9. study calendar by cohort
pd-l1 testing

| EOT                                         | Surgery                                                                                                                                      | ctDNA       | End of   |      |      |      |      |      |      |                |
|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|-------------|----------|------|------|------|------|------|------|----------------|
| Safety                                      | Collection                                                                                                                                   | Study Visit |          |      |      |      |      |      |      |                |
| Visit                                       |                                                                                                                                              |             |          |      |      |      |      |      |      |                |
| Procedure                                   | Screeninga Cycle 1 Cycle 1 Cycle 2  Cycle 2 Cycle 3 Cycle 3 Cycle 4 Cycle 4  Day 1c  Day 2c  Day 1 c Day 2 c Day 1 c Day 2 c Day 1 c Day 2 c | 4 weeks  post             |          |      |      |      |      |      |      |                |
| cystectomy  (+/- 2  weeks)                  | 12 weeks  postcystectomy  (+/- 2  weeks)                                                                                                                                              |             |          |      |      |      |      |      |      |                |
| 4 weeksm                                    |                                                                                                                                              |             |          |      |      |      |      |      |      |                |
| Scheduling Window (Days)                    | -30 to -1                                                                                                                                    | (+2)        | (+2)     | (+2) | (+2) | (+2) | (+2) | (+2) | (+2) | (+/- 2  weeks) |
| Informed Consenth                           | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Medical history                             | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Physical exam                               | X                                                                                                                                            | X           | X        | X    | X    |      |      |      |      |                |
| Vital signs, weight, & heightd              | X                                                                                                                                            | X           | X        | X    | X    |      |      |      |      |                |
| ECOG Performance Status                     | X                                                                                                                                            | X           | X        | X    | X    |      |      |      |      |                |
| Complete blood count w/differential         | Xf                                                                                                                                           | X           | X        | X    | X    |      |      |      |      |                |
| Comprehensive metabolic panel including Mgi | Xf                                                                                                                                           | X           | X        | X    | X    |      |      |      |      |                |
| Coagulation (PT, PTT, INR)                  | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| TSH                                         | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Urinalysis                                  | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Hepatitis B serology                        | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Hepatitis C serology                        | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| HIV serology                                | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Pregnancy test                              | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |
| Biomarkersk                                 | X                                                                                                                                            | X           | X        | X    | X    |      |      |      |      |                |
| 12-lead ECGg                                | X                                                                                                                                            |             |          |      |      |      |      |      |      |                |  
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin cohort ("DD **MVAC" 14-day Cycle)**  
| ECHO                                | X   |    |    |    |    |    |    |    |    |
|-------------------------------------|-----|----|----|----|----|----|----|----|----|
| Tumor specimen testing              | X   | X  |    |    |    |    |    |    |    |
| CT or MRI of abdomen and pelvise    | X   | X  | XL |    |    |    |    |    |    |
| CT or X-ray of cheste               | X   |    |    |    |    |    |    |    |    |
| Bone scan (if alk phos is elevated) | X   |    |    |    |    |    |    |    |    |
| Adverse event collection            | X   | X  | X  | X  | X  | X  | X  | X  |    |
| Concomitant medications             | X   | X  | X  | X  | X  | X  | X  | X  | X  |
| TREATMENT                           |     |    |    |    |    |    |    |    |    |
| Durvalumab (750mg)                  | X   | X  | X  | X  |    |    |    |    |    |
| Methotrexate                        | X   | X  | X  | X  |    |    |    |    |    |
| Vinblastine                         | X   | X  | X  | X  |    |    |    |    |    |
| Doxorubicin                         | X   | X  | X  | X  |    |    |    |    |    |
| Cisplatin                           | X   | X  | X  | X  |    |    |    |    |    |
| Cystectomyj                         | X   |    |    |    |    |    |    |    |    |  
| Cisplatin plus Gemcitabine cohort ("Cis-Gem," 21-day cycle) EOT   | Surgery                                                                                                                                 | ctDNA       | End of   |         |      |         |      |         |      |                |
|-------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|-------------|----------|---------|------|---------|------|---------|------|----------------|
| Safety                                                            | Collection                                                                                                                              | Study Visit |          |         |      |         |      |         |      |                |
| Visit                                                             |                                                                                                                                         |             |          |         |      |         |      |         |      |                |
| Procedure                                                         | Screeninga Cycle 1 Cycle 1 Cycle 2  Cycle 2 Cycle 3 Cycle 3 Cycle 4 Cycle 4  Day 1 b Day 8  Day 1 b Day 8  Day 1 b Day 8  Day 1 b Day 8 | 4 weeks  post             |          |         |      |         |      |         |      |                |
| cystectomy  (+/- 2  weeks)                                        | 12 weeks  postcystectomy  (+/- 2  weeks)                                                                                                                                         |             |          |         |      |         |      |         |      |                |
| 4 weeksm                                                          |                                                                                                                                         |             |          |         |      |         |      |         |      |                |
| Scheduling Window (Days)                                          | -30 to -1                                                                                                                               | (+/- 2)     | (+2)     | (+/- 2) | (+2) | (+/- 2) | (+2) | (+/- 2) | (+2) | (+/- 2  weeks) |
| Informed Consenth                                                 | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Medical history                                                   | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Physical exam                                                     | X                                                                                                                                       | X           | X        | X       | X    |         |      |         |      |                |
| Vital signs, weight, & heightd                                    | X                                                                                                                                       | X           | X        | X       | X    |         |      |         |      |                |
| ECOG Performance Status                                           | X                                                                                                                                       | X           | X        | X       | X    |         |      |         |      |                |
| Complete blood count w/differential                               | Xf                                                                                                                                      | X           | X        | X       | X    |         |      |         |      |                |
| Comprehensive metabolic panel                                     | Xf                                                                                                                                      | X           | X        | X       | X    |         |      |         |      |                |
| including Mgi  Coagulation (PT, PTT, INR)                         | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| TSH                                                               | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Hepatitis B serology                                              | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Urinalysis                                                        | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Hepatitis C serology                                              | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| HIV serology                                                      | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Pregnancy test                                                    | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Biomarkersk                                                       | X                                                                                                                                       | X           | X        | X       | X    |         |      |         |      |                |
| 12-lead ECGg                                                      | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| ECHO                                                              | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Tumor specimen testing                                            | X                                                                                                                                       | X           |          |         |      |         |      |         |      |                |
| CT or MRI of abdomen and pelvise                                  | X                                                                                                                                       | X           | XL       |         |      |         |      |         |      |                |
| CT or X-ray of cheste                                             | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |
| Bone scan (if alk phos is elevated)                               | X                                                                                                                                       |             |          |         |      |         |      |         |      |                |  
| Adverse event collection   | X   | X   | X   | X   | X   | X   | X   | X   |    |
|----------------------------|-----|-----|-----|-----|-----|-----|-----|-----|----|
| Concomitant medications    | X   | X   | X   | X   | X   | X   | X   | X   | X  |
| TREATMENT                  |     |     |     |     |     |     |     |     |    |
| Durvalumab (1500mg)        | X   | X   | X   | X   |     |     |     |     |    |
| Cisplatin                  | X   | X   | X   | X   |     |     |     |     |    |
| Gemcitabine                | X   | X   | X   | X   | X   | X   | X   | X   |    |
| Cystectomyj                | X   |     |     |     |     |     |     |     |    |  
| Carboplatin plus Gemcitabine cohort ("Carbo-Gem," 21-day cycle) EOT  Surgery   | ctDNA                                                                                                                                | End of Study   |      |         |      |         |      |         |      |
|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|----------------|------|---------|------|---------|------|---------|------|
| Safety                                                                         | Collection                                                                                                                           | Visit          |      |         |      |         |      |         |      |
| Visit                                                                          |                                                                                                                                      |                |      |         |      |         |      |         |      |
| Procedure                                                                      | Screeninga Cycle 1 Cycle 1 Cycle 2  Cycle 2 Cycle 3 Cycle 3 Cycle 4 Cycle 4  Day 1  Day 8b Day 1  Day 8b Day 1  Day 8b Day 1  Day 8b | 4              |      |         |      |         |      |         |      |
| weeksm (+/- 2  weeks)                                                          | 4 weeks  post                                                                                                                                      |                |      |         |      |         |      |         |      |
| cystectomy  (+/- 2 weeks)                                                      | 12 weeks  postcystectomy  (+/- 2 weeks)                                                                                                                                      |                |      |         |      |         |      |         |      |
| Scheduling Window (Days)                                                       | -30 to -1                                                                                                                            | (+/- 2)        | (+2) | (+/- 2) | (+2) | (+/- 2) | (+2) | (+/- 2) | (+2) |
| Informed Consenth                                                              | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Medical history                                                                | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Physical exam                                                                  | X                                                                                                                                    | X              | X    | X       | X    |         |      |         |      |
| Vital signs, weight, & heightd                                                 | X                                                                                                                                    | X              | X    | X       | X    |         |      |         |      |
| ECOG Performance Status                                                        | X                                                                                                                                    | X              | X    | X       | X    |         |      |         |      |
| Complete blood count                                                           | Xf                                                                                                                                   | X              | X    | X       | X    |         |      |         |      |
| w/differential Comprehensive metabolic panel                                   | Xf                                                                                                                                   | X              | X    | X       | X    |         |      |         |      |
| including Magnesiumi Coagulation (PT, PTT, INR)                                | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| TSH                                                                            | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Urinalysis                                                                     | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Hepatitis B serology                                                           | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Hepatitis C serology                                                           | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| HIV serology                                                                   | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Pregnancy test                                                                 | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| BiomarkersK                                                                    | X                                                                                                                                    | X              | X    | X       | X    |         |      |         |      |
| 12-lead ECGg                                                                   | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| ECHO                                                                           | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Tumor specimen testing                                                         | X                                                                                                                                    | X              |      |         |      |         |      |         |      |
| CT or MRI of abdomen and pelvise                                               | X                                                                                                                                    | X              | XL   |         |      |         |      |         |      |
| CT or X-ray of cheste                                                          | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Bone scan (if alk phos is elevated)                                            | X                                                                                                                                    |                |      |         |      |         |      |         |      |
| Amendment 5 IRB-48062                                                          | Page 56 of 66                                                                                                                        | 31 JAN 2020    |      |         |      |         |      |         |      |  
| Adverse event collection                                                                            | X   | X   | X   | X   | X   | X   | X   | X   |    |
|-----------------------------------------------------------------------------------------------------|-----|-----|-----|-----|-----|-----|-----|-----|----|
| Concomitant medications                                                                             | X   | X   | X   | X   | X   | X   | X   | X   | X  |
| TREATMENT                                                                                           |     |     |     |     |     |     |     |     |    |
| Durvalumab (1500mg)                                                                                 | X   | X   | X   | X   |     |     |     |     |    |
| Carboplatin                                                                                         | X   | X   | X   | X   |     |     |     |     |    |
| Gemcitabine                                                                                         | X   | X   | X   | X   | X   | X   | X   | X   |    |
| Cystectomyj                                                                                         | X   |     |     |     |     |     |     |     |    |
| a: Subjects must be screened within 30 days prior to Cycle 1 Day 1 with the exception of some labs. |     |     |     |     |     |     |     |     |    |  
Cystectomyj X
a: Subjects must be screened within 30 days prior to Cycle 1 Day 1 with the exception of some labs. b: For Cis/Gem and Carbo/Gem cohorts there must be at least 7 days between Day 1 and Day 8. c: Efforts should be made to conduct study visits on the day scheduled (+2 days). Delays in dosing will shift the following cycle so that there are at least 12 days between Day 8 of the previous cycle and Day 1 of the current cycle.  
d: Assessments will include vital signs (resting BP HR, RR, and body temperature) and weight. Height will be recorded at screening.  
e: PET CT for subjects with impaired renal function is an acceptable alternative.  
f: within 28 days of Cycle 1 Day 1 g: ECGs should be obtained after the subject has been in a supine position for 5 minutes and recorded while the subject 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 (eg, 30 minutes) to confirm the finding.  
h: Informed consent may be obtained greater than 30 days prior to first dose of study treatment. i: Magnesium is to be performed at baseline on Day 1 and as clinically indicated j: Within 6 weeks post completion of 4 cycles k: Biomarkers sample to be collected at pre-initiation of neoadjuvant treatment, upon completion of neoadjuvant treatment and prior to surgical cystectomy, 4 weeks (+/- 2 weeks) post-cystectomy and 12 weeks (+/- 2 weeks) post cystectomy L: May be completed within 7 days before the End of Study visit m: within 4 weeks ± 2 weeks of completion of neoadjuvant treatment, typically at the subject's cystectomy pre-operative visit
9. study calendar by cohort
10. measurements 10.1 primary outcome

The safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer who initiate study treatment will be assessed as the number, by treatment cohort, of Grade 3, 4, or 5 adverse events, considered probably or definitely related by the investigator. The outcome will be reported as a number.  
Time Frame: 120 days
- **Safety Issue**:
Is this outcome measure assessing a safety issue? Yes
9. study calendar by cohort
10.2 secondary outcome measures

The number and proportion of subjects who initiate study treatment and achieve tumor stage of pT2 N0 M0 or better (eg, pT0, pT1 N0) at cystectomy.  
T0 N0 M0 = No evidence of primary tumor T1 N0 M0 = Tumor staging by pathological assessment detected in lamina propria (T0), with no tumor-positive nodes (N0).  
T2 N0 M0 = Tumor staging by pathological assessment detected in muscularis propria (pT2),
with no tumor-positive nodes (N0) or tumor metastases (M0) observed.  
Time Frame: 20 weeks
- **Safety Issue**:
Is this outcome measure assessing a safety issue? No See also Appendix 2 National Comprehensive Cancer Network Bladder Cancer Guidelines.
9. study calendar by cohort
10.2.3 secondary outcome measurement time

Post-combination treatment of durvalumab and neoadjuvant chemotherapy for a maximum of four cycles followed by cystectomy
9. study calendar by cohort
11. regulatory considerations 11.1 institutional

The protocol and the proposed informed consent will be reviewed and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). Any changes made to the protocol will be submitted as a modification and will be approved by the IRB prior to implementation.
9. study calendar by cohort
11.2 data and safety monitoring

The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this study. The DSMC will audit study-related activities to determine whether the study has been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). This may include review of the following types of documents participating in the study: regulatory binders, case report forms, eligibility checklists, and source documents. In addition, the DSMC will regularly review serious adverse events and protocol deviations associated with the research to ensure the protection of human subjects. Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as needed.
9. study calendar by cohort
11.3 data management plan

Case Report Forms (CRFs) are printed or electronic documents designed to record all protocol-related information on each trial participant. CRFs should summarize the clinical findings and observations necessary to ensure safety of participants on the study, and to document the study outcomes. CRFs are required by the SRC for all Interventional studies. CRF design and creation must be completed prior to enrollment of the first participant. OnCore will be used for CRF's.  
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will document treatment outcomes for data analysis. Case report forms will be developed using the Online Collaborative Research Environment (OnCore) database system and will be maintained by study team. CRFs will be kept in a locked office, only accessible to the research team.
9. study calendar by cohort
12. statistical considerations 12.1 no

All subjects who initiate study treatment will be included in the safety analysis (primary objective and outcome). We set the null hypothesis of 1% for the proportion of patients experiencing a grade 3 or greater adverse event. Our sample size has 71% power at the alternative of 10%. Calculation based on binomial probabilities using a one-sided significance level of 5%. The trial will be deemed a success if no more than 2 patients experience a grade 3 or greater immune-related adverse event out of 24. Precision: A sample of 24 patients will allow proportions to be estimated with a margin of error no larger than plus or minus 21 percentage points. The margin is expected to be smaller. For example if none of the 24 patients experience grade 3 or greater toxicity, we will be able to conclude with 95% confidence that the true rate is not larger than 17%.
9. study calendar by cohort
secondary

All subjects undergoing cystectomy will be included for analysis. Subjects who complete treatment but fail to under cystectomy will be considered inevaluable for endpoint analysis for that reason.
9. study calendar by cohort
secondary

Achievement of tumor staging will be determined by pathologist at cystectomy, and reported by treatment cohort. See also Appendix 2 National Comprehensive Cancer Network Bladder Cancer Guidelines.  
In addition, molecular characterization of tissue pre- and post-cystectomy will be analyzed.  
Circulating ctDNA will be collected at baseline and at set time points.
9. study calendar by cohort
12.3 sample size 12.3.1 accrual

We expect to enroll 12 subjects/year, for a 2 year enrollment of 24 subjects.
9. study calendar by cohort
12.3.3 effect size justification

Variant histology bladder cancer subjects are not a well-studied population and are usually excluded from phase 3 studies. In traditional urothelial cancer, the percent of subjects achieving pT0 is 30%. We hope to improve this level of subjects achieving pT0 with the additional use of immunotherapy.
9. study calendar by cohort
12.4 criteria for future studies

If pT0 exceeds 50% we will then pursue a fully-powered study.
9. study calendar by cohort
13. references

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von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate,vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large,randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068-77, 2008.  
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Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with nonsmall cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032.  
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14.1. appendix 1. dosing modification
13. references

Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (Durvalumab Monotherapy) 1 November 2017 Version.
14.1. appendix 1. dosing modification
general considerations

| Dose Modifications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Drug administration modifications of study  drug/study regimen will be made to manage  potential immune-related AEs based on severity of  treatment-emergent toxicities graded per  NCI CTCAE v5.  In addition to the criteria for permanent  discontinuation of study drug/study regimen based  on CTC grade/severity (table below), permanently  discontinue study drug/study regimen for the  following conditions: - Inability to reduce corticosteroid to a dose  of ≤ 10 mg of prednisone per day (or  equivalent) within 12 weeks after last  dose of study drug/study regimen - Recurrence of a previously experienced  Grade 3 treatment-related AE following  resumption of dosing Grade 1 No dose modification Grade 2 Hold study drug/study regimen dose  until Grade 2 resolution to Grade ≤ 1. If toxicity worsens, then treat as  Grade 3 or Grade 4. Study drug/study regimen can be  resumed once event stabilizes to  Grade ≤ 1 after completion of steroid  taper. Subjects with endocrinopathies who  may require prolonged or continued  steroid replacement can be retreated  with study drug/study regimen on the  following conditions: 1. The event stabilizes and is  controlled. 2. The subject is clinically stable as  per Investigator or treating physician's clinical judgement. 3. Doses of prednisone are at  ≤10 mg/day or equivalent. Grade 3 Depending on the individual toxicity,  study drug/study regimen may be  permanently discontinued. Please  refer to guidelines below. | It is recommended that management of  immune-mediated adverse events (imAEs) follows the  guidelines presented in this table: - It is possible that events with an inflammatory or  immune mediated mechanism could occur in  nearly all organs, some of them not noted  specifically in these guidelines. - Whether specific immune-mediated events (and/or  laboratory indicators of such events) are noted in  these guidelines or not, subjects should be  thoroughly evaluated to rule out any alternative  etiology (eg, disease progression, concomitant  medications, and infections) to a possible  immune-mediated event. In the absence of a clear  alternative etiology, all such events should be  managed as if they were immune related. General  recommendations follow. - Symptomatic and topical therapy should be  considered for low-grade (Grade 1 or 2, unless  otherwise specified) events.  - For persistent (> 3 to 5 days) low-grade (Grade 2)  or severe (Grade ≥ 3) events, promptly start  prednisone 1 to 2 mg/kg/day PO or IV equivalent. - Some events with high likelihood for morbidity  and/or mortality, eg, myocarditis, or other similar  events even if they are not currently noted in the  guidelines - should progress rapidly to high dose  IV corticosteroids (methylprednisolone at  2 to 4 mg/kg/day) even if the event is Grade 2,  and if clinical suspicion is high and/or there has  been clinical confirmation. Consider, as  necessary, discussing with the study physician,  and promptly pursue specialist consultation. - If symptoms recur or worsen during corticosteroid  tapering (28 days of taper), increase the  corticosteroid dose (prednisone dose [eg, up to  2 to 4 mg/kg/day PO or IV equivalent]) until  stabilization or improvement of symptoms, then  resume corticosteroid tapering at a slower rate  (> 28 days of taper). - More potent immunosuppressives such as TNF  inhibitors (eg, infliximab) (also refer to the  individual sections of the imAEs for specific type of |
14.1. appendix 1. dosing modification
dosing modification and toxicity management

Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions
(Durvalumab Monotherapy) 1 November **2017 Version.**
Grade 4 Permanently discontinue study drug/study regimen.  
Note: For Grade ≥ 3 asymptomatic amylase or lipase levels, hold study drug/study regimen, and if complete work up shows no evidence of pancreatitis, study drug/study regimen may be continued or resumed.  
Note: Study drug/study regimen should be permanently discontinued in Grade 3 events with high likelihood for morbidity and/or mortality, eg, myocarditis, or other similar events even if they are not currently noted in the guidelines. Similarly, consider whether study drug/study regimen should be permanently discontinued in Grade 2 events with high likelihood for morbidity and/or mortality, eg, myocarditis, or other similar events even if they are not currently noted in the guidelines - when they do not rapidly improve to Grade < 1 upon treatment with systemic steroids and following full taper Note: There are some exceptions to permanent discontinuation of study drug for Grade 4 events (ie, hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).
14.1. appendix 1. dosing modification
general considerations

Dose Modifications **Toxicity Management**  
immunosuppressive) should be considered for events not responding to systemic steroids. Progression to use of more potent immunosuppressives should proceed more rapidly in events with high likelihood for morbidity and/or mortality, eg, myocarditis, or other similar events even if they are not currently noted in the guidelines - when these events are not responding to systemic steroids.  
- With long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, formerly known as *Pneumocystis carinii* pneumonia)
prophylaxis, gastrointestinal protection, and glucose monitoring.  
- Discontinuation of study drug/study regimen is not mandated for Grade 3/Grade 4 inflammatory reactions attributed to local tumor response (eg, inflammatory reaction at sites of metastatic disease and lymph nodes). Continuation of study drug/study regimen in this situation should be based upon a benefit-risk analysis for that subject.
nccn guidelines version 5.2018 bladder
general considerations

Table 1. American Joint Committee on Cancer (AJCC)
TNM Staging System for Bladder Cancer 8th ed., 2017)
T
Primary Tumor TX
Primary tumor cannot be assessed TO
No evidence of primary tumor Ta Noninvasive papillary carcinoma Tis Urothelial carcinoma in situ: "flat tumor" T1 Tumor invades lamina propria (subepithelial connective tissue)
T2 Tumor invades muscularis propria pT2a Tumor invades superficial muscularis propria (inner half)
pT2b Tumor invades deep muscularis propria (outer half)
T3 Tumor invades perivesical tissue pT3a    Microscopically pT3b    Macroscopically (extravesical mass)
T4 Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, ´uterus, vagi´na, pelvic wall, äbdominal wall T4a Extravesical tumor invades prostatic stroma, seminal vesicles, uterus, vaginal T4b Extravesical tumor invades pelvic wall, abdominal wall
nccn guidelines version 5.2018 bladder
n

NX
Lymph nodes cannot be assessed NO
No lymph node metastasis N1 Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node)
N2 Multiple regional lymph node metastasis in the true pelvis
(perivesical, obturator, internal and external iliac, or sacral lymph node metastasis)
N3 Lymph node metastasis to the common iliac lymph nodes M
Distant Metastasis MO
No distant metastasis  
| Stage 0a   | Ta   | NO   |
|------------|------|------|
| Stage Ois  | Tis  | NO   |
| Stage I    | T1   | NO   |
| Stage II   | T2a  | NO   |
| T2b        | NO   |      |
| Stage IIIA | T3a  | NO   |
| T3b        | NO   |      |
| T4a        | NO   |      |
| T1-T4a     | N1   |      |  
| MO   |
|------|
| MO   |
| MO   |  
M1 Distant metastasis M1a Distant metastasis limited to lymph nodes beyond the common iliacs M1b Non-lymph-node distant metastases Histologic Grade (G)
For urothelial histologies, a low- and high-grade designation is used to match the current World Health Organization/International Society of Urological Pathology (WHO/ISUP) recommended grading system:
Low-grade LG
HG
High-grade For squamous cell carcinoma and adenocarcinoma, the following grading schema is recommended:
GX
Grade cannot be assessed Well differentiated Moderately differentiated G3 Table 2. AJCC Prognostic Groups T
N
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.  
Version 5.2018, 07/03/18 © National Comprehensive Caroer Network, Inc. 2018, All rights reserved. The NCCN Guidelines' and Bia illustration may not be reproduced in any form ST-1
nccn guidelines version 5.2018 bladder
regional lymph nodes

Poorly differentiated G2 G1  
| M   | T          | N      | M     |     |
|-----|------------|--------|-------|-----|
| MO  | Stage IIIB | T1-T4a | N2,N3 | MO  |
| MO  | Stage IVA  | T4b    | Any N | MO  |
| MO  | Any T      | Any N  | M1a   |     |
| MO  | Stage IVB  | Any T  | Any N | M1b |
| MO  |            |        |       |     |
| MO  |            |        |       |     |