untitled h1
3.3.2 vicineum

Following any biopsy or TURBT, study drug must be interrupted for a minimum of 1 week and maximum of 2 weeks before restarting Vicineum treatment. Patients who develop low grade papillary disease will be allowed to stay on trial. In November 2016, the FDA published a draft guidance for trials involving patients with BCG-unresponsive disease in which only high-risk disease counts as a recurrence or an event. In this clinical setting, low-risk disease would lead to transurethral resection while high-risk disease would lead to cystectomy, which is a much different clinical outcome. Therefore, in this trial, low grade recurrences will be documented but will not count as a trial-ending recurrence or event. Furthermore, low grade recurrences are considered to be downstaging of disease since the inclusion criteria requires patients with high grade disease. Study drug administration must be postponed if a subject develops any Grade 3 or greater adverse event. Study treatment may resume when the AE returns to ≤ Grade 1 or baseline or sooner if there is agreement between the investigator and the sponsor. Study treatment may be postponed at the discretion of the investigator for unrelated AEs, if this is considered in the best interest of the subject. If the causal relationship between Vicineum and an AE is initially uncertain, study drug should be interrupted until that determination is made. Also study treatment may be postponed for lower grade AEs at the investigator discretion if considered in the best interest of the subject.  
| Criteria for Holding Vicineum Treatment*   |                                 |                                                |
|--------------------------------------------|---------------------------------|------------------------------------------------|
| Baseline Creatinine                        | Serum Creatinine                | Creatinine Clearance                           |
| <1.0 mg/dl or <88 µmol/L                   | >1.5 mg/dl or >133 µmol/L       | <40 ml/min or a decrease of  25% from baseline |
| ≥1.0 mg/dl or ≥88 µmol/L                   | Increase to >2 x Baseline Value | <40 ml/min or a decrease of  25% from baseline |  
The following specific criteria will be used for holding Vicineum dosing based on serum creatinine and calculation of creatinine clearance:
*Vicineum dosing should be held if either the serum creatinine or the creatinine clearance criteria, as defined in this table, are met.  
If changes in renal function are noted, the investigator should evaluate the subject for the etiology of these changes. Vicineum treatment may be resumed upon improvement or stabilization at creatinine of ≤ 2 x baseline or ≤ 2 x ULN.  
Vicineum dosing must be held for any subject whose AST or ALT doubles from their baseline value and is ≥2xULN; OR for a bilirubin ≥2mg/dl (≥34 µmol/L). However, if Grade 2 hyperbilirubinemia occurs during the DLT evaluation period, then a DLT is present and treatment will be permanently discontinued and patient will be removed from study. The investigator should evaluate subjects for the etiology of any changes in these values. Vicineum treatment may be resumed upon improvement or stabilization of AST and ALT of ≤ 2 x baseline or ≤ 2 x ULN; OR for a bilirubin ≤ 2mg/dl (≤34 µmol/L) provided that Grade 2 hyperbilirubinemia did not occur.  
The investigator should consider holding Vicineum treatment for patients with a clinically significant UTI requiring antibiotic therapy until improvement. Investigators should also consider holding Vicineum treatment for patients with grade II hematuria.
Missed doses should not be made up. In the Maintenance Phase, dosing should be restarted as soon as there is AE resolution i.e., treatment should not be postponed longer in order to align with the initial every-other-week schedule. If study treatment is postponed longer than 3 weeks, the investigator should consider whether the subject should remain on treatment. In circumstances where subjects cannot tolerate Vicineum or do not meet retreatment criteria to receive either drug, subjects will be taken off protocol therapy. The reasons and details relevant to the subject postponement and/or discontinuation of study treatment must be recorded on the CRF. The Investigator must notify Sesen Biotherapeutics if study treatment is discontinued.  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |         |             |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|-------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |         |             |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1  | Weeks 2 - 5 | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |         |             |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0 |             |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1      |             |        |              |         |     |
| Written informed  consent/assignment  of subject  identification  number                                            | X                                                                      |         |             |        |              |         |     |
| Inclusion/Exclusion  criteria                                                                                       | X                                                                      |         |             |        |              |         |     |
| Demography                                                                                                          | X                                                                      |         |             |        |              |         |     |
| Medical and  surgical history                                                                                       | X                                                                      |         |             |        |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |                                    |             |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|------------------------------------|-------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |                                    |             |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1                             | Weeks 2 - 5 | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |                                    |             |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0                            |             |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1                                 |             |        |              |         |     |
| Previous treatments  for bladder cancer  including  dates/doses of prior  BCG                                       | X                                                                      |                                    |             |        |              |         |     |
| Confirmation of  diagnosis by NCI  LP                                                                               | X                                                                      | X (every 3  months as per  SCHEMA) |             |        |              |         |     |
| Cystoscopy                                                                                                          | X                                                                      | X (every 3  months as              |             |        |              |         |     |
| indicated as per  SCHEMA)                                                                                           |                                                                        |                                    |             |        |              |         |     |
| Bladder biopsies /  TURBTs                                                                                          | X                                                                      |                                    |             |        |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |                                 |                    |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------------------------------|--------------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |                                 |                    |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1                          | Weeks 2 - 5        | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |                                 |                    |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0                         |                    |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1                              | X (every 3  months |        |              |         |     |
| preceding each  cystoscopy as  per SCHEMA)                                                                          |                                                                        |                                 |                    |        |              |         |     |
| Urine cytology                                                                                                      | X                                                                      |                                 |                    |        |              |         |     |
| EpCAM                                                                                                               | Last biopsy on                                                         |                                 |                    |        |              |         |     |
| determination                                                                                                       | X                                                                      | trial                           |                    |        |              |         |     |
| Last biopsy on                                                                                                      |                                                                        |                                 |                    |        |              |         |     |
| Tissue PD-L1 assay                                                                                                  | X                                                                      | trial                           |                    |        |              |         |     |
| Hepatitis B and C;  HIV                                                                                             | X                                                                      | Prior to each  durvalumab  dose |                    |        |              |         |     |
| Urine hCG or  serum βhCG2                                                                                           | X3                                                                     | Week 4                          | Week 8             | X      |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |                                                         |                                                                                                                                      |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |                                                         |                                                                                                                                      |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1                                                  | Weeks 2 - 5                                                                                                                          | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |                                                         |                                                                                                                                      |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0                                                 |                                                                                                                                      |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1                                                      | Every 4 weeks  resuming in  week 15 and as  per SCHEMA.  Every 3 months  if optional  maintenance  performed after  first 12 months. |        |              |         |     |
| Week 6 Week 10                                                                                                      |                                                                        |                                                         |                                                                                                                                      |        |              |         |     |
| Durvalumab  administration3                                                                                         | Starting  Week 2                                                       | Every 2 weeks  resuming in  week 15 and as  per SCHEMA. |                                                                                                                                      |        |              |         |     |
| Vicineum  administration4                                                                                           | X                                                                      | X                                                       | X                                                                                                                                    | X      | X            |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |         |                          |                          |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|--------------------------|--------------------------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |         |                          |                          |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1  | Weeks 2 - 5              | Week 6                   | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |         |                          |                          |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0 |                          |                          |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1      | Targeted  physical       |                          |              |         |     |
| examination as  needed.                                                                                             |                                                                        |         |                          |                          |              |         |     |
| Physical  examination  including weight5                                                                            | X                                                                      | X       | Week 2                   | Weeks 6, 10              | X            |         |     |
| Vital signs (preduring and postdurvalumab  infusion; pre- and  post-Vicineum  drainage)6                                                                                                                     | X                                                                      | X       | All treatment visits     |                          |              |         |     |
| Electrocardiogram7                                                                                                  | X                                                                      | Week 2  | If clinically  indicated | If clinically  indicated |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |            |             |        |              |         |     |               |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|------------|-------------|--------|--------------|---------|-----|---------------|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |            |             |        |              |         |     |               |
| Screening                                                                                                           | Baseline                                                               | Week 1     | Weeks 2 - 5 | Week 6 | Weeks 7 - 11 | Week 12 | and |               |
| Maintenance                                                                                                         |                                                                        |            |             |        |              |         |     |               |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0    |             |        |              |         |     |               |
| Week                                                                                                                | -12 to -1                                                              | -1         |             |        |              |         |     |               |
| Adverse  event/serious  adverse event  assessment                                                                   | All visits                                                             |            |             |        |              |         |     |               |
| Concomitant  medications                                                                                            | X                                                                      | All visits |             |        |              |         |     |               |
| ECOG  performance status                                                                                            | X                                                                      | X          | X           |        |              |         |     |               |
| Acute care panel7                                                                                                   | X                                                                      | X          | X           | X      | X            | X       | X   | Every 2 weeks |
| LDH                                                                                                                 | X                                                                      | X          | X           | X      | X            | X       | X   | Every 2 weeks |
| Pre-albumin                                                                                                         | X                                                                      |            |             |        |              |         |     |               |
| Pancreatic enzymes  (amylase, lipase)                                                                               | X                                                                      | X          | X           | X      | X            | X       | X   | Every 2 weeks |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |         |             |                                 |              |            |     |               |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|-------------|---------------------------------|--------------|------------|-----|---------------|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |         |             |                                 |              |            |     |               |
| Screening                                                                                                           | Baseline                                                               | Week 1  | Weeks 2 - 5 | Week 6                          | Weeks 7 - 11 | Week 12    | and |               |
| Maintenance                                                                                                         |                                                                        |         |             |                                 |              |            |     |               |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0 |             |                                 |              |            |     |               |
| Week                                                                                                                | -12 to -1                                                              | -1      |             |                                 |              |            |     |               |
| Hepatic panel                                                                                                       | X                                                                      | X       | X           | X                               | X            | X          | X   | Every 2 weeks |
| Mineral panel                                                                                                       | X                                                                      | X       | X           | X                               | X            | X          | X   | Every 2 weeks |
| Thyroid function  tests (TSH and fT3  and fT4)8                                                                     | Prior to each  durvalumab  dose                                        |         |             |                                 |              |            |     |               |
| Week 6                                                                                                              |                                                                        |         |             |                                 |              |            |     |               |
| X                                                                                                                   | X                                                                      | Week 2  | Week 10     | Prior to each  durvalumab  dose |              |            |     |               |
| Week 2                                                                                                              |                                                                        |         |             |                                 |              |            |     |               |
| Hematology7                                                                                                         | X                                                                      | X       | X           | Week 8                          | X            |            |     |               |
| Week 4                                                                                                              | X (prior to each  Vicineum  treatment)                                 |         |             |                                 |              |            |     |               |
| Urinalysis                                                                                                          | X                                                                      | X       | X           | X (weekly)                      | X            | X (weekly) | X   |               |
| Urine culture and  sensitivity                                                                                      | X                                                                      |         |             |                                 |              |            |     |               |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |                        |             |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|------------------------|-------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |                        |             |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1                 | Weeks 2 - 5 | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |                        |             |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0                |             |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1                     |             |        |              |         |     |
| 24 hour urine (only  if CrCl to be  measured rather  than calculated)                                               | X                                                                      |                        |             |        |              |         |     |
| PPD testing (if  indicated)                                                                                         | X                                                                      |                        |             |        |              |         |     |
| Coagulation  parameters                                                                                             | X                                                                      | As clinically indicted |             |        |              |         |     |
| Urine cytokines                                                                                                     | X                                                                      | X                      | 6 months    |        |              |         |     |
| Serum circulating                                                                                                   | Weeks 2, 3,                                                            |                        |             |        |              |         |     |
| cytokine profile                                                                                                    | X                                                                      | and 5                  |             |        |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |         |             |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|-------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |         |             |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1  | Weeks 2 - 5 | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |         |             |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0 |             |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1      |             |        |              |         |     |
| sPD-L1  concentration (to  assess target  engagement)                                                               | Weeks 2, 3,                                                            |         |             |        |              |         |     |
| X                                                                                                                   | and 5                                                                  |         |             |        |              |         |     |
| Gene expression  analysis                                                                                           | X                                                                      |         |             |        |              |         |     |
| Tissue immune  correlates (IHC and  possibly RNAseq)                                                                | Last biopsy on                                                         |         |             |        |              |         |     |
| X                                                                                                                   | trial                                                                  |         |             |        |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |         |               |        |              |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|---------------|--------|--------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |         |               |        |              |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1  | Weeks 2 - 5   | Week 6 | Weeks 7 - 11 | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |         |               |        |              |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0 |               |        |              |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1      |               |        |              |         |     |
| Flow cytometry of  PBMCs for  immune subsets  and antigenspecific responses  (T-cell clonal  expansion if  feasible)                                                                                                                     | X                                                                      | X       | 6 months      |        |              |         |     |
| Immunogenicity                                                                                                      | Week 8:                                                                |         |               |        |              |         |     |
| assessment                                                                                                          | X                                                                      | ADA     | Week 12:  AVA |        |              |         |     |
| Tumor CT/CT  urogram or  MRI/MRI urogram  of abdomen and  pelvis9                                                   | Every 12                                                               |         |               |        |              |         |     |
| months while  on study                                                                                              |                                                                        |         |               |        |              |         |     |
| X                                                                                                                   |                                                                        |         |               |        |              |         |     |  
SCHEDULE OF STUDY ASSESSMENTS: Screening (Weeks -12 to -1), Induction Phase (Weeks 1 - 12), and PostInduction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays and scheduling difficulties)  
| and scheduling difficulties) Assessments to be                                                                      | All assessments to be performed pre-infusion unless stated otherwise   |         |             |                       |                             |         |     |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|-------------|-----------------------|-----------------------------|---------|-----|
| performed at the  times stipulated in  the table and as  clinically required  in the management  of the subject15 . | Post-Induction                                                         |         |             |                       |                             |         |     |
| Screening                                                                                                           | Baseline                                                               | Week 1  | Weeks 2 - 5 | Week 6                | Weeks 7 - 11                | Week 12 | and |
| Maintenance                                                                                                         |                                                                        |         |             |                       |                             |         |     |
| Day                                                                                                                 | -84 to -1                                                              | -7 to 0 |             |                       |                             |         |     |
| Week                                                                                                                | -12 to -1                                                              | -1      |             |                       |                             |         |     |
| Urinary PK for  Vicineum                                                                                            | X                                                                      | X10,11, | X12         | X (before  Vicineu m) | Week 10  (before  Vicineum) |         |     |
| Urinary EpCAM  levels                                                                                               | X                                                                      | X10,11  | X12         | X (before  Vicineum)  |                             |         |     |
| Follow-up Safety  Visits for patients  who come off  treatment or  complete study13, 14                             | Every month up  to 90 days post  the last dose of  immunotherapy14     |         |             |                       |                             |         |     |
| 1.                                                                                                                  | May be performed up to 12 weeks prior to enrollment.                   |         |             |                       |                             |         |     |  
1. May be performed up to 12 weeks prior to enrollment. 2. Pre-menopausal female subjects of childbearing potential only. 3. Dose can be administered within +/- 7 days of scheduled administration to accommodate schedule and holidays. 4. Once weekly intravesical administration for weeks 1-12; Dose can be administered within +/- 7 days of scheduled administration to accommodate schedule and holidays.  
5. Full physical examination at screening and/or baseline; targeted physical examination at other timepoints and when clinically indicated.  
6. Vital signs will be obtained at a single timepoint at screening and baseline. Subjects will have their blood pressure and pulse measured before, during and after the infusion at the following times (based on a 60-minute infusion):
At the beginning of the infusion (at 0 minutes)
At 30 minutes during the infusion (±5 minutes)
At the end of the infusion (at 60 minutes ±5 minutes) In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the infusion) (±5 minutes) - for the first infusion only and then for subsequent infusions as clinically indicated.  
If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should be collected every 30 minutes (±5 minutes) and as described above or more frequently if clinically indicated.  
7. ECG during screening required to measure QTc as specified above and 1 ECG is needed while on treatment (pre-durvalumab infusion) and as clinically indicated. 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. 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) to confirm prolongation. If screening laboratory assessments are performed within 3 days prior to Day 1, they do not need to be repeated at Day 1.  
8. Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine system. During maintenance phases 4-7, TSH will be drawn prior to each durvalumab dose and subsequently 4 weeks and 8 weeks after durvalumab administration.  
9. Can be given without contrast if severe contrast allergy or renal function does not allow contrast administration per institutional recommendations. MRIs will be done per PI discretion and when clinically indicated.  
10. First void after Vicineum administration in Week 1. 11. First void after the next morning after Vicineum administration in Week 1. 12. Day 8 void prior to Vicineum administration in Week 2. 13. H&P, Labs including renal, liver, complete blood count + platelets, coagulation studies monthly for up to 90 days after last immunotherapy.  
14. End of treatment visit will occur 90 days after the last dose of immunotherapy. If clinically indicated, patients may continue to be followed by phone or clinic visits beyond that time and up to a year at the NIH/NCI or their local urologist.  
15. Per PI discretion, a remote evaluation may be done by phone by a member of the study team. This evaluation will be conducted in compliance with NIH guidelines and FDA regulations. A patient may be asked to come to the NIH Clinical Center or may be referred to their local provider for an in-person assessment, if deemed necessary by the PI. In the case of any visits with participants' local providers, records will be obtained.
untitled h1
3.5 cost and compensation 3.5.1

NIH does not bill health insurance companies or participants for any research or related clinical care that participants receive at the NIH Clinical Center. If some tests and procedures are performed outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered by their insurance company. Medicines that are not part of the study treatment will not be provided or paid for by the NIH Clinical Center.
untitled h1
3.5.3 reimbursement

The NCI will cover the costs of some expenses associated with protocol participation. Some of these costs may be paid directly by the NIH and some may be reimbursed to the participant/guardian as appropriate. The amount and form of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.
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3.6 criteria for removal from

Prior to removal from study, effort must be made to have all subjects complete monthly safety visits (+/- 7 days) for 90 days following the last dose of study therapy. These visits will consist of H&P and labs (including renal, liver, complete blood count + platelets, coagulation studies). Patients will revert to standard of care once coming off study. If clinically indicated, patients may continue to be followed by phone or clinic visits beyond that time and up to a year at the NIH/NCI or their local urologist.
untitled h1
3.6.1 criteria for removal from

Subjects are free to withdraw from further treatment or to withdraw consent to participate in this study at any time and without prejudice to further treatment. For subjects who withdraw their consent for study participation, no further study specific assessments will be performed and no additional study data will be collected. For subjects who withdraw from further treatment only will remain on study for further evaluations but receive no additional study treatment. The investigator may also withdraw a subject from study treatment or from the study if he or she deems it to be in the best interest of the subject or if the subject is unable to comply with the study. All subjects withdrawing only from further treatment should have enter the PostTreatment Period and have the appropriate assessments performed 90 days after the last dose of study drug, unless the subject withdraws consent for the procedures. If clinically indicated, patients may continue to be followed by phone or clinic visits beyond that time and up to a year at the NIH/NCI or their local urologist. The reasons and details relevant to subject withdrawal must be recorded in the source documents and in the CRFs. In addition, an individual subject will not receive any further investigational product if any of the following occur in the subject in question:
Completion of protocol therapy Unacceptable toxicity as defined in section 3.3 and **Appendix C**  
Adverse event that, in the opinion of the investigator, contraindicates further dosing of either study drug Subject experiences a DLT during the DLT evaluation period (see section **3.1.1**)
Requirement for prohibited medications/therapies Subject met eligibility criteria at screening but then subsequently is determined to have met one or more of the exclusion criteria for study participation and continuing investigational therapy might constitute a safety risk Subjects refuses to use contraception as required by the protocol Disease progression (as defined in section **6.2.4.3**) or confirmation that the subject is no longer benefiting from study treatment Grade 2 or greater hyperbilirubinemia
Participant requests to be withdrawn from active therapy  
Unacceptable Toxicity as defined as any serious adverse event that is unexpected relative to the known safety profile of the investigational agents in the opinion of the investigator Sponsor or Manufacturer terminates the study The FDA requests that the sponsor terminate treatment of a specific subject or subjects or all subjects Subject noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal; e.g. refusal to adhere to scheduled visits Investigator discretion Positive pregnancy test or intent to become pregnant or intent to breast-feed or is breastfeeding
Disease recurrence with high-grade bladder cancer
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3.6.2 off-study criteria

The following are off study criteria that will preclude further follow-up:
Completed study follow-up period  
Participant requests to be withdrawn from study
Death  
Patient is lost to follow-up Patient enrolled into another clinical study
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3.6.3 lost to follow-up

A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits and is unable to be contacted by the study site staff. The following actions must be taken if a participant fails to return to the clinic for a required study visit:  
The site will attempt to contact the participant and reschedule the missed visit and counsel the participant on the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should continue in the study.  
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, an IRB approved certified letter to the participant's last known mailing address or local equivalent methods). These contact attempts should be documented in the participant's medical record or study file.  
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from the study with a primary reason of lost to follow-up.
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4 concomitant medications/measures 4.1 permitted

Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for those medications identified as "excluded" as listed in Section 4.2.
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4.2 excluded concomitant medications

The following medications are considered exclusionary during the study.  
1. Any investigational drugs  
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy),
immunotherapy, biologic or hormonal therapy, including investigational therapy for cancer treatment. Concurrent use of hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Subjects who enter the study with low risk prostate cancer and then progress to require androgen-deprivation therapy (ADT) when already enrolled on this trial may continue on trial as per investigator discretion.  
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of investigational product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of inhaled and intranasal corticosteroids is permitted.  
4. Live attenuated vaccines within 30 days of durvalumab dosing (i.e., 30 days prior to the first dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab. Inactivated vaccines, such as the injectable influenza vaccine, are permitted.)  
| Prohibited & concomitant meds Prohibited medication/class of drug:                                                                                                   | Usage:                                                                                                                                                                                                                                                                                                                                                                   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Any investigational anticancer therapy other                                                                                                                         | Should not be given concomitantly whilst the patient                                                                                                                                                                                                                                                                                                                     |
| than those under investigation in this study                                                                                                                         | is on study treatment                                                                                                                                                                                                                                                                                                                                                    |
| mAbs against CTLA-4, PD-1, or PD-L1 other                                                                                                                            | Should not be given concomitantly whilst the patient                                                                                                                                                                                                                                                                                                                     |
| than those under investigation in this study                                                                                                                         | is on study treatment                                                                                                                                                                                                                                                                                                                                                    |
| Any concurrent chemotherapy, radiotherapy,  immunotherapy, or biologic or hormonal  therapy for cancer treatment other than those  under investigation in this study | Should not be given concomitantly whilst the patient  is on study treatment. (Concurrent use of hormones  for non-cancer-related conditions [e.g., insulin for  diabetes and hormone replacement therapy] is  acceptable. Local treatment of isolated lesions,  excluding target lesions, for palliative intent is  acceptable [e.g., by local surgery or radiotherapy]) |
| Live attenuated vaccines                                                                                                                                             | Should not be given through 30 days after the last  dose of IP                                                                                                                                                                                                                                                                                                           |
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5 correlative studies for research

Please note that tubes and media may be substituted based on availability with the permission of the PI or laboratory investigator.
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5.1.1 blood studies 5.1.1.1 serum

Refer to the table in section 5.2 for volume, tube types and sample collection schedule. Samples will be assessed for:  
IL-1B, IL–2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-18, IFN-y, IL-6, TNFalpha, and IL-10. This will be done with a commercial ELISA kit such as V-plex in collaboration with Liang Cao, William D. Figg, and Dr. Andrea Apolo.  
Soluble PD-L1 (total and free unbound PD-L1)
For Serum collection of samples for cytokines and soluble PDL-1, please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 5.1.1.2 PBMCs for immune analysis Samples will be collected at the timeframes indicated in the table in section 5.2  
Flow cytometry of immune subsets (include CD4+ and CD8+ T-cells, Tregs, NK
cells, and MDSCs and PD-L1 expression on immune cells) - This will be processed
in Dr. Schlom's laboratory as described below. Dr. Schlom's laboratory now has the ability to analyze 123 peripheral immune cell subsets31 as shown in **Appendix D**.  
T-cell clonal expansion assay if appropriate funding and material is available Antigen-specific responses of cytotoxic lymphocytes for tumor associated antigens
(e.g. brachyury, EPCAM)
Immunogenicity Assessment (anti-durvalumab antibodies and anti-vicineum antibodies) - Samples will be collected at baseline and stored in Dr. Linehan's Lab i. Week 8 for ADA and Week 12 for AVA (separate blood collection at the weeks specified - Stored in Dr. Linehan's Lab
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5.1.1.2.1 sample processing

For PBMCs, green top tubes will be obtained and then processed at the Clinical Services Program (CSP) NCI Frederick Cancer Research and Development Center, PO Box B, Frederick, MD 21702 in collaboration with Dr. Schlom's research group. On days samples are drawn, Jen Bangh at CSP should be notified (phone: [301] 846-5893; fax [301] 846-6222). Once a patient's treatment schedule has been determined, Caroline Jochems should be notified at jochemscm@mail.nih.gov for planning purposes. Dr. Schlom and colleagues recently published their ability to analyze PBMCs for 123 subsets of peripheral immune cells using 30 unique markers in 5 immune flow cytometry panels. These subsets are subsets of CD4+ T cells, CD8+ T cells, Tregs, B cells, NK cells, NK-T cells, conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), and MDSCs. A full list is enclosed in **Appendix D**.
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5.1.2 research urine studies 5.1.2.1

Urine collection at the timepoints indicated in the table in section 5.2 for correlative/exploratory research aims (e.g. inflammatory cells, cytokines) at baseline. This will be performed through a commercial vendor, Luminex, using a platform of 12 urinary cytokines.32 5.1.2.2 Urine EpCAM, Pharmacokinetics and Pharmacodynamics This will be done in direct collaboration with Dr. Cao's laboratory  
Evaluate PK for urinary Vicineum by testing for VB4-845 - see table in section 5.2 for PK timepoints Evaluate pharmacodynamics (PD) for EpCAM shedding in the urine [baseline, first void after drug administration in Week 1, first void the next morning after treatment, and the day 8 void prior to start of week 2 treatment, Week 6 before Vicineum, Week 10 before Vicineum, Week 12 before Vicineum - - see table in section 5.2 for PD timepoints Evaluate EpCAM in the urine for the ability to monitor or predict response to therapy
- see table in section 5.2 for PK timepoints
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5.1.2.3 sample processing

For urine collection, it will be processed according to standard protocol (refer to **Appendix E**) and stored in the Urologic Oncology Branch in Dr. Linehan's lab. Samples will be batched at the end of the trial and then analyzed.
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5.1.3 tissue studies

Samples will be obtained pre-and post treatment as indicated in the table in section 5.2 to:
Perform immunohistochemistry (IHC) or cytogenetic analysis of baseline tissue (FFPE or frozen tissue specimen) for EpCAM, PD-1/PD-L1, TILS, CD4, CD8, Tregs, MDSCs, Macrophages, and monocytes. In addition, mesenchymal markers such as vimentin, TWIST, Snail, Slug, and Sip1 may also be assessed by immunohistochemistry of baseline tissue. This can be compared to similar IHC of tissue obtained from the last biopsy on trial. This analysis will be performed by the NCI Laboratory of Pathology upon accruing at least 4 patients or by PI's discretion. Baseline FFPE slides will be obtained from paraffinembedded blocks stored within NCI's Laboratory of Pathology at a future date when analysis will be performed. In the event that patients have had baseline biopsy at an outside institution, every effort will be made to obtain the paraffin-embedded blocks in order to generate baseline FFPE slides for further analysis. In particular to the current study, we would like to study the T-cell infiltration pattern within bladder tumors pre- and post-treatment. Specifically, we will look at:  
1. The presence of CD4 and CD8 T cells in bladder tumor specimens pre- and posttreatment 2. The presence of regulatory T cells (Tregs) by double staining with FoxP3 and CD4 in bladder tumor specimens pre- and post-treatment 3. The presence of myeloid derived suppressor cells (MDSC) in bladder tumor specimens pre- and post-treatment 4. The presence of myeloid derived suppressor cells (MDSC) in bladder tumor specimens pre- and post-treatment 5. The presence of PD-L1 staining pre- and post-treatment as specified below in section **5.1.3.2**.  
6. The presence of EpCAM and mesenchymal markers.
If sufficient tissue is available, cell lines may be generated. Cell lines may be characterized by karyotyping, interphase fluorescence in situ hybridization (FISH) mapping, immunohistochemistry, and/or flow cytometry. Differences between cell lines will be manipulated to study the various molecular pathways active in nutrient sensing, cell cycle, cell signaling, proliferation, apoptosis, angiogenesis, and metastatic potential in urothelial cancer.  
If adequate tissue and funding available, then may perform mutational load analysis through a targeted panel (RNAseq or DNA mutation panel) of tumor tissue. This analysis will be performed by the NCI CORE facility, NCI collaborator (Paul Meltzer), or outside entity (e.g. Foundation Medicine)
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5.1.3.1 tissue collection procedures

If tissue is clinically available, the Urologic Oncology Branch procedures for tissue collection will be followed. This is usually done with standard of care procedures such as such as transurethral resection of bladder tumor. CT guided biopsy is not a procedure by which to procure non-muscle invasive bladder tumor and so it will not be performed on this protocol. A procurement form will be completed. The tissue procurement nurse or a UOB-designated procurement staff member will work with an NCI pathologist following resection of the specimen to obtain tumor tissue from the resected specimen. this will be done using standard of care procedures This will then be delivered by the procurement nurse or UOB Procurement staff member to the Urologic Oncology Branch Research Laboratory for individual processing. Specimens will be placed in cryovials and also be snap frozen in OCT for frozen tissue sections. Tissue sent to pathology will be processed in standard fashion but when formalin-fixed paraffin embedded slides made, they will be modified as below in section **5.1.3.2** to allow for PD-L1 testing in a standardized fashion. Pathologic material, such as fixed tissue blocks from surgery performed at the NIH Clinical Center, outside surgeries or autopsy materials, may be obtained at the request of, and with written permission from the subject, or appropriate relatives. These samples may undergo pathologic analysis by individuals in the NCI Laboratory of Pathology to confirm diagnosis and may undergo histo-immunologic or other analysis.
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5.1.3.2 tissue pd-l1 testing

To ensure comparability of data across all studies of durvalumab and to gain real world experience on the performance of this assay, it is strongly encouraged that all studies that include PD-L1 testing utilize the Ventana SP263 assay. Testing should be restricted to the Ventana SP263 assay and should be performed in accordance with the package insert on the Ventana Benchmark platform (Ultra or XT). The Ventana SP263 assay is fully analytically validated test characterized through to the completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head & neck (SCCHN). For these tumors, the Ventana SP263 assay has a fully reproducibility data package supporting cut-off and scoring algorithm. Following completion of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical utility. In other cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, ovarian, esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, small cell lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only limited clinical performance data.
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5.1.3.2.1 sample collection for pd-l1

The preferred tumor sample for the determination of a patient's PD-L1 status is the one taken following the completion of the most recent prior line of therapy. Samples taken at this time reflect the current PD-L1 status of the tumor and considered clinically most relevant.  
In AstraZeneca studies, the preferred sample for PD-L1 testing was less than or equal to 3 months old. In cases where a sample a less than 3 months old was not available, patients
were asked to undergo a new biopsy if considered clinically appropriate by their treating physician.  
Samples should be collected via a core needle of 18 gauge or larger or be collected by an incisional or excisional tumor biopsy. Where institutional practice uses a smaller gauge needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) to allow for adequate PD-L1 immunohistochemistry analyses.
When the collection of a new sample is not clinically appropriate, archival samples may be utilized provided the specimen it is not older than 3 years of age. When archival samples are used to assess PD-L1 status, the age of the sample / date of collection should be captured.  
Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.  
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for PDL1 analysis.
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5.1.3.2.2 sample data collection for

The following fields of data should be collected from the site/institution collecting and if, indicated shipping of the samples:
Patient identifier (unique identifier)
Specimen identifier (written on the specimen) Site identifier Specimen collection date Type of specimen submitted Quantity of specimen Date of sectioning Archival of fresh tumor Tumor type Primary tumor location Metastatic tumor location (if applicable)
Fixative
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the following fields of data

Are the negative and positive controls stained correctly Is the H&E material acceptable Is morphology acceptable Total percent positivity of PD-L1 in tumor cells PD-L1 status (positive, negative or NA) in tumor cells Total percent positivity of PD-L1 in infiltrating immune cells The Ventana SP263 assay to measure PD-L1 in tumors is experimental. As with all tests, there is a chance of false positive (the test shows high PD-L1 when it is not there) or false negative (the test does not show PD-L1 when it is there) results may occur.
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5.1.3.2.3 sample processing for pd-l1

Where samples already exist, they should be retrieved from the Bio-Bank storage location.  
These blocks should undergo quality review, prior to evaluation or shipment. Where it is not possible or indicated to ship the block to a testing laboratory, unstained slides should be prepared from the paraffin-embedded tumor sample block (described below) prior to evaluation or shipment.
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preparing newly acquired samples for

If patients are undergoing a biopsy procedure that provides the option to submit newly acquired samples, this sample should be used to determine PD-L1 status. Where clinically acceptable, a minimum of 2 core biopsies should be collected and processed to FFPE in a single block. The provision of 2 cores is advised in order to provide sufficient tissue for PD-L1 assessment.  
It is recommended that core needle tumor biopsies are collected using an 18 gauge or larger needle and the process should be image-guided. Excisional or incisional samples are also adequate. If this is not per the institutions normal practice and a smaller gauge needle is used then the number of cores collected should be increased to allow sufficient material for successful PD-L1 testing (>100 tumor cells) and embedded in the same block. If available, a single excisional biopsy of at least 4 mm in diameter may substitute for all core biopsies.
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fixation of biopsy samples for

Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing. To fix newly acquired tissue, place immediately (within 30 min of excision) into an adequate volume of 10% v/v neutral buffered formalin (NBF). Samples should remain in fixative for 24 - 48 hours at room temperature.  
It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 volume excess) and that large specimens (if any) are incised prior to fixation to promote efficient tissue preservation.
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embedding in paraffin for pd-l1

An overnight processing schedule into paraffin wax is recommended Below is the suggested routine overnight processing schedule
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storage of tumor blocks for

FFPE blocks should be stored at ambient temperature and protected from light until shipment by courier at ambient temperature. FFPE blocks are stable under these conditions for an indefinite period.  
Quality control of samples to be used for PD-L1 testing Tissue should be assessed by the site pathologist prior to PD-L1 testing. Each sample should be reviewed for:
Adequate fixation Good preservation of morphology Presence of tumor tissue  
Histopathology consistent with indication Greater than 100 tumor cells are required to determine PD-L1 status - tumor cell content must be reviewed prior to testing in order for PD-L1 obtain a valid result.
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if indicated shipping samples to

When submitting sample to for PD-L1 testing the recommendation is to ship the block in order for sectioning to occur at the laboratory. Blocks should be shipped - containing enough material to be provided to allow a minimum of 5, and preferably 10, sections to be cut (each 4 micron thick) to be used for PD-L1 testing.
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sectioning instructions

Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, unstained slides should be prepared from the paraffin-embedded tumor sample block as described below:
A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be provided for PD-L1 testing A new disposable microtome blade must be used for each block to prevent contamination between Slides are stable under these conditions for 6 months.  
patient samples Apply one section per slide to positively-charged Superfrost glass slides The sections should be dried overnight between room temperature and 37°C. Do not dry sections at temperatures above 37°C.  
Sections should be stored at ambient temperature and protected from light until use or shipment to testing lab by courier at ambient temperature. It is recommended that slides are cut freshly prior to PD-L1 testing and they are used within 90 days of being cut to obtain PD-L1 status Any additional FFPE tissue obtained that is not used for PD-L1 testing can be used for the following additional correlative assays:  
1. Tissue Immune Correlates - (FFPE or frozen tissue specimens) - pre-treated and posttreated samples can be analyzed by IHC (FFPE) for Epcam, TILs, CD4, CD8, Tregs, MDSCs, Macrophages, and monocytes. In addition, mesenchymal markers such as vimentin, TWIST, Snail, Slug, and Sip1 may also be assayed by IHC.  
2. Frozen tissue specimens or a single FFPE slide can be analyzed later for tumor mutational load through targeted sequencing panel.
Frozen tissue specimens or a single FFPE slide for gene expression using HT Seq immuneoncology panel of 500+ genes and/or microRNA analysis.  
| 5.2                                                  | SAMPLE COLLECTION SCHEDULE     |                                                                         |                                                                                                                                                                                          |                                                                            |
|------------------------------------------------------|--------------------------------|-------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|
| Test/assay                                           | Volume blood                   | Type of                                                                 | Collection                                                                                                                                                                               |                                                                            |
| (approx)                                             | tube a                         | point (+/- 7  days)                                                     | Location of  specimen analysis                                                                                                                                                           |                                                                            |
| 50-100 mLs                                           | Urine  specimen  cup           |                                                                         |                                                                                                                                                                                          |                                                                            |
| Urine collection  for Urinary  Cytokines             | Baseline, 3  months, 6  months | Stored and processed  in Linehan Lab  (Appendix E) using  Luminex Assay |                                                                                                                                                                                          |                                                                            |
| (Section 5.1.2) Serum collection  for cytokines      | 20 mLs                         | 2 Red Top  (SST)  Tubes                                                 | Baseline, 2  weeks, 3 weeks,  5 weeks                                                                                                                                                    | Stored in Dr. Figg's  Lab and processed by  Dr. Liang Cao's lab            |
| (section 5.1.1) Plasma collection  for soluble PD-L1 | 6 mLs                          | EDTA                                                                    | Baseline, 2  weeks, 3 weeks,  5 weeks                                                                                                                                                    | Stored in Dr. Figg's  Lab and processed by  Dr. Liang Cao's lab            |
| (secion 5.1.1) Urinary PK for  Vicineum              | 50-100 mLs                     | Urine  specimen  cup                                                    | Baseline, First  void after Week  1 Vicineum,  First void  morning after  Week 1  Vicineum, Day  8 void prior to  Week 2  Vicineum                                                       | Stored in Linehan  Lab (Appendix E)  and processed by Dr.  Liang Cao's Lab |
| (Section 5.1.2.2) Urinary EpCAM                      | 50-100 mLs                     | Urine  specimen  cup                                                    | Baseline, First  void after Week  1 Vicineum,  First void  morning after  Week 1  Vicineum, Day  8 void prior to  Week 2  Vicineum,  Week 6 before  Vicineum,  Week 10 before  Vicineum, | Stored in Linehan  Lab (Appendix E)  and processed by Dr.  Liang Cao's Lab |
| (Section 5.1.2.2)                                    |                                |                                                                         |                                                                                                                                                                                          |                                                                            |  
| Version Date: 01/10/2023 Test/assay Volume blood                                                                                                          | Type of                              | Collection                                                                                         |                                         |                                                                             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|----------------------------------------------------------------------------------------------------|-----------------------------------------|-----------------------------------------------------------------------------|
| (approx)                                                                                                                                                  | tube a                               | point (+/- 7  days)                                                                                | Location of  specimen analysis          |                                                                             |
| Week 12 before  Vicineum                                                                                                                                  |                                      |                                                                                                    |                                         |                                                                             |
| Gene Expression                                                                                                                                           | Single FFPE  slide or frozen  tissue | N/A                                                                                                | Baseline                                | Stored in Linehan  Lab and processed by  Dr. Jane Trepel's lab  or NCI CORE |
| (see section 5.4.1) Tissue IHC                                                                                                                            | Single FFPE                          | N/A                                                                                                | Baseline, Last                          | Will be obtained from                                                       |
| slide                                                                                                                                                     | Biopsy on Trial                      | tissue blocks in  Laboratory of  Pathology and  analyzed by Dr.  Merino (Laboratory  of Pathology) |                                         |                                                                             |
| (see section 5.1.2) RNAseq and/or  DNA mutational  panel for  mutational load                                                                             | Single FFPE  slide or frozen  tissue | N/A                                                                                                | Baseline                                | NCI CORE facility or  outside entity  (Foundation  Medicine)                |
| (see section 5.1.2) PBMCs for  immune subsets,  antigen specific  responses (section  5.1.1.2)                                                            | 60 mL                                | 6 green top                                                                                        | Baseline, 3                             |                                                                             |
| Tubes                                                                                                                                                     | months, 6  months                    | Schlom Laboratory  (Deliver to Frederick  Lab)                                                     |                                         |                                                                             |
| Immunogenic  Assessment  (ADA, AVA)                                                                                                                       | 8 mL                                 | 2 lithium  heparin (4  mL each)  tubes                                                             | Baseline, Week  8 (ADA), Week  12 (AVA) | Linehan Laboratory  in collaboration with  AZ and Sesen  Biotherapeutics    |
| (section 5.1.1.2) a. Please note that tubes and media may be substituted based on availability with the permission of the PI or  laboratory investigator. |                                      |                                                                                                    |                                         |                                                                             |
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5.3 sample storage tracking and

Samples will be ordered in CRIS and tracked through Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside the NIH without appropriate approvals and/or agreements, if required.
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5.3.1 uob research laboratory

All specimens obtained for research purposes will be coded upon arrival in the UOB research laboratory to maintain patient confidentiality. All samples will be accessioned and entered into a database (such as LabMatrix) with access limited to the PI and UOB research data managers. The location of all samples will be carefully tracked in the database. All stored samples will be coded and identifying patient information will not be placed on sample containers. Stored samples will be kept in freezers/refrigerators or secure containers located in the Urologic Oncology Branch research laboratories or in approved storage facilities. The research samples collected will be used for the correlative/biomarker studies mentioned above in Section 5.1. Tissue slides/blocks may be obtained in order to determine protocol eligibility. Tissues are submitted to the NCI Laboratory of Pathology at the NIH Clinical Center for clinical determination of histologic features. Specialized stains/assays may be used to clarify tissue phenotype. After completion of analysis, tissue slides/blocks are either returned to the originating pathology department or archived in the Laboratory of Pathology or Urologic Oncology Branch and tracked in the UOB database (LabMatrix). Archived material will be retained for the duration of the study unless the originating pathology department requests return. Coded/anonymous samples with minimal clinical information may be shared with qualified NIH and non-NIH researchers who have IRB-approved protocols with similar research objectives. No personal identifying information such as name, address, or date of birth will be provided to the non-UOB investigator. In the event a subject is eligible to participate in a clinical trial based on tumor characteristics, coded tissue samples may be sent to an outside laboratory.
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5.3.2 samples (serum samples for

Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data entered and stored in the Labmatrix utilized by the CPP. This is a secure program, with access to Labmatrix limited to defined CPP personnel, who are issued individual user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without Labmatrix access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the Clinical Center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.).  
5.3.2.2 Procedures for sample storage at the Clinical Pharmacology Program:
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20oC or - 80oC
according to stability requirements. These freezers are located onsite in the CPP and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned to the CPP. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval.  
Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If, at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested. The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section **7.2.1**. Sample barcodes are linked to patient demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the Labmatrix. It is critical that the sample remains linked to patient information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variables.
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5.3.3 clinical services program

All data associated with the patient samples is protected by using a secure database. All samples drawn at the NIH Clinical Center will be transported to the NCI Frederick Central Repository by couriers. Samples will be tracked and managed by the Central Repository database. All samples will be stored in liquid nitrogen. These freezers are located at NCI Frederick Central Repository in Frederick, Maryland. NCI Frederick Central Repositories (managed under a subcontract) store, among other things, biological specimens in support of NIH clinical studies. All specimens are stored in secure, limited access facilities with sufficient security, back-up and emergency support capability and monitoring to ensure long-term integrity of the specimens for research. The subcontractor's role is limited to clinical research databases and repositories containing patient specimens. The subcontractor neither conducts nor has any vested interest in research on human subjects, but does provide services and supports the efforts of its customers, many of which are involved in research on human subjects. It is the intent and purpose of the subcontractor to accept only codedsamples and sample information. If the coded data are linked, the code key will not be accepted.To the best of our ability, every effort will be made to ensure that protected information is not sent electronically or by hard copy or on vial labels. Sample data is stored in the BioSpecimen Inventory (BSI) System II. This inventory tracking system is used to manage the storage and retrieval of specimens as well as maintain specimen data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user environment for tracking millions of specimens. The system controls how and in what order database updates and searches are performed. This control prevents deadlocks and race conditions. For security, BSI has user password access, 3 types of user access levels, and 36 user permissions (levels of access) that can be set to control access to the system functions. BSI provides audit tracking for processes that are done to specimens including shipping, returning to inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for specimens received by the repository. If a specimen goes out of the inventory, the system maintains data associated with the withdrawal request. Vials are labeled with a unique BSI ID which is printed in both eye-readable and bar-coded format. No patient-specific information is encoded in this ID. Investigators are granted view, input and withdrawal authority only for their specimens. They may not view specimen data or access specimens for which they have not been authorized. Access to specimen storage is confined to repository staff. Visitors to the repositories are escorted by repository staff at all times.
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5.3.4 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. Any specimens remaining at the completion of the protocol will be stored in the conditions described above. The study will remain open as long as sample or data analysis continues. Samples will be stored until they are no longer of scientific value or until a subject withdraws consent for their continued use, at which time they will be destroyed. If the patient withdraws consent, the participants data will be excluded from future distributions but data that have already been distributed for approved research use will not be able to be retrieved.  
Once primary research objectives for the protocol are achieved, intramural researchers can request access to remaining samples, provided they have an IRB-approved protocol and patient consent or an exemption from OHSRP. The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section 7.2.
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5.4 samples for genetic/genomic analysis

Protein, DNA mutational analysis, and miRNA/mRNA for immune gene expression profile analysis (quantitative polymerase chain reaction [Q-PCR]) of known and putative targets obtained from tumor tissue at baseline if adequate tumor tissue is available for such an analysis. The analysis will be performed through one of the following platforms:  
Targeted DNA mutational panel from frozen tissue or FFPE via NCI Core facility, collaborator (Paul Meltzer), or outside entity (e.g. Foundation Medicine) if adequate funding and tissue available HT seq from single FFPE slide for immune-oncology panel of 500+ genes or microRNA analysis - NCI CORE facility or Jane Trepel Nanostring panel for immune oncology related genes obtained from tumor tissue
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5.4.2 description of how privacy

Using a computerized inventory system (LabMatrix), each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected but personal identifiers will be removed.  
For each specimen, the corresponding subject demographics and clinical information will be assigned in the database as described in section 6.1 and only be accessible by the PI and research nurses within the UOB through a password-protected database. Samples provided to other researchers will be bar coded and these researchers will not have access to any information in LabMatrix. Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required. Data from genomic analysis will be deposited in dbGAP.
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5.4.3 management of results

Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects will be contacted at this time with a request to provide a sample to be sent to a CLIA certified laboratory. If the research findings are verified in the CLIA certified lab, the subject will be offered the opportunity to come to NIH (at our expense) to have genetic education and counseling to explain this result. If the subject does not want to come to NIH, a referral to a local genetic healthcare provider will be provided (at their expense). This is the only time during the course of the study that incidental findings will be returned. No interrogations regarding clinically actionable findings will be made after the primary analysis. Note: incidental findings considered clinically relevant will be discussed among Senior Scientific Staff at meetings such as the weekly UOB conference prior to being communicated to subjects.
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5.4.4 genetic counseling

Genetic counseling will be recommended should any clinically relevant incidental findings be discovered and consultation with the NCI Genetics Branch will be offered.
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6 data collection and evaluation

The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Document AEs from the first study intervention, Week 1/Day 1, through 90 days after the last administration of the study intervention. After 90 days, only adverse events which are serious and related to the study intervention need to be recorded. An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any of the following:  
Results in discontinuation from the study Is associated with clinical signs or symptoms Requires treatment or any other therapeutic intervention Is associated with death or another serious adverse event, including hospitalization. Is judged by the Investigator to be of significant clinical impact If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section **7.2.1**.
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6.2 data sharing plans 6.2.1

I will share human data generated in this research for future research as follows:
Coded, linked data in an NIH-funded or approved public repository.  
Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
Coded, linked or identified data with approved outside collaborators under appropriate agreements.
How and where will the data be shared? Data will be shared through:  
An NIH-funded or approved public repository. Insert name or names: clinicaltrials.gov, dbGaP.  
BTRIS (automatic for activities in the Clinical Center)
Approved outside collaborators under appropriate individual agreements.  
Publication and/or public presentations.
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when will the data be

Before publication.  
At the time of publication or shortly thereafter.
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6.2.2 genomic data sharing plan

Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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6.2.3 response criteria

Patients will be evaluated every 3 months as per standard of care with cystoscopy. Biopsy will be done at PI discretion pending cystoscopic findings. Any biopsies done will be for clinical reasons to rule out tumor recurrence, however, extra biopsy material if available will be used for research purposes. Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with vicineum or durvalumab. All observed toxicities will be tabulated using CTCAE v5.0.
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6.2.4 evaluable for objective secondary

Only those patients who have biopsy-proven disease present at baseline, have received at least one intravesical dose of Vicineum therapy and one intravenous dose of durvalumab, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. 6.2.4.1 Recurrence-free survival The recurrence-free survival duration will be measured from the start of Vicineum therapy until disease recurrence, progression, or death due to any cause. Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a TURBT. Positive cytology in the absence of pathologic confirmation is not considered to be a recurrence. Low grade papillary tumor will not be considered recurrent disease. 6.2.4.2 Complete Response Rate for CIS In patients with any component of CIS upon study entry, the complete response (CR) rate will be determined at 3 months, 6 months, and 12 months from the start of Vicineum therapy. Complete response will be defined as the absence of CIS upon follow-up biospies. These rates can be compared to historical rates of CR for CIS at these various time points.  
6.2.4.3 Disease Progression & Progression-Free Survival PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. The duration of progression-free survival is measured from the start of vicineum therapy until progression or death due to any cause. Disease progression is defined as upstaging from a lower stage to a higher stage (e.g., Ta to T1-T4 or T1 to T2-4; CIS to T1 or CIS to T2-T4; or any N+ or M+ in these high grade tumors). 6.2.4.4 Time to Tumor Recurrence The duration of time measured from the start of Vicineum therapy until recurrence is noted.
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6.3 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50).
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7 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research Events found at:
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835\#Policies&Guidance800Series-ComplianceandResearchEventReportingRequirements.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found at:
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835\#Policies&Guidance800Series-ComplianceandResearchEventReportingRequirements.  
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies.
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7.2.2 irb requirements for pi

Please refer to the reporting requirements in Policy 801: Reporting Research Events found at:
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835\#Policies&Guidance800Series-ComplianceandResearchEventReportingRequirements.
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7.3 nci clinical director reporting

Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to the NCI Clinical Director/designee; therefore, a separate submission for these reports is not necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 nih required data and

The clinical research team will meet on a regular weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section **7.2.1** will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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8 sponsor safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2)).
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8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
Death, A life-threatening adverse event (see **8.1.3**) Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient or subject convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.3 life-threatening

An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32).
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8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
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8.1.5 relationship to study product

All AEs will have their relationship to study product assessed using the terms: related or not related.  
Related - There is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
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8.1.6 adverse events of special

An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding of the Investigational Product and may require close monitoring and rapid communication by the investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and understand them in association with the use of this investigational product. AESIs for durvalumab include but are not limited to events with a potential inflammatory or immune-mediated mechanism and which may require more frequent monitoring and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is associated with drug exposure and is consistent with an immune-mediated mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  
In the event of imAE or suspected imAE, the AstraZeneca study team may request relevant clinical information (including images) for those subjects who demonstrate the event, and may request the independent review by external experts based on the acquired clinical information. AESIs observed with durvalumab include:
Diarrhea / Colitis and intestinal perforation  
Pneumonitis / ILD
hepatitis / transaminase increases Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and hypothyroidism and type I diabetes mellitus)
Rash / Dermatitis Nephritis / Blood creatinine increases Pancreatitis / serum lipase and amylase increases Myositis / Polymyositis Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) Intestinal Perforations
Other inflammatory responses that are rare/less frequent with a potential immune-mediated etiology include, but are not limited to:
Myocarditis  
Pericarditis Sarcoidosis Uveitis Other events involving the eye and skin Hematological events Rheumatological events Vasculitis Non-infectious meningitis Non-infectious encephalitis Pemphigoid  
It is possible that events with an inflammatory or immune mediated mechanism could occur in nearly all organs. In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different underlying pharmacological aetiology are also considered AESIs. Further information on these risks (e.g., presenting symptoms) can be found in the current version of the durvalumab Investigator's Brochure. More specific guidelines for their evaluation and treatment are described in detail in the Dosing Modification and Toxicity Management Guidelines (see **Appendix C**). These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs considered causally related to the study drug/study regimen by the reporting investigator.
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:  
Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor.
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8.3 reporting of serious adverse

Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. All SAE reporting must include the elements described in 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 safety reporting criteria to

All SAEs will be reported, whether or not considered causally related to the investigational product, or to the study procedure(s). The reporting period for SAEs is the period immediately following the time that written informed consent is obtained through 90 days after the last dose of durvalumab or until the initiation of alternative anticancer therapy. The investigator and/or Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE as per local requirements. The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any serious or unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A copy of the MedWatch/AdEERs report must be emailed to AstraZeneca at the time the event is reported to the FDA. It is the responsibility of the sponsor to compile all necessary information and ensure that the FDA receives a report according to the FDA reporting requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the same time. * A cover page should accompany the MedWatch/AdEERs form indicating the following:  
"Notification from an Investigator Sponsored Study" The investigator IND number assigned by the FDA
The investigator's name and address The trial name/title and AstraZeneca ISS reference number (ESR-\#\#-\#\#\#\#\#)
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in relation to all study medications and if the SAE is related to disease progression, as determined by the principal investigator. * Send SAE report and accompanying cover page by way of email to AstraZeneca's designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided to AstraZeneca and the FDA. 8.4.1.2 Safety Reports sent by the Study Team Serious adverse events that do not require expedited reporting to the FDA still need to be reported to AstraZeneca preferably using the MedDRA coding language for serious adverse events. This information should be reported on a monthly basis and under no circumstance less frequently than quarterly. In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of the randomization code/ code break information or unblind those SAEs which require expedited reporting.  
On a monthly basis, non-expedited SAEs will be provided to Collaborator Patient Safety Department via fax at: (301) 398-4205 and email to: drugsafety@medimmune.com and AEMailboxClinicalTrialTCS@astrazeneca.com.
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8.4.2 safety reporting criteria to

As soon as the investigator becomes aware that an adverse event meets the criteria for being a serious adverse event (SAE) the following is required:  
The investigator will notify Sesen Biotherapeutics within twenty-four (24) hours of becoming aware of the SAE by submitting a completed SAE form and any supporting documentation to Sesen Biotherapeutics.  
The SAE form and supporting documentation should be scanned and emailed to Sesen Biotherapeutics at with joycelyn.entwistle@sesenbio.com and rachelle.dillon@sesenbio.com.  
Follow-up information must be submitted in a timely fashion
All suspected unexpected serious adverse reactions (SUSARs), also called serious and unexpected suspected adverse reaction (i.e., serious, unexpected and related SAEs), must be reported to all appropriate regulatory authorities and IRBs/Ethics Committees as required by 21 CFR 312.32 utilizing the MedWatch 3500A form or the CIOMS-1. The final forms for the initial and all follow-up reports must be submitted within two (2) business days of submission to the FDA or other health authorities. These reports should be scanned and emailed to Sesen Biotherapeutics at joycelyn.entwistle@sesenbio.com and rachelle.dillon@sesenbio.com.
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8.5 reporting pregnancy

All required pregnancy reports/follow-up to OSRO will be submitted to: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions can be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
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8.5.1 maternal exposure

If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section **8.1.2**) should be reported as SAEs. The outcome of all pregnancies should be followed up and documented.
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8.5.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 120 days after the last dose of Durvalumab and Vicineum. Pregnancy of the patient's partner is not considered to be an AE. The outcome of all pregnancies occurring from the date of the first dose until 120 days after the last dose should, if possible, be followed up and documented. Pregnant partners may be offered the opportunity to participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to provide data about the outcome of the pregnancy for safety reporting purposes.
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8.6 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format.
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8.7 sponsor protocol deviation reporting

A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or protocol-specific procedural requirements on the part of the participant, the Investigator, or the study site staff inclusive of site personnel performing procedures or providing services in support of the clinical trial. It is the responsibility of the study Staff to document any protocol deviation identified by the Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. The entries into the PDTS online application should be timely, complete, and maintained per CCR PDTS user requirements. In addition, any deviation to the protocol should be documented in the participant's source records and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
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9 clinical monitoring plan

Clinical site monitoring is conducted to ensure:  
that the rights of the participants are protected; that the study is implemented per the approved protocol, Good Clinical Practice and standard operating procedures; and, the quality and integrity of study data and data collection methods are maintained.
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory requirements.  
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human subject protections and integrity of the study data. OSRO will determine the intensity and frequency of monitoring based on several factors, including study type, phase, risk, complexity, expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger CMP updates. OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit (SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close-Out Visit (COV). Some monitoring activities may be performed remotely, while others will occur at the study site(s). Monitoring visit reports will describe visit activities, observations, and associated action items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating center (if applicable), and the Sponsor regulatory file. The site Monitor will inform the study team of any deviations observed during monitoring visits. If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per institutional and IRB guidance.
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10 statistical considerations 10.1 statistical

The primary objective of this trial is to determine whether the use of a combination of Vicineum and durvalumab in patients with high grade NMIBC previously treated with BCG is safe and tolerable as determined by a 3+3 dose de-escalation trial design. The primary endpoint will be the fraction of patients who have adverse events.
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secondary endpoints

A secondary endpoint will be to determine if the combination of the two agents can be associated with an increase in the disease-free survival (DFS) probability in patients with high grade NMIBC previously treated with BCG. If accrual is rapid, an amendment may be made to accrue additional patients to evaluate DFS as described in section **10.2**. A secondary objective is whether the combination is associated with changes in a set of immune parameters obtained from blood and biopsies. A secondary objective is whether the pharmacokinetics of Vicineum can be determined from urine samples obtained within the first 7 days of Vicineum treatment. A secondary objective is whether urinary EpCAM levels correlate with response to therapy. A secondary objective is to 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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10.2 sample size determination

The trial will begin with a 3-patient run-in at the proposed doses of Vicineum and durvalumab (1500mg; 30 mg) and if 0/3 or 1/3 patients have a DLT, then the next 3 patients will also be treated at the full doses of the agents (1500mg durvalumab; 30 mg Vicineum). If 0/6 or 1/6 has a DLT, then the remaining 18 patients will be treated at the full doses if the cumulative fraction of patients experiencing a DLT is <1/3. If 2 or more patients among 3 to 6 have a DLT at 1500mg durvalumab and 30mg Vicineum, then 3 patients will be enrolled at the lower dose level (1500mg durvalumab and 20mg Vicineum),
and if 0/3 or 1/3 patients have a DLT, then the next 3 patients will also be treated at the reduced doses of the agents. If 1/6 has a DLT, then the remaining patients will be treated at the lower dose level of the agents (1500mg durvalumab and 20mg Vicineum) if the cumulative fraction of patients experiencing a DLT is <1/3. As the secondary endpoint, all the evaluable patients will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. The changes in the parameters obtained from biopsies will be obtained from baseline vs. a single second biopsy at 6 months. A very large number of parameters may be evaluated, and unless more parameters than anticipated are to be evaluated, we will assume that 24 patients will be adequate to evaluate changes in these parameters based on the following. As an illustration, we will assume that a total of 25 paired tests will be considered of equal, primary importance. Paired results from 24 evaluable patients, including those used in the initial run-in portion who are treated at the highest safe dose, will provide 90% power to detect a change from baseline of 1.0 SD of the change (effect size=1.0) using a two-sided 0.002 significance level paired t-test, to allow an overall 0.05 significance level test, applying a very conservative Bonferroni adjustment to the set of approximately 25 paired comparisons. In practice, comparisons of the paired values will likely be performed using a Wilcoxon signed rank test instead of a paired t-test, and a Hochberg adjustment may be used instead of an overly stringent Bonferroni adjustment. If accrual is sufficiently rapid, that is, if the 24 evaluable patients can be accrued within 2.5 years, then these 24 patients will be included in an expansion cohort, opened by an amendment to the study, designed to evaluate DFS, as follows that would allow for the enrollment of an additional 23 patients: It has been estimated from published trials that the 6 month DFS in patients with high grade NMIBC previously treated with BCG is approximately 50%, and that it is 35% at 12 months, and 25% at 18 months. In this expansion cohort, the goal is to determine if use of a combination of Vicineum and durvalumab can be potentially associated with a 50% 1-year DFS probability. With 47 evaluable patients receiving the proposed therapy, including those in the initial 6 patients at the intended dose level as well as those in the evaluation of biologic endpoints, assuming accrual would take place over approximately 4 years, and that there would be at least 2 years of additional potential follow-up after the last patient has begun the therapy, there would be 80% power to determine whether there is a difference between a 35% 1 year DFS and an improved 50% 1-year DFS, with a one sided 0.10 alpha level test, using the method of Brookmeyer and Crowley.33 In practice, Kaplan-Meier curves and appropriate confidence intervals at selected time points will be provided to help interpret results relative to the expected results.  
It is anticipated that one patient per month may enroll onto this trial; thus, allowing for 6 to 12 separate patients as a run-in if needed, and 24 evaluable patients at the intended dose level, approximately 24-30 months would be the approximate accrual duration for the secondary endpoint based on evaluating biologic correlates. To allow for a small number of invaluable patients, the accrual ceiling will be set at 40. If the expansion to evaluate DFS will be undertaken, this will be modified by an amendment.
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10.3 populations for analysis

Modified intention to treat: all patients who receive at least one dose of the two drugs will be included in the statistical analyses performed.
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10.4 statistical analyses 10.4.1 general

For the toxicity evaluation, the fraction of patients with toxicity will be determined and reported at each of the dose levels explored. The immune parameters will be obtained at baseline, 3 months, and 6 months and for each parameter, the change between baseline and the later time points will be calculated and evaluated for the statistical significance of the change. If the disease-free survival (DFS) is evaluated, a Kaplan-Meier curve for DFS will be constructed.
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10.4.2 analysis of the primary

All patients will be evaluated for the grades of toxicity identified, and the number of patients will DLTs at each dose level will be reported. The MTD will be identified based on being the dose level at which 0 or 1 patient in 6 has a DLT. All toxicities will be tabulated for all 24 or more patients to be enrolled onto the trial.
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10.4.3 analysis of the secondary

Efficacy: A DFS curve will be created using the Kaplan-Meier method based on all patients considered to be evaluable based on having received protocol treatment, provided that adequate patients are enrolled in order to address this following an amendment to increase accrual. The response to treatment will be determined for patients who receive treatment; the response rate for those patients who are evaluable for response, along with a 95% two-sided confidence interval will be reported. As another secondary endpoint, all the evaluable patients will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. The changes in the parameters obtained from biopsies will be obtained from baseline vs. a single second biopsy at 6 months. As an illustration, we will assume that a total of 25 paired tests will be considered of equal, primary importance. Paired results from 24 evaluable patients, including those used in the initial run-in portion who are treated at the highest safe dose, will be formed and tested for a difference from zero using a two-sided 0.002 significance level paired t-test, to  
allow an overall 0.05 significance level test, applying a very conservative Bonferroni adjustment to the set of approximately 25 paired comparisons. In practice, comparisons of the paired values will likely be performed using a Wilcoxon signed rank test instead of a paired t-test, and a Hochberg adjustment may be used instead of an overly stringent Bonferroni adjustment.  
Another secondary objective is to evaluate the pharmacokinetic parameters of Vicineum obtained by urine samples. This will be a descriptive analysis and will report sample statistics such as mean, standard error, median, minimum, maximum and other descriptive measures only. Urinary EpCAM will be measured and will be compared between patients who have a clinical response to therapy vs. those who do not respond. The results will be presented for both response categories using descriptive statistics such as mean, standard error, median, minimum, maximum and other descriptive measures. Although it is expected to have low power, a comparison of the EpCAM levels may be compared between the two response categories using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted. PD-L1 and PD-1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders, as well as between those who respond or have SD (clinical benefit=CR+PR+SD) and those with PD. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
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10.4.4 safety analyses

All patients will be evaluated for the grades of toxicity identified, and the number of patients will DLTs at each dose level will be reported. The MTD will be identified based on being the dose level at which 0 or 1 patient in 6 has a DLT. All toxicities will be tabulated.
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10.4.5 baseline descriptive statistics

Demographic and clinical characteristics of all patients will be reported. 10.4.6 Planned Interim Analyses None will be performed. 10.4.7 Subgroup Analyses None will be performed. 10.4.8 Tabulation of Individual Participant Data None will be provided.
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11 collaborative agreements 11.1 cooperative

This Protocol will be carried out under a collaboration between NCI, Sesen Biotherapeutics Inc. and AstraZeneca AB. Sesen Biotherapeutics will provide Vicineum (VB4-845) under NCI CRADA \#3149, and AstraZeneca will provide Durvalumab (MEDI 4736) under NCI CRADA \#3155.
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12 human subjects protections 12.1

Subjects from all racial/ethnic groups and both genders are eligible for this study if they meet the eligibility criteria.
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12.2 participation of children

Individuals under the age of 18 will not be eligible for participation in this study based on the fact that patients under 18 are unlikely to have this disease and there are unknown toxicities in pediatric patients.
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12.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **12.4**), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subject and to identify an LAR. Please see section **12.5.1** for the consent procedure.
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12.4 evaluation of benefits and

Patients may benefit from the study as treatment may delay or avoid having the bladder removed. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. Patients will be examined and evaluated prior to enrollment. All evaluations to monitor the treatment of patients will be recorded in the patient chart. If patients suffer any physical injury as a result of the participation in this study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations. In all publications and presentations resulting from this trial, patients' anonymity will be protected to the maximum extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug Administration (FDA) or other regulatory authorities may have access to research files in order to verify that patients' rights have been safeguarded. In addition, patient names will be given to the Central Registration to register and verify patients' eligibility.
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12.4.1 study agents risks

Potential adverse reactions attributable to the administration of the study agents utilized in this trial are discussed in sections **14.1.2** and **14.2.2**. Additional information is located in the investigator brochures.
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12.4.2 research blood sampling risks

Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
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12.4.3 risks from bladder procedures

Risks associated with cystoscopy, TURBT, biopsies and catheterization include: burning when passing urine, blood-tinged urine, bladder infection or the need to urinate frequently following the procedures. The insertion of a catheter into the bladder through the urethra may cause discomfort. There is also a small risk that these procedures, particularly cystoscopy, TURBT and biopsies, could damage the lining of the bladder or cause a perforation of the bladder. This could lead to urine or drugs leaking out of the bladder causing severe side effects.
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12.4.4 non-physical risks of genetic

Risk of receiving unwanted information: Anxiety and stress may arise as a result of the anticipation of unwanted information regarding disease. Subjects will be clearly informed that the data related to genetic analysis is coded, investigational and will not be shared with family members or health care providers. However, as specified above in Section **5.4.3**, subjects who have indicated a desire to be informed of these data will be given an opportunity.  
Risk related to possibility that information may be released: This includes the risk that data related to genotype or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies.  
Risk to family or relatives: Family members or relatives may or may not want to be aware of familial tendencies or genetic risks of disease which may cause anxiety about possible future health problems.
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12.4.5 radiation risks

The risk of radiation exposure is expected from up to 1 CT scan a year. The total estimated effective dose for one year is approximately 1.4 rem.
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12.4.6 ct contrast risks

Itching, hives or headaches are possible risks associated with contrast agents that may be used during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath and swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT can cause kidney problems for certain patients, such as those with impaired kidney function.
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12.4.7 electrocardiogram risks

Other than possibly experiencing some minor skin irritation from the electrodes, there are no anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
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12.5 consent process and documentation

The informed consent document will be provided as a physical or electronic document to the participant or consent designee(s) (e.g. legally authorized representative [LAR] if participant is an adult unable to consent) for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes the printout of an electronic document sent to participant) or on the electronic document. Signatures on electronic documents are described below. Note: FDA only regulates electronic signatures (i.e., an electronic timestamp is generated at the time of signature) in FDA regulated research. Manual (non-electronic) signature on electronic document: When a manual signature on an electronic document is used for the documentation of consent at the NIH Clinical Center, this study will use the following to obtain the required signatures:
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the approved consent document on screens at their respective locations (if remote consent); the same screen may be used when in the same location but is not required. Both the investigator and the participant will sign the document using a finger, stylus or mouse. Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process for additional information (e.g., verification of participant identity when obtaining consent remotely) found https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
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12.5.1 consent process for adults

For participants addressed in section **12.3**, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in section **12.5**.
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13 regulatory and operational considerations

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
Determination of unexpected, significant, or unacceptable risk to participants Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
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13.2 quality assurance and quality

The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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13.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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13.4 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant's contact information will be securely stored at the clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be stored at the NCI CCR. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical site and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NIH. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
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14 pharmaceutical information 14.1 durvalumab

Durvalumab will be supplied by the Investigational Products supply section of AstraZeneca/MedImmune under NCI CRADA \#3155. There are no manufacturing differences between the clinical supply that will be used in this study and the supply of marketed agent.
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14.1.2 toxicity

For additional information, refer to the investigator brochure.  
Table 1. F**requency of ADRs for Durvalumab Monotherapy From Pooled Data Across Multiple**  
Tumour Types (N=3006)  
| Tumour Types (N=3006) SOC PT/medical concept        | CIOMS frequency             |             |            |          |
|-----------------------------------------------------|-----------------------------|-------------|------------|----------|
| MedDRA (v24.0)                                      | indicator a /               |             |            |          |
| overall frequency all  CTC grades                   | All                         |             |            |          |
| CTCAE  Grades n (%)                                 | Grade 3  or 4 n (%)         |             |            |          |
| Respiratory,  thoracic, and  mediastinal  disorders | ILD                         | Uncommon    | 18 (0.6)   | 4 (0.1)  |
| b, c                                                | Common                      | 244 (8.1)   | 69 (2.3)   |          |
| Hepatobiliary                                       | ALT increased/AST increased |             |            |          |
| disorders                                           | Hepatitis b, c              | Uncommon    | 25 (0.8)   | 12 (0.4) |
| Diarrhea                                            | Very common                 | 491 (16.3)  | 19 (0.6)   |          |
| Abdominal pain b                                    | Very common                 | 383 (12.7)  | 53 (1.8)   |          |
| Colitis b                                           | Uncommon                    | 28 (0.9)    | 10 (0.3)   |          |
| Cough/productive cough b                            | Very common                 | 646 (21.5)  | 11 (0.4)   |          |
| Pneumonitis b,c                                     | Common                      | 114 (3.8)   | 26 (0.9)   |          |
| Dysphonia                                           | Common                      | 93 (3.1)    | 2 (<0.1)   |          |
| Gastrointestinal  disorders                         | Pancreatitis b              | Uncommon    | 6 (0.2)    | 5 (0.2)  |
| Endocrine  disorders                                | Hypothyroidism b            | Very common | 345 (11.5) | 5 (0.2)  |
| Hyperthyroidism b                                   | Common                      | 164 (5.5)   | 0          |          |
| Thyroiditis b                                       | Uncommon                    | 23 (0.8)    | 2 (<0.1)   |          |
| Adrenal insufficiency                               | Uncommon                    | 18 (0.6)    | 3 (<0.1)   |          |
| Type 1 diabetes mellitus                            | Rare                        | 1 (<0.1)    | 1 (<0.1)   |          |
| Hypophysitis/Hypopituitarism  b                     | Rare                        | 2 (<0.1)    | 2 (<0.1)   |          |
| Diabetes insipidus                                  | Rare                        | 1 (<0.1)    | 1 (<0.1)   |          |
| Renal and  urinary disorders                        | Dysuria                     | Common      | 39 (1.3)   | 0        |
| Blood creatinine increased                          | Common                      | 105 (3.5)   | 3 (<0.1)   |          |
| Nephritis b                                         | Uncommon                    | 9 (0.3)     | 2 (<0.1)   |          |
| Skin and  subcutaneous  tissue disorders            | Rash b                      | Very common | 480 (16.0) | 18 (0.6) |
| Pruritus                                            | Very common                 | 325 (10.8)  | 1 (<0.1)   |          |
| Night sweats                                        | Common                      | 47 (1.6)    | 1 (<0.1)   |          |
| Dermatitis b                                        | Uncommon                    | 22 (0.7)    | 2 (<0.1)   |          |
| Pemphigoid b                                        | Rare                        | 3 (<0.1)    | 0          |          |
| Cardiac disorders                                   | Myocarditis                 | Rare        | 1 (<0.1)   | 1 (<0.1) |
| General                                             | Pyrexia                     | Very common | 414 (13.8) | 10 (0.3) |
| disorders and  administration                       | edema peripheral b          | Common      | 291 (9.7)  | 9 (0.3)  |
| site conditions                                     |                             |             |            |          |  
| SOC                                                                                                                   | PT/medical concept                    | CIOMS frequency   |            |          |
|-----------------------------------------------------------------------------------------------------------------------|---------------------------------------|-------------------|------------|----------|
| MedDRA (v24.0)                                                                                                        | indicator a /                         |                   |            |          |
| overall frequency all  CTC grades                                                                                     | All                                   |                   |            |          |
| CTCAE  Grades n (%)                                                                                                   | Grade 3  or 4 n (%)                   |                   |            |          |
| Infections and  infestations                                                                                          | Upper respiratory tract  infections b | Very common       | 407 (13.5) | 6 (0.2)  |
| Pneumonia b,c                                                                                                         | Common                                | 269 (8.9)         | 106 (3.5)  |          |
| Oral candidiasis                                                                                                      | Common                                | 64 (2.1)          | 0          |          |
| Dental and oral soft tissue  infections b                                                                             | Common                                | 50 (1.7)          | 1 (<0.1)   |          |
| Influenza                                                                                                             | Common                                | 47 (1.6)          | 2 (<0.1)   |          |
| Musculoskeletal  and connective                                                                                       | Myositis b                            | Uncommon          | 6 (0.2)    | 1 (<0.1) |
| tissue disorders                                                                                                      | Polymyositis d                        | Not determined    | -          | -        |
| Myasthenia gravis b, e                                                                                                | Not determined                        | -                 | -          |          |
| Nervous system  disorders                                                                                             | Encephalitis b, f                     | Not determined    | -          | -        |
| Myalgia                                                                                                               | Common                                | 178 (5.9)         | 2 (<0.1)   |          |
| Injury,  poisoning, and  procedural  complications                                                                    | Infusion related reaction b           | Common            | 49 (1.6)   | 5 (0.2)  |
| Blood and  lymphatic system                                                                                           | Immune thrombocytopenia c             | Rare              | 2 (<0.1)   | 1 (<0.1) |
| disorders a The corresponding frequency category for each ADR is based on the CIOMS III convention and is defined as: |                                       |                   |            |          |  
a The corresponding frequency category for each ADR is based on the CIOMS III convention and is defined as:
(1) very common (≥1/10); (2) common (≥1/100 to <1/10); (3) uncommon (≥1/1000 to <1/100); (4) rare (≥1/10000 to <1/1000); (5) very rare (<1/10000); not determined (cannot be estimated from available data).  
b Denotes a medical concept. See Table 31 of investigator brochure for individual PTs. c Fatal events have been reported.  
d Polymyositis (fatal) was observed in a patient treated with durvalumab from an ongoing AstraZenecasponsored clinical study outside of the pooled dataset.  
e Reported frequency from AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare, with no events at Grade >2.  
f Reported frequency from ongoing AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare and includes 2 events of encephalitis, one fatal (PT: Immune-mediated encephalitis) and one Grade 2 (PT: Autoimmune encephalitis).  
ADR = adverse drug reaction; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CIOMS = Council for International Organisations of Medical Sciences; CTCAE = Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease; MedDRA = Medical Dictionary for Regulatory Activities; n = number of patients; PT = preferred term; SOC = system organ class.  
Table 2. Serious Adverse Reactions for Durvalumab Monotherapy Considered Expected for Safety Reporting Purposes  
| for Safety Reporting Purposes                       | Number (%) of subjects  exposed (N=5208) Occurrence  of fatal  suspected  SARs n (%) b   |          |    |    |
|-----------------------------------------------------|------------------------------------------------------------------------------------------|----------|----|----|
| Pneumonitis                                         | 43 (0.8)                                                                                 | 0        | 0  |    |
| Respiratory,  thoracic, and  mediastinal  disorders | Occurrence of  life-threatening  suspected SARs n (%) b                                  |          |    |    |
| Suspected                                           |                                                                                          |          |    |    |
| MedDRA (v25.0)                                      | PT                                                                                       | SARs n   |    |    |
| SOC                                                 | (%) a                                                                                    |          |    |    |
| Interstitial lung disease                           | 10 (0.2)                                                                                 | 0        | 0  |    |
| Injury, poisoning,  and procedural  complications   | Infusion related reaction                                                                | 7 (0.1)  | 0  | 0  |
| Pneumonia                                           | 16 (0.3)                                                                                 | 0        | 0  |    |
| Infections and                                      | Pneumocystis jirovecii                                                                   | 2 (<0.1) | 0  | 0  |
| infestations                                        | pneumonia Colitis                                                                        | 12 (0.2) | 0  | 0  |
| Diarrhoea                                           | 13 (0.2)                                                                                 | 0        | 0  |    |
| Abdominal pain                                      | 3 (<0.1)                                                                                 | 0        | 0  |    |
| Gastrointestinal  disorders                         | Enterocolitis                                                                            | 3 (<0.1) | 0  | 0  |
| Pancreatitis                                        | 2 (<0.1)                                                                                 | 0        | 0  |    |
| Proctitis                                           | 2 (<0.1)                                                                                 | 0        | 0  |    |
| Adrenal insufficiency                               | 6 (0.1)                                                                                  | 0        | 0  |    |
| Hyperthyroidism                                     | 3 (<0.1)                                                                                 | 0        | 0  |    |
| Endocrine disorders                                 | Hypopituitarism                                                                          | 3 (<0.1) | 0  | 0  |
| Hypothyroidism                                      | 3 (<0.1)                                                                                 | 0        | 0  |    |
| Hepatitis                                           | 5 (<0.1)                                                                                 | 0        | 0  |    |
| Hepatobiliary  disorders                            | Autoimmune hepatitis                                                                     | 3 (<0.1) | 0  | 0  |
| Nephritis                                           | 3 (<0.1)                                                                                 | 0        | 0  |    |
| Renal and urinary  disorders                        | Blood creatinine                                                                         | 2 (<0.1) | 0  | 0  |
| increased AST increased                             | 6 (0.1)                                                                                  | 0        | 0  |    |
| Investigations                                      | ALT increased                                                                            | 5 (<0.1) | 0  | 0  |
| Hepatic enzyme                                      | 2 (<0.1)                                                                                 | 0        | 0  |    |
| increased Transaminases                             | 2 (<0.1)                                                                                 | 0        | 0  |    |
| increased                                           |                                                                                          |          |    |    |  
| Number (%) of subjects  exposed (N=5208) Occurrence of  life-threatening  suspected SARs n (%) b Occurrence  of fatal  suspected  SARs n (%) b   |                 |          |    |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|----------|----|----|
| Suspected                                                                                                                                        |                 |          |    |    |
| MedDRA (v25.0)                                                                                                                                   | PT              | SARs n   |    |    |
| SOC                                                                                                                                              | (%) a           |          |    |    |
| Pyrexia                                                                                                                                          | 5 (<0.1)        | 0        | 0  |    |
| General disorders  and administration  site conditions                                                                                           | Myositis        | 4 (<0.1) | 0  | 0  |
| Musculoskeletal and  connective tissue  disorders                                                                                                | Rash            | 4 (<0.1) | 0  | 0  |
| Skin and  subcutaneous tissue  disorders                                                                                                         | Immune          | 2 (<0.1) | 0  | 0  |
| thrombocytopenia                                                                                                                                 |                 |          |    |    |
| Blood and lymphatic  system disorders Metabolism and  nutrition disorders                                                                        | Type 1 diabetes | 2 (<0.1) | 0  | 0  |
| mellitus Myasthenia                                                                                                                              | 2 (<0.1)        | 0        | 0  |    |
| gravis                                                                                                                                           |                 |          |    |    |
| Nervous system  disorders a  n = number of patients who have experienced the SAR.                                                                |                 |          |    |    |  
b All fatal and all life-threatening events for durvalumab monotherapy are considered unexpected for reporting purposes and are excluded from this table. Pooled dataset from studies CD-ON-MEDI4736-1108, ATLANTIC, MYSTIC, EAGLE, ARCTIC, CONDOR, HAWK, PACIFIC, D4190C00002, BISCAY, STRONG, PACIFIC 6, DANUBE, HIMALAYA, KESTREL, NeoCOAST, D4190C00007, D4190C00021, D4190C00022, and D4198C00001. Only patients exposed to 10 mg/kg Q2W or 20 mg/kg Q4W durvalumab, or equivalent fixed dosing of durvalumab 750 mg Q2W or 1500 mg Q4W schedule, are included. ALT = alanine aminotransferase; AST = aspartate aminotransferase; DCO = data cut-off; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; Q2W = every 2 weeks; Q4W = every 4 weeks; SAR = serious adverse reaction; SOC = system organ class.
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14.1.2.1 other potential risks for

Hypersensitivity reactions and anaphylaxis are considered potential risks for durvalumab monotherapy and the durvalumab + tremelimumab combination. In the durvalumab monotherapy pooled dataset (N=3006), hypersensitivity/anaphylactic reactions (grouped term including  
reported PTs of hypersensitivity, drug hypersensitivity, drug eruption, anaphylactic shock, and anaphylactic reaction), were uncommonly reported in 28 patients (0.9%); 5 patients had Grade 3 or 4 events. Of the 28 patients, 16 patients had events of drug hypersensitivity (1 patient had a Grade 4 event), 5 patients had events of drug eruption (2 patients had Grade 3 events), 4 patients had events of hypersensitivity (Grade 1 or 2 events), 3 patients had events of anaphylactic reaction (1 patient had a Grade 4 event), and 1 patient had a Grade 2 event of anaphylactic shock.
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subcutaneous injection site reaction

Subcutaneous injection site reactions can occur via immune or non-immune mechanisms. A potential immunogenic mechanism could be due to antigen presentation and processing by lymph node and migratory cutaneous dendritic cells in the subcutaneous space. Non-immune mechanisms by which injection site reactions may arise can be related to biophysical characteristics of the drug and preservative/stabilizing agents. Patients should be closely monitored for signs and symptoms of subcutaneous injection site reactions including, but not limited to pain, blistering, induration, burning, and erythema at the site of injection.
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immunogenicity

As with the administration of any therapeutic protein, there is a potential for an immune response. The incidence of durvalumab ADA-positive patients in clinical studies is low. Overall, of the 4045 patients who were treated with durvalumab monotherapy 10 mg/kg Q2W, 20 mg/kg Q4W, or 1500 mg Q4W, 3069 patients were evaluable for the presence of ADAs, of which 6.2%
(191/3069) patients were ADA-positive at any visit and 2.7% (84/3069) patients were treatmentemergent ADA-positive. Neutralising antibodies against durvalumab were detected in 0.5%
(16/3069) patients. The presence of ADAs did not have a clinically relevant effect on PK. The presence of durvalumab ADA did not have an influence on durvalumab exposure metric, and there was no apparent effect on the safety of durvalumab.
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other rare or less frequent

Events with an inflammatory or immune mediated mechanism could occur in nearly all organs. Potential risks with an immune-mediated aetiology that are rare or less frequent include, but are not limited to, Guillain-Barre Syndrome, pericarditis, sarcoidosis, uveitis, cholangitis sclerosing, immune-mediated cystitis and other events involving the eye (eg, keratitis and optic neuritis),
skin (eg, scleroderma and vitiligo), haematological (eg, hemolytic anaemia and immunemediated neutropenia), rheumatological events (polymyalgia rheumatica and autoimmune arthritis), vasculitis, non-infectious meningitis and psoriasis.
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14.1.3 formulation packaging and storage

Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion after dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Durvalumab must be used within the individually assigned expiration date on the label.
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14.1.4 study drug preparation

The dose of durvalumab for administration must be prepared by the Investigator's or site's designated IP manager using aseptic technique. Total time from needle puncture of the durvalumab vial to the start of administration should not exceed:  
- 24 hours at 2°C to 8°C (36°F to 46°F) - 4 hours at room temperature
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion solutions must be allowed to equilibrate to room temperature prior to commencement of administration.
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14.1.7 accountability and dispensation

The investigator is responsible for keeping accurate records of the clinical supplies received, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion of the trial.
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14.1.8 disposition of unused investigational

Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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14.2 vicineum (ind # 136199)

Vicineum (investigational supply) will be supplied by Sesen Biotherapeutics under NCI CRADA
\#3149. Commercial supply will be provided for the study after the 31st Aug 2021.
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14.2.2 toxicity 14.2.2.1 phase 1/2

The most frequently reported treatment-related AEs were those associated with renal and urinary disorders (23.4% of subjects). Within this class, dysuria (14.1% of subjects) and hematuria (10.9% of subjects) were reported most frequently. All other AEs assessed as possibly, probably, or definitely related to Vicineum occurred in less than 10% of the subject population. Of the related systemic AEs, fatigue was reported as an AE by 7.8% of subjects and myalgia was reported by 4.7% of subjects.
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14.2.2.2 phase 2 trial (study

The most commonly reported treatment-emergent adverse events regardless of causality were associated with renal and urinary disorders, including dysuria (60.9% of subjects), hematuria (26.1% of subjects), pollakiuria (23.9% of subjects), micturition urgency (21.7% of subjects), nocturia (15.2% of subjects), incontinence (urge incontinence and urinary incontinence; 13.0% of subjects), urinary tract infections (13.0% of subjects), and bladder pain (10.9% of subjects).  
Other treatment related AEs that occurred in 10% or more of subjects were fatigue (21.7%), flulike symptoms (10.9%), fever (10.9%), joint pain (13%), and dizziness (10.9%).  
14.2.2.3 Phase 3 trial (Study No. VB4-845-02-IIIA) Table 3. Treatment-Emergent Adverse Events Considered Related to Vicineum occurring in ≥5% of subjects, VB4-845-02-IIIA  
| Adverse Event                                                                                                                                                                             | Grade 1 - 2   | Grade 3 - 4   | Grade 5   | Total    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|---------------|-----------|----------|
| Any Event Related to Vicineum                                                                                                                                                             | 61 (46%)      | 4 (3%)        | 1 (1%)    | 66 (50%) |
| Renal and Urinary Disorders                                                                                                                                                               | 45 (34%)      | 1 (1%)        | 1 (1%)    | 47 (35%) |
| Dysuria                                                                                                                                                                                   | 18 (14%)      | 0             | 0         | 18 (14%) |
| Haematuria                                                                                                                                                                                | 17 (13%)      | 0             | 0         | 17 (13%) |
| Pollakiuria                                                                                                                                                                               | 15 (11%)      | 0             | 0         | 15 (11%) |
| Micturition Urgency                                                                                                                                                                       | 15 (11%)      | 0             | 0         | 15 (11%) |
| General Disorders and                                                                                                                                                                     | 12 (9%)       | 0             | 0         | 12 (9%)  |
| Administration Site Conditions Fatigue                                                                                                                                                    | 10 (8%)       | 0             | 0         | 10 (8%)  |
| Gastrointestinal Disorders                                                                                                                                                                | 9 (7%)        | 0             | 0         | 9 (7%)   |
| Infections and Infestations                                                                                                                                                               | 15 (11%)      | 2 (2%)        | 0         | 17 (13%) |
| Urinary Tract Infection                                                                                                                                                                   | 14 (11%)      | 2 (2%)        | 0         | 16 (12%) |
| Investigations                                                                                                                                                                            | 7 (5%)        | 3 (2%)        | 0         | 10 (8%)  |
| Note: Treatment-emergent adverse events were assessed as possibly, probably, or definitely related to study treatment  per Investigator Data Source: VB4-845-02-IIIA Interim CSR Table 28 |               |               |           |          |
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table 4. serious adverse events

| Relationship  to Study   | Day of                                | Duration    |        |         |         |                             |
|--------------------------|---------------------------------------|-------------|--------|---------|---------|-----------------------------|
| Druga                    | Severity                              | Onsetb      | (days) | Outcome |         |                             |
| 70 / M                   | Pyelonephritis                        | Not related | Gr. 3  | Day 17  | 4       | Recovered/Resolved          |
| 76 / M                   | Asthma                                | Not related | Gr. 3  | Day 264 | 9       | Recovered/Resolved          |
| 91 / M                   | Hepatitis cholestatic                 | Related     | Gr. 4  | Day 46  | Ongoing | Not recovered/Not  resolved |
| Age/                     | Adverse Event                         |             |        |         |         |                             |
| Gender                   | (MedDRA Preferred Term) Renal failure | Related     | Gr. 5  | Day 46  | 24      | Fatal                       |  
| Version Date: 01/10/2023 81 / M Small intestinal obstruction                                                                           | Not related                  | Gr. 3       | Day 212   | 5        | Recovered/Resolved   |                                   |
|----------------------------------------------------------------------------------------------------------------------------------------|------------------------------|-------------|-----------|----------|----------------------|-----------------------------------|
| 59 / M                                                                                                                                 | UTI                          | Not related | Gr. 3     | Day 72   | 3                    | Recovered/Resolved                |
| Acute kidney injury                                                                                                                    | Related                      | Gr. 3       | Day 20    | 3        | Recovered/Resolved   |                                   |
| 74 / M                                                                                                                                 | Acute kidney injury          | Related     | Gr. 3     | Day 29   | 6                    | Recovered/Resolved                |
| 70 / M                                                                                                                                 | Esophageal obstruction       | Not related | Gr. 3     | Day 140  | 3                    | Recovered/Resolved                |
| Fall                                                                                                                                   | Not related                  | Gr. 3       | Day 407   | 3        | Recovered/Resolved   |                                   |
| Hematuria                                                                                                                              | Not related                  | Gr. 2       | Pre-drug  | 4        | Recovered/Resolved   |                                   |
| Urinary retention                                                                                                                      | Not related                  | Gr. 2       | Pre-drug  | 10       | Recovered/Resolved   |                                   |
| UTI                                                                                                                                    | Not related                  | Gr. 2       | Pre-drug  | 25       | Recovered/Resolved   |                                   |
| Pericardial effusion                                                                                                                   | Not related                  | Gr. 3       | Day 61    | 4        | Recovered/Resolved   |                                   |
| UTI                                                                                                                                    | Not related                  | Gr. 3       | Day 61    | 4        | Recovered/Resolved   |                                   |
| 82 / M                                                                                                                                 | Small intestinal obstruction | Not related | Gr. 1     | Day 75   | 3                    | Recovered/Resolved                |
| 86 / M                                                                                                                                 | Hematuria                    | Not related | Gr. 1     | Day 475  | 3                    | Recovered/Resolved                |
| 73 / M                                                                                                                                 | Lung neoplasm surgery        | Not related | Gr. 4     | Day 287  | 15                   | Recovered/Resolved with  sequelae |
| 70 / M                                                                                                                                 | Pyrexia                      | Related     | Gr. 2     | Day 32   | 2                    | Recovered/Resolved                |
| 75 / F                                                                                                                                 | Acute kidney injury          | Not related | Gr. 3     | Day 121  | 3                    | Recovered/Resolved                |
| Small intestinal obstruction                                                                                                           | Not related                  | Gr. 3       | Day 380   | 3        | Recovered/Resolved   |                                   |
| 83 / M                                                                                                                                 | Rib fracture                 | Not related | Gr. 3     | Day 85   | Ongoing              | Not recovered/Not  resolved       |
| 77 / M                                                                                                                                 | Hematuria                    | Not related | Gr. 3     | Pre-drug | 2                    | Recovered/Resolved                |
| Acute kidney injury                                                                                                                    | Not related                  | Gr. 2       | Day 32    | 3        | Recovered/Resolved   |                                   |
| Cystitis                                                                                                                               | Not related                  | Gr. 3       | Day 32    | 4        | Recovered/Resolved   |                                   |
| 75 / F                                                                                                                                 | Urinary retention            | Not related | Gr. 2     | Day 102  | 5                    | Recovered/Resolved                |
| 89 / M                                                                                                                                 | Hematuria                    | Not related | Gr. 3     | Day 214  | 2                    | Recovered/Resolved                |
| 76 / M                                                                                                                                 | Tachycardia                  | Not related | Gr. 3     | Day 17   | 4                    | Recovered/Resolved                |
| 82 / M                                                                                                                                 | Aortic valve disease         | Not related | Gr. 4     | Day 694  | 2                    | Recovered/Resolved with  sequelae |
| 77 / F                                                                                                                                 | Pelvic pain                  | Not related | Gr. 3     | Day 36   | 3                    | Recovered/Resolved                |
| F = female; M = male; MedDRA = Medical Dictionary for Regulatory Activities; UTI = urinary tract infection a Investigator's assessment |                              |             |           |          |                      |                                   |  
F = female; M = male; MedDRA = Medical Dictionary for Regulatory Activities; UTI = urinary tract infection  
a Investigator's assessment b Initial dose of Vicineum = Day 1  
Data source: VB4-845-02-IIIA Interim CSR Table 26
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14.2.3 formulation packaging and storage

Vicineum™ (oportuzumab monatox, VB4-845) is a clear, colorless solution for intravesical administration. It is provided as a frozen product in a glass vial, and then thawed at room temperature prior to preparation for administration. Cloudiness, a change in color and/or the presence of particulate matter may indicate the product has deteriorated. If this occurs, Sesen  
Biotherapeutics should be contacted immediately and the product must not be used. Vicineum is packaged in a 10 mL glass borosilicate vial containing 7 mL of study drug at a concentration of 5 mg/mL. Each vial is sealed with grey butyl stoppers and covered with an aluminum cap center tear-off seal.  
Vicineum will be mixed with phosphate buffered saline prior to intravesical administration. Refer to the Vicineum Dose Preparation and Administration Manual for details.
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14.2.4 product preparation

Refer to the Vicineum Dose Preparation and Administration Manual for details.
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14.2.6 incompatibilities

Vicineum is administer intravesically via a catheter. Only material indicated as qualified in the Vicineum Dose Preparation and Administration Manual in Section 6 should be used.
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14.2.7 accountability and dispensation

The Investigator agrees that the study drug will be administered only to subjects who have provided written informed consent, have met all entry criteria, and are enrolled in the study. The Investigator must not loan or dispense clinical study material to another Investigator or site. Drug accountability records will be maintained by the Investigator or authorized site staff for all clinical trial supplies (includes Vicineum and phosphate buffered saline). Sesen Biotherapeutics . or designee will provide the Investigator with drug accountability logs to document receipt and dispensing. Any discrepancy and/or deficiency must be recorded, reported to Sesen Biotherapeutics or designee, and a plan for resolution documented. If at any point in the conduct of the study a vial is deemed unacceptable for use, the site will document the damage on the drug accountability log and immediately notify Sesen Biotherapeutics or designee. Sesen Biotherapeutics or designee will monitor the completeness and accuracy of all accountability records throughout the study and verify product accountability against site documentation.
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14.2.8 disposition of unused investigational

Any expired Vicineum, or Vicineum vial deemed unacceptable for use or any Vicineum supply remaining at the end of the study should be destroyed at each clinical site in accordance with the site's drug destruction policy.