., chemotherapy, biologic therapy, immunotherapy, targeted therapy, endocrine therapy, radiation therapy, intravesical therapy, investigational agent) within 28 days of the first dose of study therapy (and within 6 weeks for nitrosourea or mitomycin C) other than a single dose of intravesical chemotherapy which is permitted between 28 days and 14 days prior to the first dose of study treatment.  
2.1.2.10 The subject has a diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancer, localized prostate cancer on active surveillance, or localized solid tumors deemed cured by surgery and not treated with systemic anticancer therapy and not expected to require anticancer therapy in the next 2 years i.e., while the subject may be taking study treatment.  
2.1.2.11 Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
2.1.2.12 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:  
Subjects with vitiligo or alopecia  
Subjects with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormonal replacement
Any chronic skin condition that does not require systemic therapy Subjects without active disease in the last 5 years may be included but only after consultation with the Principal Investigator Subjects with celiac disease controlled by diet alone 2.1.2.13 History of primary immunodeficiency. 2.1.2.14 History of allogeneic organ transplant. 2.1.2.15 History of hypersensitivity to durvalumab or any excipient 2.1.2.16 History of hypersensitivity to Vicineum or its components  
2.1.2.17 Active infection with tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and PPD testing if indicated), hepatitis B (known positive HBV surface antigen (HBsAg) result, hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with HIV are excluded from participating on this clinical trial because their immunodeficiency would confound the evaluation of adverse events which would hinder meeting the primary objective. Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
2.1.2.18 History of leptomeningeal carcinomatosis 2.1.2.19 Receipt of live attenuated vaccination within 30 days prior to the first dose of Vicineum or durvalumab  
2.1.2.20 Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
2.1.2.21 Subjects with uncontrolled seizures  
2.1.2.22 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Principal Investigator.
Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Principal Investigator.  
2.1.3 Recruitment Strategies This study will be posted on NIH websites and on NIH social media forums. Additionally, this study will be listed on available websites (www.clinicaltrials.gov and others) and participants will be recruited from the current patient population at NIH.
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2.2 screening evaluation

Note: Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program Clinical Protocols). Assessments performed at outside facilities or on another NIH protocol within the timeframes below may also be used to determine eligibility once a participant has signed the consent. Evaluations to be performed within 12 weeks prior to starting treatment:
History and physical examination (including medications, medical history, surgical history, previous treatments for bladder cancer with dates, allergies, and demography)  
ECOG performance status Formal review of available previous bladder tumor specimens by the Laboratory of Pathology, NCI, to confirm the bladder cancer diagnosis prior to enrollment into the study.  
o If outside bladder tumor specimens are inadequate to accurately stage the patient's disease, then additional biopsies will be performed at the NCI as part of standard of care therapy. Tissues obtained at the NCI will be used to confirm diagnosis and for study of immune-related markers. With preoperative patient permission, extra tissue not sent to Laboratory of Pathology, NCI, will be frozen for future analysis of immune-related markers and tumor infiltrates. This additional harvested tissue will be used for research purposes only and is not required for a candidate to participate in this protocol.  
o If outside bladder tumor specimens are adequate to accurately stage the patient's disease, cystoscopy with or without biopsy and/or TURBT to confirm diagnosis and resect and remove any residual papillary disease and fulgurate any CIS may be performed as part of standard of care therapy. With preoperative patient permission, extra tissue not sent to the Laboratory of Pathology, NCI, will be frozen for the future analysis of immune-related markers and tumor infiltrates. This additional harvested tissue will be used for research purposes only and is not required for a candidate to participate in this protocol.Blue light cystoscopy can be performed at urologist's discretion.
Laboratory studies  
o Hematology (Complete blood count plus differential and platelet count) o Serum chemistries and liver function tests (Na+, K+, Cl-, CO2, glucose, BUN,
creatinine, albumin, calcium, magnesium, phosphorus, alkaline phosphatase, ALT, AST, total bilirubin, LDH, pre-albumin, amylase, lipase o Coagulation parameters (PT, PTT)  
o Viral Studies (Hepatitis B and C; HIV) o Thyroid function tests Urinalysis 24 hour urine (only if CrCL will not be calculated) PPD if indicated  
Computerized Tomography (CT) urogram or Magnetic Resonance Imaging (MRI)
urogram. If urogram protocol not available or contrast allergy/poor renal function preclude such imaging, then CT or MRI of the abdomen/pelvis without contrast will suffice and investigator may perform retrograde pyelogram at their discretion.  
Electrocardiogram (ECG) for QT interval - Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) will be calculated from a single ECG. If QTcF ≥ 470ms, then the patient must be excluded from trial.  
o Resting 12-lead ECGs will be recorded according to the assessment schedule.  
ECGs should be obtained after the patient has been in a supine position for 5 minutes and should be recorded while the patient remains in that position.  
o ECG will be recorded at Screening, in Week 2 (pre-durvalumab treatment) and as clinically indicated.  
o In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes and at least 5 minutes apart) to confirm prolongation
Serum or urine beta-HCG for women of child-bearing age See section **3.4, Study Calendar** for more details.
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2.3 participant registration and status

Registration and status updates (e.g. when a participant is taken off protocol therapy and when a participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant Registration & Status Updates found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
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2.3.1 treatment assignment procedures

| Number   | Name                                                                                           | Description                                                                                                              |
|----------|------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------|
| 1        | Run in Cohort                                                                                  | Subjects with high grade non-muscle invasive urothelial (transitional  cell carcinoma) of the bladder. Up to 12 subjects |
| 2        | Expansion                                                                                      | Subjects with high grade non-muscle invasive urothelial (transitional                                                    |
| Cohort   | cell carcinoma) of the bladder. Up to 24 subjects enrolled after the  run in cohort is filled. |                                                                                                                          |  
Arms  
| Number   | Name      | Description                                                                                                  |
|----------|-----------|--------------------------------------------------------------------------------------------------------------|
| 1        | Run In    | Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will  be evaluated in the first 6 - 12 subjects |
| 2        | Expansion | Durvalumab + Vicineum, at the MTD. Up to 24 subjects                                                         |  
Subjects in cohort 1 will be directly assigned to arm 1. Subjects in cohort 2 will be directly assigned to arm 2.
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2.4.1 baseline studies

Performed within 7 days before starting treatment. If Clinical evaluation laboratory work was also performed within 7 days before starting treatment, then those values can be used for baseline evaluation.  
Hematology (Complete blood count plus differential and platelet count)
Acute care panel (Na+, K+, Cl-, CO2, glucose, BUN, creatinine)
LDH
Pre-albumin Pancreatic enzymes (amylase, lipase)
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin)
Mineral panel (albumin, calcium, magnesium, phosphorus)
Thyroid function tests
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3 study implementation

This is a single arm study. A run in cohort of up to 12 evaluable subjects and an expansion cohort of up to 24 evaluable will be evaluated. No randomization of stratification will be performed.
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3.1 study design see schema.

A DLT will be defined as any Grade 3 or higher toxicity that occurs during the initial 6-week period the subject is on treatment (i.e., the DLT evaluation period). Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from this definition. Since this trial also involves immunotherapy, immune-related AEs (irAEs) are defined as AEs of an immune nature (i.e. inflammatory) in the absence of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat laboratory testing will be conducted to confirm significant laboratory findings prior to designation as a DLT. The following will be DLTs:
Inability to reduce prednisone dose below 10 mg within 6 weeks (rather than 12 weeks)
due to ongoing immune-related adverse reaction of Grade >1  
Any Grade 4 irAE not attributed to local tumor response (e.g., inflammatory reaction attributed to local tumor response or inflammatory reaction at sites of metastatic disease or lymph nodes)
Any ≥ Grade 3 colitis Any Grade encephalopathy Any ≥ Grade 3 neurotoxicity Any ≥ Grade 3 peripheral neuromotor syndromes Any Grade 2 or higher noninfectious pneumonitis irrespective of duration Any Grade 3 irAE, excluding colitis that does not downgrade to Grade 2 within 3 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days
Total bilirubin >1.5 - 3.0 x ULN (Grade 2 Hyperbilirubinemia)  
ALT or AST >8x ULN ALT or AST >5x ULN for more than 2 weeks
ALT or AST >3x ULN and  
ALT or AST >3x ULN and INR >1.5 ALT or AST >3x ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Any Grade ≥3 non-irAE toxicity that does not downgrade to Grade ≤1 or baseline status
(for patients who entered the study with an existing laboratory abnormality) within 14 days Inability to receive ≥ 75% or more of scheduled study treatment (both Vicineum and durvalumab) during the first six weeks of the trial Persistent Grade 2 events possibly related to study drugs such as persistent nausea, vomiting, diarrhea, or fatigue that are refractory to maximal intervention or are severely limiting to the patient's ability to carry out activities of daily living.
The definition excludes the following conditions:  
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with or without systemic corticosteroid therapy and/or hormone replacement therapy and the subject is asymptomatic Concurrent vitiligo or alopecia of any AE grade Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) that resolves within 6 hours with appropriate clinical management Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or symptoms and are reversed with appropriate maximal medical intervention within 3 days.  
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g.,
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.)
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3.1.2 dose de-escalation / cohort

This trial will begin with a fixed dose of Vicineum 30 mg intravesical (Dose Level 1)
administered once weekly for the first 12 weeks. Durvalumab administration will begin after 1 week of Vicineum monotherapy, at 1500mg IV once every 4 weeks.  
In the initial six patients, three subjects at a time will enroll at these doses and schedules (Dose Level 1). Dose-limiting toxicity (DLT) for each subject will be determined during the initial 6week period that the subject is on treatment (i.e., the DLT period). When all subjects in the initial cohort have been on treatment through the DLT period, all available safety data will be considered in the decision to enroll additional subjects at this dose level, or to de-escalate the doses of the study drugs to Dose Level -1, based on a standard "3 + 3" design (see table below). There will be no dose-escalations in this study.
After the first six to twelve patients, an additional 18 subjects will be enrolled at the highest dose level at which fewer than 2 of 6 subjects experienced DLT in order to obtain additional safety data and preliminary anti-tumor activity. Treatment at this level will continue as long as the cumulative fraction of patients experiencing DLT is < 1/3.  
| Dose De-Escalation Schedule                                                 |                                    |                                         |
|-----------------------------------------------------------------------------|------------------------------------|-----------------------------------------|
| Dose Level                                                                  | Dose of IND Agent                  |                                         |
|                                                                            | Durvalumab 1500mg IV every 4 weeks |                                         |
| Level 1                                                                     |                                   | Vicineum 30 mg intravesically per dose* |
|                                                                            | Durvalumab 1500mg IV every 4 weeks |                                         |
| Level -1                                                                    |                                   | Vicineum 20 mg intravesically per dose* |
| * Vicineum administered weekly during the first 12 weeks of the study, then |                                    |                                         |  
  
  
* Vicineum administered weekly during the first 12 weeks of the study, then
Dose de-escalation will follow the rules outlined in the Table below. If 2 or more DLTs occur at dose level -1, then accrual to the trial will end pending an amendment to consider other dosing options to explore for safety before proceeding to explore efficacy.  
| Number of Patients with  DLT at a Given Dose Level   | De-Escalation Decision Rule                                                                                                                                                                                                                           |                                                        |
|------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|
| 0 out of 3                                           | Enter an additional 3 patients at same dose level                                                                                                                                                                                                     |                                                        |
| 1 of 3                                               | Enter an additional 3 patients at Dose Level 1  If 0 of these 3 patients experience DLT, enter  additional patients at Dose Level 1  If 1 or more of this group suffer DLT then enter  up to 3 patients at the next lowest dose level.  Reduce by 1 |                                                        |
| ≥2                                                   |                                                                                                                                                                                                                                                      | Enter up to 3 patients at the next lowest dose  level. |
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3.2 drug administration

In this trial, patients will receive both drugs in certain weeks as specified in the schema. The order of administration will be determined by drug delivery by pharmacy to the day hospital on the day of administration. Therefore, patients can receive either both drugs concurrently or sequentially without a particular order.
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3.2.1 durvalumab 3.2.1.1 durvalumab doses

The initial dose of durvalumab (Cohort 1) is 1500 mg IV every 4 weeks for up to 52 weeks. Please note, at the end of each maintenance cycle there is a 2 week window in order to allow the patients sufficient time to recover from biopsies prior to continuing treatment. Refer to the schema for a detailed description of Durvalumab administration weeks. Study treatment should be discontinued prior to 12 months if there is confirmed PD, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study treatment occur. Subjects who have a dose interruption due to toxicity at any point in the first 12 months of treatment may resume treatment and complete the 12-month treatment period. For patients without recurrent high grade disease and who are tolerating therapy well, optional maintenance therapy may be continued in the second year. The maintenance dose will be durvalumab 1500 mg administered intravenously once every 3 months to provide an immune boost. During that second year, as per standard of care for high grade disease, cystoscopy and urine cytology will be performed every 3 months. This is depicted graphically in the schema in the optional maintenance section. No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been observed. Dose of 1500mg durvalumab (for patients >30 kg in weight) will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie. 1500 mg of durvalumab (MEDI4736)) to the IV bag. The IV bag size should be selected such that the final concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. For patients who lose weight (<30 kg) during the course of the trial and maintain their enrollment ECOG status, further treatment with durvalumab will be weight based. The dose volume of durvalumab and number of vials needed for the subject to achieve the accurate dose will be calculated according to **Appendix B**. Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion via an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a deviation. The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming volume of the infusion set used after the contents of the IV bag are fully administered, or complete the infusion according to institutional policy to ensure the full dose is administered and document if the line was not flushed. Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total allowed time should not exceed 4 hours at room temperature. The table below summarizes time allowances and temperatures.
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durvalumab hold and infusion times

| Maximum time from needle puncture to   | 4 hours at room temperature, 24 hours at 2°C to   |     |    |     |           |                             |
|----------------------------------------|---------------------------------------------------|-----|----|-----|-----------|-----------------------------|
| start of administration                | 8°C                                               |     |    |     |           |                             |
| Maximum                                | time                                              | for | IV | bag | infusion, | 8 hours at room temperature |
| including interruptions                |                                                   |     |    |     |           |                             |  
In the event that either preparation time or infusion time exceeds the time limits outlined in the table above, a new dose must be prepared from new vials. Durvalumab does not contain preservatives, and any unused portion must be discarded.
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3.2.1.2 monitoring of dose administration

Subjects will be monitored before, during and after the infusion with assessment of vital signs at the times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure) every 30 minutes during the infusion period (including times where infusion rate is slowed or temporarily stopped). In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate until completion of the infusion. For subjects with a ≤Grade 2 infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be administered at the discretion of the investigator. If the infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The standard infusion time is one hour, however if there are interruptions during infusion, the total allowed time from infusion start to completion of infusion should not exceed 4 hours at room temperature, with maximum total time at room temperature not exceeding 4 hours (otherwise requires new infusion preparation). As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be immediately available, and study personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate access to emergency resuscitation teams and equipment in addition to the ability to admit subjects to an intensive care unit if necessary.
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3.2.2 vicineumtm 3.2.2.1 doses and

The initial dose of vicineum is 30 mg in 50 mL of saline (Dose level 1). Vicineum will be instilled through a catheter into the bladder. Subjects will be instructed to hold study drug in the bladder for 2 hours, and asked to refrain from fluid intake to reduce urine flow during this period. After complete administration of the Vicineum dose, the catheter may be clamped and remain in for the 2-hour dwell time, or may be removed, per the discretion of the investigator. Subjects will be encouraged, when physically possible, to be upright (sitting or standing), prone, supine, and in the left and right lateral decubitus positions, for at least 15 minutes each, in any order. If physically unable, this should be recorded in the CRF. At the end of 2-hour period, the catheter will be unclamped and the bladder will be drained (if the catheter remained in place) or the subject will void to empty the bladder.  
| Study Phase                         | Treatment Regimen                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|-------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Induction Phase (Weeks 1-12)        | One intravesical dose of Vicineum in 50 mL of saline instilled  once weekly for a total of 12 weeks.  One intravesical dose of Vicineum 50 mL saline instilled once  every other week for 12 months from the start of the Induction  phase. Please note, at the end of each maintenance cycle there  is a 2 week window in order to allow the patients sufficient  time to recover from biopsies prior to continuing treatment.  Refer to the schema for a detailed description of Vicineum  administration weeks. If remain disease-free, therapy can be  continued for up to 24 months (Week 104) from the start of  the Induction Phase. |
| Maintenance Phase (up to  Week 104) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
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3.3 dose modifications 3.3.1 durvalumab

Following any biopsy or TURBT, study drug must be interrupted for a maximum of 2 weeks before restarting Durvalumab treatment. For adverse events (AEs) that are considered at least partly due to administration of durvalumab outside of the DLT evaluation period, the following dose adjustment guidance may be applied:  
Treat each of the toxicities with maximum supportive care (including holding the agent suspected of causing the toxicity where required).  
If the symptoms promptly resolve with supportive care, consideration should be given to resuming the same dose of durvalumab along with appropriate continuing supportive care.  
If medically appropriate, dose modifications are permitted for durvalumab. All dose modifications should be documented with clear reasoning and documentation of the approach taken (see **Appendix C**).
In addition, there are certain circumstances in which durvalumab should be permanently discontinued (see **Appendix C)**. In circumstances where subjects cannot tolerate durvalumab or do not meet retreatment criteria to receive either drug, subjects will be taken off protocol therapy. Following the first dose of durvalumab, subsequent administration of durvalumab can be modified based on toxicities observed (see **Appendix C**). Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, there is the possibility of observing immune related Adverse Events (irAEs) during the conduct of this study. Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs. In the absence of an alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be immune-related. Dose modification recommendations and toxicity management guidelines for immune-mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in Appendix C.