Conditions: Invasive Bladder Cancer
Keywords: localized muscle invasive bladder cancer bladder preservation durvalumab tremelimumab radiotherapy
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 32
Healthy volunteers: no

Brief summary:
Combined-modality treatment of localized muscle invasive bladder cancer including transurethral resection (TUR), radiotherapy and dual checkpoint inhibition immunotherapy could achieve pathological complete response in some patients. These patients could avoid to undergone radical surgery with radical cystectomy and preserve their bladder, without the side-effects associated with chemotherapy and surgery. This study has been design to determine the efficacy of durvalumab plus tremelimumab with concurrent radiotherapy in terms of pathological response rate in patients with localized muscle invasive bladder cancer treated with bladder preservation intent.

Detailed description:
The treatment consisted of initial TUR of the tumor, with multiple random biopsies of normal-appearing bladder urothelium, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for a total of 3 doses.

Two weeks after the initiation of immunotherapy, normofractionated external-beam radiotherapy with high-energy photons will be started. Radiotherapy will be administered concurrently with immunotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder.

Six weeks after the end of radiotherapy, ALL patients will undergo a new cystoscopy with biopsies of the tumor bed and all residual present lesions as an efficacy determination. In patients with persistent prominent inflammatory reaction at this moment, the cystoscopy can be performed 1-2 weeks later (6 to 8 weeks after the end of radiotherapy). Response is defined as an absence of invasive cancer at post immunotherapy biopsy (≤cT1). Patients with response to immunotherapy will be candidates to bladder preservation, whereas in those with residual muscle invasive tumor the possibility of salvage radical cystectomy must be evaluated. Patients developing an isolated bladder invasive relapse during follow-up will be also possible candidates to salvage cystectomy, whereas those developing a superficial relapse in the preserved bladder will be managed with TUR and intravesical BCG.

Patients will be followed up every 3 months the first year, every 4 months the second year and every 6 months thereafter with abdomen and pelvis CT scan, Rx thorax, urine cytology. Additionally, the mandatory efficacy cystoscopy and bladder biopsy (6w post RT), other cystoscopy and bladder biopsy will be performed in case of detection abnormalities in the cytology or imaging studies. The study will be closed 2 years after the last patient inclusion.

Arms:
arm 1: The treatment consisted of initial TUR of the tumor, with multiple random biopsies of normal-appearing bladder urothelium, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for a total of 3 doses.

Two weeks after the initiation of immunotherapy, normofractionated external-beam radiotherapy with high-energy photons will be started. Radiotherapy will be administered concurrently with immunotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder.

Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab intervention 3: Radiotherapy
Intervention descriptions: intervention 1: All patients will receive durvalumab (MEDI4736) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to \>30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W. intervention 2: All patients will receive durvalumab (MEDI4736) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to \>30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W. intervention 3: Radiotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder.

Protocol document:
Prot_SAP_000.pdf: 
 Investigational 
 Drug 
 Substance(s) 
 Durvalumab and 
 tremelimumab 
 Study Number 
 ESR-17-12664 
 EudraCT 
 2017-003159-44 
 Sponsor Code 
 SOGUG-2017-A-IEC(VEJ)-1 
 Version Number 
 3.0. 
 Date 
 12 /NOV/2019 
 Phase  II  trial  of  durvalumab  (Medi4736)  plus  tremelimumab  with 
 concurrent  radiotherapy  in  patients  with  localized  muscle  invasive 
 bladder cancer treated with a selective bladder preservation approach 
 Sponsor: 
 Spanish Oncology Genitourinary Group (SOGUG) 
 Velázquez, 7, 3ª planta, 28001 
 Madrid 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  1 / 135 


 SPONSOR’S SIGNATURE PAGE 
 Study  title:  Phase  II  trial  of  durvalumab  (Medi4736)  plus  tremelimumab  with  concurrent 
 radiotherapy  in  patients  with  localized  muscle  invasive  bladder  cancer  treated  with  a 
 selective bladder preservation approach 
 Study number:  ESR-17-12664 
 Sponsor code:  SOGUG-2017-A-IEC(VEJ)-1 
 EudraCT Number:  2017-003159-44 
 Version number and date:  3.0 – 12/NOV/2019 
 I  have  read  this  protocol  and  agree  to  conduct  this  trial  in  accordance  with  all  provisions 
 of the protocol, GCPs and the Declaration of Helsinki. 
 Dr. José Ángel Arranz Arija 
 SOGUG Chairman 
 Signature 
 Signature date 
 (DD-mm-YYYY) 
 Dr. Xavier García del Muro 
 Coordinating Investigator 
 Signature 
 Signature date 
 (DD-mm-YYYY) 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  2 / 135 


 INVESTIGATOR’S SIGNATURE PAGE 
 Study  title:  Phase  II  trial  of  durvalumab  (Medi4736)  plus  tremelimumab  with  concurrent 
 radiotherapy  in  patients  with  localized  muscle  invasive  bladder  cancer  treated  with  a 
 selective bladder preservation approach 
 Study number:  ESR-17-12664 
 Sponsor code:  SOGUG-2017-A-IEC(VEJ)-1 
 EudraCT Number:  2017-003159-44 
 Version number and date:  3.0 – 12/NOV/2019 
 I  have  read  this  protocol  and  agree  to  conduct  this  trial  in  accordance  with  all  provisions 
 of the protocol, GCPs and the Declaration of Helsinki. 
 Principal Investigator’s 
 Name 
 Principal Investigator’s 
 Signature 
 Signature date 
 (DD-mm-YYYY) 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  3 / 135 


 PROTOCOL SYNOPSIS 
 Study Title: 
 Phase  II  trial  of  durvalumab  (Medi4736)  plus  tremelimumab  with  concurrent  radiotherapy  in 
 patients  with  localized  muscle  invasive  bladder  cancer  treated  with  a  selective  bladder 
 preservation approach 
 Study Number: 
 ESR-17-12664 
 Sponsor Code: 
 SOGUG-2017-A-IEC(VEJ)-1 
 EudraCT No. : 
 2017-003159-44 
 Clinicaltrials.gov : 
 NCT3702179 
 Clinical Phase: 
 Phase II 
 Study Duration: 
 - Authorities submission                                                                       2Q 2018 (May 31, 2018) 
 - Trial start date                                                                                     4Q 2018 (Nov. 14, 2018) 
 -  F irst patient 
 1Q 2019 (Jan. 24, 2019) 
 - Estimated last patient in                                                                                               3Q 2020 
 - Estimated last patient last treatment                                                                            3Q 2022 
 - Estimated trial completion date                                                                                   2Q 2023 
 Investigational Product(s) and Reference Therapy: 
 Durvalumab  (MEDI4736)  will  be  supplied  in  glass  vials  containing  500  mg  of  liquid  solution  at  a 
 concentration of 50 mg/mL for intravenous (IV) administration. 
 Tremelimumab  is  supplied  as  a  sterile  solution  for  IV  infusion,  filled  in  20  mL  clear  glass  vials  with  a 
 rubber  stopper  and  aluminum  seal.  Each  vial  contains  20 mg/mL  (with  a  nominal  fill  of  20 mL, 
 accounting  to  400  mg/vial  and  a  nominal  fill  of  1.25  mL  for  the  25mg/vial)  of  tremelimumab,  in  an 
 isotonic solution at pH 5.5. 
 Radiotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. 
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 Research Hypothesis: 
 Combined-modality  treatment  of  localized  muscle  invasive  bladder  cancer  including  transurethral 
 resection  (TUR),  radiotherapy  and  dual  checkpoint  inhibition  immunotherapy  could  achieve 
 pathological  complete  response  in  some  patients  (Twyman-Saint  Victor  C,  Rech  AJ,  Maity  A,  et  al. 
 2015).  These  patients  could  avoid  to  undergone  radical  surgery  with  radical  cystectomy  and  preserve 
 their bladder, without the side-effects associated with chemotherapy and surgery. 
 Objectives: 
 Primary Objectives: 
 To  determine  the  efficacy  of  durvalumab  plus  tremelimumab  with  concurrent  radiotherapy  in  terms  of 
 pathological  response  rate  in  patients  with  localized  muscle  invasive  bladder  cancer  treated  with 
 bladder preservation intent. 
 Secondary Objective(s): 
 ●  To  determine  the  rate  of  patients  with  bladder  preserved,  the  rate  of  immediate  and  late 
 salvage  cystectomies  and  the  survival  with  bladder  preserved  free  of  tumor,  defined  as  the 
 time  from  the  start  of  immunotherapy  to  either  the  date  of  cystectomy  or  the  date  of  recurrence 
 of muscle- invasive bladder carcinoma or metastasis. 
 ●  To  determine  the  disease-free  survival,  defined  as  the  time  from  the  start  of  therapy  to  the  date 
 of  recurrence  of  muscle  invasive  bladder  carcinoma  or  metastases,  and  overall  survival, 
 defined as the time from the start of immunotherapy to the date of death due to any cause. 
 ●  To  assess  the  safety  profile  and  tolerability  of  the  combination  of  durvalumab  plus 
 tremelimumab with concurrent radiotherapy. 
 ●  To  evaluate  the  long-term  functionalism  and  late  sequelae  of  the  treatment  in  the  preserved 
 bladders. 
 Exploratory Objective(s): 
 An  associated  translational  study  will  be  performed  to  analyze  and  characterize  changes  in  the  tumor 
 cell  and  inflammatory  stroma  induced  by  the  study  treatment  in  patients  with  poor  response. 
 Additionally,  the  predictive  value  of  immune  biomarkers  on  response  and  bladder  preservation  will  be 
 explored. 
 Exploratory objectives will be determined according the following determinations: 
 1. Peripheral blood: 
 Peripheral  lymphocytes  would  be  isolated  before  starting  first  dose  and  at  different  time  points  during 
 the  treatment  and  progression.  Recently  has  been  demonstrated  that  combination  of  anti-CTLA4  and 
 anti-PD1  leads  to  striking  change  in  characteristics  of  circulating  leukocytes  in  vivo,  so  peripheral 
 blood  analysis  might  carry  more  information  that  allow  us  to  unveil  the  dynamics  of  inflammatory  and 
 cancer  cells  in  peripheral  blood.  Blood  would  be  processed  for  DNA,  RNA,  miRNA,  and  exosomes 
 studies. 
 2. Urine samples (only for patients included in ICO L’Hospitalet): 
 The  samples  will  be  collected  at  the  time  of  screening  period  and  the  end  of  treatment  visit  to  detect 
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 and  to  quantify  CD8  and  CD4  lymphocytes  and  assess  their  immune  profile  (PD-1,  TIM-3,  CTLA-4, 
 ICOS,  and  4-1BB  expression  and  TCR  sequence.),  in  order  to  evaluate  possible  correlations  between  a 
 high  number  of  CD8-PDL1  with  worse  prognosis  (as  previously  reported  by  Dr.  Quezada,  J.  Exp. 
 Med.  2018).  Further  analysis  could  be  implemented  and  will  be  detailed  in  the  final  Clinical  Study 
 Report. 
 3. Tumor tissue: 
 Before  treatment  a  fresh  biopsy  from  primary  tumor  (initial  TUR)  will  be  processed  to  isolate  DNA, 
 RNA  and  paraffin  embedded  tissue  Ventana  SP263  assay  will  be  performed,  whole  exome-seq  (WES), 
 and  RNA-seq  to  get  information  on  tumor  somatic  mutations,  included  the  amino-acid  change  in 
 missense  mutations,  and  its  position  into  the  protein.  Additionally,  we  will  predict  the 
 immune-peptides  repertoire  for  each  patient,  combining  information  about  missense  mutations  and 
 inferred  HLA  alleles.  DNA  from  tumor  will  be  used  to  analyze  TCR-β  chain  clonality  analysis  to 
 achieve  information  about  T-cell  diversity  and  clonality  and  associate  to  treatment  benefit.  Paraffin 
 embedded  tissue  will  be  used  for  immunohistochemistry  to  study  tumor  inflammatory  stroma  (CD3; 
 CD4;  CD8;  CD45RO;  FoxP3,  CD20,  CD56;  CD64;  CD11b;  CD68;  among  others),  and  lymphocyte 
 exhaustion  markers  (PD-1;  PD-L1;  CD137;  Granzyme  B;  Perforin;  among  others).  It  won’t  be 
 necessary to wait to have the result of IHC to start study treatment. 
 A  second  biopsy  will  be  performed  after  therapy  in  patients  who  do  not  achieve  CR  and  the  sample 
 will  be  processed  the  same  way  as  the  original  biopsy  was.  The  objective  of  this  second  biopsy  is  to 
 study  inflammatory  changes  induced  by  treatment  by  immunohistochemistry  and  changes  in  T-cell 
 clonality.  WES  and  RNA-seq  will  allow  us  to  explore  whether  immunoediting  has  a  role  or  not  in 
 resistance  to  combined  treatment  with  checkpoint  inhibitors  and  radiotherapy,  as  immunogenic 
 antigens should be silenced during the treatment. 
 Study Design: 
 This  is  an  open,  multicenter,  phase  II  trial  of  the  combination  of  durvalumab  plus  tremelimumab  with 
 concurrent  normofractionated  radiotherapy  in  patients  with  localized  muscle  invasive  bladder  cancer 
 treated  with  a  selective  multi-modality  bladder  conservative  approach.  The  study  will  be  conducted  in 
 7  centers  with  multidisciplinary  teams  with  wide  experience  in  multi-modality  bladder  preservation 
 therapy. 
 The  treatment  consists  of  initial  transurethral  resection  (TUR)  of  the  tumor,  with  multiple  random 
 biopsies  of  normal-appearing  bladder  urothelium,  followed  by  durvalumab  1500  mg  i.v.  plus 
 tremelimumab  75  mg  i.v.,  every  4  weeks  for  a  total  of  3  doses.  Two  weeks  after  the  initiation  of 
 immunotherapy,  normofractionated  external-beam  radiotherapy  with  high-energy  photons  will  be 
 started.  Radiotherapy  will  be  administered  concurrently  with  immunotherapy  at  doses  of  46  Gy  to  the 
 minor  pelvis  and  64-66  Gy  to  the  bladder.  Afterwards,  a  urologic  evaluation  of  response  will  be 
 performed.  Response  is  defined  as  an  absence  of  invasive  cancer  at  post-immunotherapy  biopsy 
 (≤cT1).  Patients  with  response  to  immunotherapy  will  be  candidates  to  bladder  preservation,  whereas 
 in  those  with  residual  muscle  invasive  tumor  the  possibility  of  salvage  radical  cystectomy  must  be 
 evaluated.  Patients  developing  an  isolated  bladder  invasive  relapse  during  follow-up  will  be  also 
 possible  candidates  to  salvage  cystectomy,  whereas  those  developing  a  superficial  relapse  in  the 
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 preserved bladder will be managed with TUR and intravesical BCG. 
 The  primary  endpoint  of  the  study  is  pathological  response  evaluated  by  biopsy  performed  via 
 cystoscopy  at  the  end  of  the  treatment.  Pathological  response  is  defined  as  the  absence  of 
 muscle-invasive  bladder  cancer  at  post-treatment  biopsy  (≤cT1).  The  study  will  be  conducted  using  a 
 two-stage  sequential  design.  Using  the  assumption  that  the  treatment  would  be  considered  ineffective 
 if  it  had  a  response  proportion  similar  to  radiotherapy  alone  (P0:  0.5)  but  would  be  of  considerable 
 interest  if  it  had  a  response  proportion  of  70%  of  more  (P1:  0.7),  the  sample  size  requirement  is  12 
 patients  for  the  first  stage  and  20  additional  patients  for  the  second  stage.  Six  or  more  responses  in  the 
 first  stage  were  required  for  continuation  to  second  stage  accrual.  The  study  was  planned  to  have  a 
 type I error of 0.10 and a power of 80% in a one sided test. 
 Number of Centers: 
 7 centers belonging to the Spanish Oncology Genitourinary Group (SOGUG) 
 Number of Patients: 
 The  total  sample  size  will  be  32  patients:  12  patients  for  the  first  stage  and  20  additional  patients  for 
 the second stage (see study design) 
 Study Population: 
 Patients with non-previously treated localized muscle invasive bladder cancer 
 Inclusion Criteria: 
 Patients  diagnosed  with  urothelial  carcinoma  of  the  bladder,  in  clinical  stages  T2-4a  N0  M0,  who  are 
 not candidates for radical cystectomy by medical reasons, refusal or patient’s choice. 
 1.  Patients must have signed the informed consent prior to undergoing any study procedure. 
 2.  Patients must be 18 years of age or older. 
 3.  Patients must have ECOG performance status 0 or 1. 
 4.  A paraffin-embedded tumor sample must be available for the associate molecular study. 
 5.  Body weight >30 Kg. 
 6.  Adequate normal organ and marrow function as defined in section 4.1 of this protocol. 
 7.  Evidence  of  post-menopausal  status  or  negative  urinary  or  serum  pregnancy  test  for  female 
 pre-menopausal patients, according to what is detailed in section 4.1 of this protocol. 
 8.  Patient is willing and able to comply with the protocol for the duration of the study. 
 Exclusion Criteria: 
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 1.  Involvement  in  the  planning  and/or  conduct  of  the  study  (applies  to  both  Sponsor  staff  and/or 
 staff at the study site). 
 2.  Participation in another clinical study with an investigational product during the last 30 days. 
 3.  Concurrent 
 enrolment 
 in 
 another 
 clinical 
 study 
 unless 
 it  is  an  observational 
 (non-interventional) clinical study or during the follow-up period of an interventional study. 
 4.  Involvement  in  the  planning  and/or  conduct  of  the  study  (applies  to  both  Sponsor  staff  and/or 
 staff at the study site). 
 5.  Participation in another clinical study with an investigational product during the last 30 days. 
 6.  Concurrent 
 enrolment 
 in 
 another 
 clinical 
 study 
 unless 
 it  is  an  observational 
 (non-interventional) clinical study or during the follow-up period of an interventional study. 
 7.  Previous  treatment  with  radiotherapy  to  the  bladder,  systemic  chemotherapy  or  immune 
 checkpoint  inhibitors.  Prior  intravesical  Bacillus  Calmette-Guérin  (BCG)  treatment  for 
 non-muscle invasive bladder cancer is allowed, 28 days prior to study. 
 8.  Presence of regional lymph node or metastatic extension of the disease. 
 9.  Any  unresolved  toxicity  NCI  CTCAE  Grade  ≥2  from  previous  anticancer  therapy  with  the 
 exception  of  alopecia,  vitiligo,  and  the  laboratory  values  defined  in  the  inclusion  criteria. 
 Patients  with  Grade  ≥2  neuropathy  will  be  evaluated  on  a  case-by-case  basis  after  consultation 
 with  the  Study  Physician.  Patients  with  irreversible  toxicity  not  reasonably  expected  to  be 
 exacerbated  by  treatment  with  durvalumab  or  tremelimumab  may  be  included  only  after 
 consultation with the Study Physician. 
 10.  Any  concurrent  chemotherapy,  investigational  product  (IP)  other  than  studied  in  this  protocol, 
 biologic,  or  hormonal  therapy  for  cancer  treatment.  Concurrent  use  of  hormonal  therapy  for 
 non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable. 
 11.  Major  surgical  procedure  (as  defined  by  the  Investigator)  within  28  days  prior  to  the  first  dose 
 of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
 12.  History of  allogeneic  organ transplantation. 
 13.  Active  or  prior  documented  autoimmune  or  inflammatory  disorders,  as  it  is  detailed  in  section 
 4.2 of this protocol. 
 14.  Uncontrolled intercurrent illness, please see section 4 of this protocol. 
 15.  History of another primary malignancy as detailed in section 4 of this protocol. 
 16.  History of active primary immunodeficiency 
 17.  Active infection (see section 4 of this protocol) 
 18.  Current  or  prior  use  of  immunosuppressive  medication  within  14  days  before  the  first  dose  of 
 durvalumab or tremelimumab. Exceptions are listed in section 4 of this protocol. 
 19.  Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP 
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 20.  Female  patients  who  are  pregnant  or  breastfeeding  or  male  or  female  patients  of  reproductive 
 potential  who  are  not  willing  to  employ  effective  birth  control  according  what  is  detailed  in 
 this protocol (section 4) 
 21.  Known  allergy  or  hypersensitivity  to  any  of  the  study  drugs  or  any  of  the  study  drug 
 excipients. 
 22.  Prior  randomisation  or  treatment  in  a  previous  durvalumab  and/or  tremelimumab  clinical 
 study. 
 23.  Judgment  by  the  investigator  that  the  patient  is  unsuitable  to  participate  in  the  study  and  the 
 patient is unlikely to comply with study procedures, restrictions and requirements. 
 24.  Known allergy or hypersensitivity to IP or any excipient 
 Investigational Product(s), Dose, and Mode of Administration: 
 Durvalumab  1500mg  plus  tremelimumab  75mg  via  IV  infusion  Q4W,  starting  on  Week  0,  for  a  total  of 
 3  doses.  N.B  If  a  patient’s  weight  falls  to  30kg  or  below  the  patient  should  receive  weight-based 
 dosing  equivalent  to  20  mg/kg  of  durvalumab  Q4W  and  1mg/kg  tremelimumab  Q4W  until  the  weight 
 improves  to  >30  kg,  at  which  point  the  patient  should  start  receiving  the  fixed  dosing  of  durvalumab 
 1500mg plus tremelimumab 75 mg Q4W). 
 Two  weeks  after  the  initiation  of  immunotherapy,  normofractionated  external-beam  radiotherapy  with 
 high-energy  photons  will  be  started.  Radiotherapy  will  be  administered  concurrently  with 
 immunotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. 
 Study Assessments and Criteria for Evaluation: 
 Safety Assessments: 
 Toxicity  of  the  treatment  will  be  assessed  and  graded  using  Common  Terminology  Criteria  for 
 Adverse  Events  CTCAE  v4.03  and  the  Toxicity  criteria  of  the  Radiation  Therapy  Oncology  Group 
 (RTOG)  and  the  European  Organization  for  Research  and  Treatment  of  Cancer  (EORTC)  criteria. 
 Patients will be evaluated weekly from the start until the end of treatment (week 12). 
 To  monitor  accurately  the  potential  toxicity  of  radiotherapy  associated  with  durvalumab  and 
 tremelimumab,  an  initial  cohort  of  5  patients  will  be  treated.  If  no  dose  limiting  toxicity  is  observed  in 
 ≥2  of  these  patients  (in  observation  period  of  12  weeks  (4  weeks  after  RT)  ,  the  rest  of  patients  will  be 
 treated  at  full  doses.  In  contrast,  if  severe  toxicity  is  observed  in  ≥2  of  these  patients,  3  additional 
 patients  will  be  treated.  If  dose-limiting  toxicity  is  seen  in  one  of  these  additional  patients  during 
 observation  period,  the  therapeutic  regimen  will  be  modified  in  the  subsequent  ones,  administering  full 
 doses of durvalumab but discontinuing tremelimumab after the first dose. 
 Efficacy Assessments: 
 The  primary  endpoint  of  the  study  is  pathological  response  evaluated  by  biopsy  performed  via 
 cystoscopy  at  the  end  of  the  treatment.  Pathological  response  is  defined  as  the  absence  of 
 muscle-invasive bladder cancer at post-treatment biopsy (≤cT1). 
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 Secondary  endpoints  are:  Rate  of  patients  with  bladder  preserved,  rate  of  immediate  and  late  salvage 
 cystectomies;  survival  with  bladder  preserved  free  of  tumor,  defined  as  the  time  from  the  start  of 
 immunotherapy  to  either  the  date  of  cystectomy  or  the  date  of  recurrence  of  muscle-  invasive  bladder 
 carcinoma  or  metastasis;  disease-free  survival,  defined  as  the  time  from  the  start  of  therapy  to  the  date 
 of  recurrence  of  muscle  invasive  bladder  carcinoma  or  metastases,  and  overall  survival,  defined  as  the 
 time  from  the  start  of  immunotherapy  to  the  date  of  death  due  to  any  cause;  safety  profile  and 
 tolerability  of  the  combined-modality  treatment  and  long-term  functionalism  and  late  sequelae  of  the 
 treatment in the preserved bladders . 
 Statistical Methods and Data Analysis: 
 The  primary  endpoint  of  the  study  is  pathological  response  evaluated  by  biopsy  performed  via 
 cystoscopy  at  the  end  of  the  treatment.  Pathological  response  is  defined  as  the  absence  of 
 muscle-invasive  bladder  cancer  at  post-treatment  biopsy  (≤cT1).  The  study  will  be  conducted  using  a 
 two-stage  sequential  _Simon  optimal  design.  Using  the  assumption  that  the  treatment  would  be 
 considered  ineffective  if  it  had  a  response  proportion  similar  to  radiotherapy  alone  (P0:  0.5)  but  would 
 be  of  considerable  interest  if  it  had  a  response  proportion  of  70%  of  more  (P1:  0.7),  the  sample  size 
 requirement  is  12  patients  for  the  first  stage  and  20  additional  patients  for  the  second  stage.  Six  or 
 more  responses  in  the  first  stage  are  required  for  continuation  to  second  stage  accrual.  The  study  is 
 planned to have a type I error of 0.10 and power of 80% one sided test. 
 Sample Size Determination: 
 The  sample  size  requirement  is  12  patients  for  the  first  stage  and  20  additional  patients  for  the  second 
 stage. Six or more responses in the first stage are required for continuation to second stage accrual. 
 Protection of Personal Data 
 The  Sponsor  is  committed  to  compliance  with  Organic  Law  3/2018,  of  December  5,  Protection  of 
 Personal  Data  and  guarantee  of  digital  rights  as  well  as  Regulation  (EU)  2016/679  of  the  European 
 Parliament and the Council of April 27 of 2016 Data Protection (RGPD). 
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 Protocol assessments: 
 Protocol Activities 
 Screening 
 ( ≤28 Days Prior 
 to 
 Randomization ) 
 Treatment Period (treatment period for durvalumab + tremelimumab 
 and radiotherapy). 
 Response 
 evaluation to 
 therapy  j 
 Follow-up  k 
 W 
 1 
 W 
 2 
 W 
 3 
 W 
 4 
 W 
 5 
 W 
 6 
 W 
 7 
 W 
 8 
 W 
 9 
 W1 
 0 
 W1 
 1 
 W12 
 (End of 
 treatment visit) 
 Written informed 
 consent/assignment of patient 
 identification number 
 X 
 Preliminary eligibility fulfillment 
 (investigator’s opinion) 
 X 
 Demography and history of 
 tobacco and alcohol use 
 X 
 Previous treatments for bladder 
 cancer 
 X 
 Recent formalin-fixed tumour 
 biopsy 
 X 
 Formal verification of eligibility 
 criteria 
 X 
 Medical and surgical history 
 X 
 Hepatitis B and C; HIV 
 X 
 Urine hCG or serum βhCG  a 
 X 
 X 
 Durvalumab administration 
 X 
 X 
 X 
 Tremelimumab administration 
 X 
 X 
 X 
 Radiotherapy administration 
 X 
 X 
 X 
 X 
 X 
 X 
 Physical examination  b 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Vital signs 
 (pre-, during and post-infusion vital 
 signs assessments)  c 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Weight 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 12- lead ECG  d 
 X 
 X 
 Adverse event/serious adverse 
 event assessment 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Concomitant medications 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 ECOG 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Serum chemistry 
 (complete clin. chem. panel 
 including liver enzymes)  e 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Thyroid function tests 
 (TSH and fT3 and fT4)  f 
 X 
 X 
 X 
 X 
 X 
 Hematology  e 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Urinalysis  g 
 X 
 X 
 X 
 X 
 X 
 Coagulation parameters  h 
 X 
 X 
 Cystoscopy and random biopsies 
 X 
 X 
 Tumour assessment (CT scan)  i 
 X 
 X 
 X 
 Biomarker/pharmacodynamic 
 sampling 
 Peripheral blood  l 
 X 
 X 
 X 
 X 
 Fresh tumor biopsies  m 
 X 
 X 
 Urine samples  n 
 X 
 X 
 a  Pre-menopausal female patients of childbearing potential  only 
 b  Full physical examination at baseline; targeted  physical examination at other time points 
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 c  Patients  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  (i.e.,  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  follow  the  principles  as  described  above 
 or more frequently if clinically indicated. 
 d  ECG during screening and on cycle 1 Day 1 within  1 hr prior to the start of the first study treatment. Thereafter as clinically indicated. 
 e  According  what  is  detailed  on  tables  4  and  5.  If  screening  laboratory  assessments  are  performed  within  3  days  prior  to  Day  1  they  do  not 
 need  to  be  repeated  at  Day  1.  Results  for  safety  bloods  must  be  available  and  reviewed  before  commencing  an  infusion.  Gamma 
 glutamyltransferase  tested  at  Screening,  Day  1  and  as  clinically  indicated.  Depending  on  the  profile  of  the  combination  agent,  the 
 frequency of the hematology, serum chemistry and LFT testing may need to be increased to every two weeks. 
 f  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. 
 g  Urinalysis performed at Screening, Day 1, every  4 weeks and as clinically indicated. 
 h  Coagulation  tests:  prothrombin  time,  APTT  and  INR  –  to  be  performed  at  screening  and  EoT  visit,  and  only  as  clinically  indicated 
 thereafter. 
 i  Timing of CT scans: 
 - Initial Staging: thorax, abdomen and pelvis CT scan 
 - Post-therapy re-staging (week 12): thorax, abdomen and when applicable pelvis  CT scan 
 j  Six weeks since the end of radiotherapy. Cystoscopy  and bladder biopsy will be performed for ALL patients as an efficacy determination 
 k  Follow-up:  Pelvis  and  abdomen  CT  scan,  urine  cytology  and  Rx  Thorax  every  3  months  the  first  year,  every  4  months  the  second  year 
 and  every  6  months  thereafter.  Additional  cystoscopy  and  bladder  biopsy  will  be  performed  in  case  of  detection  abnormalities  in  the 
 cytology or imaging studies 
 l  Peripheral  blood:  Week  1  prior  to  the  administration  of  durvalumab  and  tremelimumab,  W2  before  initiation  of  RT,  W8  at  the  end  of  RT, 
 and W12 at the time of tumor response 
 m  Fresh  tumor  biopsies:  A  fresh  biopsy  sample,  optional,  at  the  time  of  initial  TUR.  Those  patients  who  have  not  achieved  complete 
 response  will  be  submitted  to  a  fresh  biopsy,  if  not  clinically  contraindicated.  It  will  be  required  to  send  fresh  and  formalin  fixed  samples 
 of the pathological surgical specimen from patients who are candidate to salvage cystectomy. 
 n  Urine  samples  (Optional):  only  for  patients  included  in  ICO  L’Hospitalet.  The  samples  will  be  collected  at  the  time  of  screening  periode 
 and the end of treatment visit. The first urine in the morning would be collected using a standard testing tube of 50 ml. 
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 Table of contents 
 PROTOCOL SYNOPSIS 
 4 
 ABBREVIATIONS AND DEFINITION OF TERMS 
 18 
 1. INTRODUCTION 
 22 
 1.1. Disease background 
 22 
 1.1.1. Immunotherapies 
 22 
 1.1.2. Durvalumab 
 24 
 1.1.3. Tremelimumab 
 24 
 1.1.4. Durvalumab in combination with tremelimumab 
 25 
 1.1.5. Combination with Radiotherapy 
 25 
 1.2. Research hypothesis 
 26 
 1.3. Rationale for conducting this study 
 26 
 1.3.1. Durvalumab + tremelimumab combination therapy dose rationale 
 27 
 1.3.2. Rationale for fixed dosing 
 29 
 1.3.3. Radiotherapy dose 
 30 
 1.4. Benefit-risk and ethical assessment 
 30 
 1.4.1. Durvalumab + tremelimumab 
 30 
 1.4.1.1. Overall risks 
 30 
 1.4.1.2. Durvalumab 
 31 
 1.4.1.3. Tremelimumab 
 32 
 1.4.2. Durvalumab + tremelimumab 
 33 
 2. STUDY OBJECTIVE 
 34 
 2.1. Primary objective(s) 
 34 
 2.2. Secondary objective(s) 
 34 
 2.3. Exploratory objective(s) 
 34 
 3. STUDY DESIGN 
 34 
 3.1. Overview of study design 
 34 
 3.2. Study schema 
 36 
 3.3. Study oversight for safety evaluation 
 38 
 4. PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, RESTRICTIONS, 
 DISCONTINUATION AND WITHDRAWAL 
 38 
 4.1. Inclusion criteria 
 38 
 4.2. Exclusion criteria 
 40 
 4.3. Study oversight for safety evaluation 
 43 
 4.4. Withdrawal of patients from study treatment 
 43 
 4.5. Withdrawal of patients from study 
 44 
 4.6. Withdrawal of consent 
 44 
 5. INVESTIGATIONAL PRODUCTS 
 45 
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 5.1. Durvalumab and tremelimumab 
 45 
 5.2. Durvalumab (MEDI4736) 
 45 
 5.3. Tremelimumab 
 45 
 5.4. Formulation/packaging/storage 
 45 
 5.5 Dose and treatment regimens 
 46 
 5.5.1. Treatment regimens 
 46 
 5.5.2. Study drug preparation of durvalumab and tremelimumab 
 46 
 5.5.2.1. Preparation of durvalumab doses for administration with an IV bag 
 46 
 5.5.2.2. Preparation of tremelimumab doses for administration with an IV bag 
 47 
 5.5.3. Monitoring of dose administration 
 48 
 5.5.4. Accountability and dispensation of IMPs 
 49 
 5.5.5. Disposition of unused investigational study drug 
 49 
 6. TREATMENT PLAN 
 50 
 6.1. Dose modification and toxicity management 
 50 
 6.1.1. Radiotherapy 
 50 
 6.1.2. Durvalumab and tremelimumab 
 51 
 7. RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENTS 
 52 
 7.1. Restrictions during the study 
 52 
 7.2. Concomitant treatment(s) 
 54 
 7.2.1. Permitted concomitant medications 
 54 
 7.2.2. Excluded concomitant medications 
 54 
 8. STUDY PROCEDURES 
 55 
 8.1. Schedule of study procedures 
 55 
 8.1.1. Screening phase 
 56 
 8.1.2. Treatment phase 
 57 
 8.1.3. End of treatment and follow-up visits 
 58 
 8.1.4. Safety 
 58 
 8.1.5. Follow-up Visits 
 58 
 8.2. Description of study procedures 
 59 
 8.2.1. Medical history and physical examination, electrocardiogram, weight and vital 
 signs 
 59 
 8.2.2. Physical examination 
 59 
 8.2.3. Electrocardiograms 
 59 
 8.2.4. Vital signs 
 59 
 8.2.4.1. First infusion 
 60 
 8.2.4.2. Subsequent infusions 
 60 
 8.2.5. Clinical laboratory tests 
 60 
 8.3. Biological sampling procedures 
 62 
 8.3.1. Biomarker/pharmacodynamic sampling and evaluation methods 
 62 
 8.3.1.1. Peripheral blood 
 62 
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 8.3.1.2. Urine  samples 
 63 
 8.3.2. Estimate of volume of blood to be collected 
 64 
 8.3.3 Fresh tumor biopsies 
 64 
 8.3.4. Future biomarker studies and sample disposal 
 69 
 If future biomarker research is not consented samples will be kept at the central 
 laboratory and then disposed of in five years. 
 69 
 8.3.5. Withdrawal of informed consent for donated biological samples 
 69 
 9. DISEASE EVALUATION AND METHODS 
 70 
 9.1. Efficacy variable 
 71 
 10. ASSESSMENT OF SAFETY 
 72 
 10.1. Safety parameters 
 73 
 10.1.1.  Definition of adverse events 
 73 
 10.1.2. Definition of serious adverse events 
 73 
 10.1.3. Durvalumab + tremelimumab adverse events of special interest 
 73 
 10.2. Assessment of safety parameters 
 75 
 10.2.1. Assessment of severity 
 75 
 10.2.2. Assessment of relationship 
 76 
 10.3. Recording of adverse events and serious adverse events 
 77 
 10.3.1. Study recording period and follow-up for adverse events and serious adverse 
 events 
 78 
 10.3.2. Causality collection 
 78 
 10.3.3. A guide to the interpretation of the causality question is found in next section. 
 Relationship to protocol procedures 
 79 
 10.3.4. Adverse events based on signs and symptoms 
 79 
 10.3.5. Adverse events based on examinations and tests 
 79 
 10.3.6. Hy’s Law 
 80 
 10.3.7. Disease progression 
 80 
 10.3.8. New cancers 
 80 
 10.3.9. Reporting of serious adverse events 
 80 
 10.3.9.1. Reporting of deaths to 
 81 
 10.3.10. Other events requiring reporting 
 82 
 10.3.10.1. Overdose 
 82 
 10.3.10.2. Pregnancy 
 83 
 10.3.11. Maternal exposure 
 83 
 10.3.12. Paternal exposure 
 83 
 10.4. Medication error 
 84 
 11. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
 85 
 11.1. Description of analysis sets 
 85 
 11.1.1. Safety analysis set 
 85 
 11.1.2. Efficacy analysis set 
 85 
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 11.2. Methods of statistical analyses 
 85 
 11.2.1. Safety analyses 
 85 
 11.2.2. Efficacy analyses and exploratory analyses 
 86 
 11.2.3. Interim analyses 
 87 
 11.3. Determination of sample size 
 87 
 12. ETHICAL AND REGULATORY REQUIREMENTS 
 87 
 12.1. Ethics Committee 
 87 
 12.2. Ethical Conduct of the Study 
 88 
 12.3. Patient Information and Consent 
 88 
 13. STUDY MANAGEMENT 
 89 
 13.1. Training of study site personnel 
 89 
 13.2. Monitoring of the study 
 89 
 13.3. Source data 
 90 
 13.4. Study timetable and end of study 
 91 
 14. DATA MANAGEMENT 
 91 
 14.1. Data Management Plan 
 91 
 14.2. Data Handling and Report Keeping 
 92 
 14.2.1. Electronic Data Capture 
 92 
 14.2.2. Record Retention 
 93 
 14.3. Sponsor Discontinuation Criteria 
 93 
 14.4. Study governance and oversight 
 94 
 14.4.1. Trial Insurance Policy 
 94 
 14.4.2. Publication Policy 
 94 
 14.4.3. Authorship 
 94 
 15. INVESTIGATIONAL PRODUCT AND TREATMENTS 
 95 
 15.1. Identity of investigational product(s) 
 95 
 16. LIST OF REFERENCES 
 95 
 APPENDICES 
 103 
 APPENDIX 1. DOSING MODIFICATION AND TOXICITY MANAGEMENT 
 GUIDELINES FOR IMMUNE-MEDIATED, INFUSION-RELATED, AND 
 NON-IMMUNE-MEDIATED REACTIONS (MEDI4736 MONOTHERAPY OR 
 COMBINATION THERAPY WITH TREMELIMUMAB OR TREMELIMUMAB 
 MONOTHERAPY) 
 103 
 APPENDIX 2. DURVALUMAB DOSE CALCULATIONS 
 134 
 APPENDIX 3. DURVALUMAB DOSE VOLUME CALCULATIONS 
 135 
 APPENDIX 4. TREMELIMUMAB DOSE CALCULATIONS 
 136 
 APPENDIX 5. TREMELIMUMAB DOSE VOLUME CALCULATIONS 
 137 
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 ABBREVIATIONS AND DEFINITION OF TERMS 
 The  following  abbreviations  and  special  terms  are  used  in  this  study  Clinical  Study 
 Protocol. 
 Abbreviation or special 
 term 
 Explanation 
AChE 
Acetylcholinesterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion  of  patients  alive  and  progression  free  at  12 months  from 
randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC  0-28day 
Area  under  the  plasma  drug  concentration-time  curve  from  time  zero  to  Day 
28 post-dose 
AUC  ss 
Area under the plasma drug concentration-time curve at steady state 
BCG 
Bacillus Calmette-Guérin 
BICR 
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
C  max 
Maximum plasma concentration 
C  max,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
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CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
C  trough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 
EC 
Ethics  Committee,  synonymous  to  Institutional  Review  Board  and 
Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
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IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
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PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
SOGUG 
Grupo Español para el Estudio del Cáncer Urológico 
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sPDL1 
Soluble programmed cell death ligand 1 
T  3 
Triiodothyronine 
T  4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
TUR 
Transurethral resection 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web-Based Data Capture 
WHO 
World Health Organization 
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 1. 
 INTRODUCTION 
 The  purpose  of  the  present  study  is  to  explore  feasibility,  toxicity  and  activity  of  the 
 integration  of  double-checkpoint  inhibition  immunotherapy,  associated  with  transurethral 
 resection  (TUR)  and  radiotherapy,  to  the  treatment  of  localized  muscle-invasive  bladder 
 cancer with selective bladder-preservation intent. 
 1.1. 
 Disease background 
 Urothelial  cancer  of  the  bladder  is  the  second  most  common  genitourinary  malignancy  in 
 developed  countries  and  third  most  common  cause  of  death  among  genitourinary  tumors. 
 Radical  cystectomy  has  long  been  considered  the  standard  treatment  for  patients  with 
 muscle-invasive  bladder  carcinoma.  Because  of  the  morbidity  and  decreased  quality  of 
 life  associated  with  this  procedure,  organ-preserving  alternatives  to  cystectomy  have  been 
 extensively  explored  (James  ND  et  al,  2012;  Milosevic  M  et  al  2007;  Mark  RH  et  al, 
 2014; Ploussard G et al, 2014; Shipley WU et al, 1998) . 
 1.1.1.  Immunotherapies 
 It  is  increasingly  understood  that  cancers  are  recognized  by  the  immune  system,  and, 
 under  some  circumstances,  the  immune  system  may  control  or  even  eliminate  tumors 
 (Dunn  2004)  PD-L1  is  a  member  of  the  B7  family  of  ligands  that  inhibit  T-cell  activity 
 through  binding  to  the  PD-1  receptor  (Keir  et  al  2008)  and  to  CD80  (Butte  et  al,  2007). 
 PD-L1  expression  is  an  adaptive  response  that  helps  tumors  evades  detection  and 
 elimination  by  the  immune  system.  Expression  of  PD-L1  protein  is  induced  by 
 inflammatory  signals  that  are  typically  associated  with  an  adaptive  immune  response 
 (e.g.,  IFNγ)  and  can  be  found  on  both  tumor  cells  (TC)  and  tumor  infiltrating  IC.  To 
 address  this  issue  is  important  in  bladder  cancer  context  because  PD-L1  is  widely 
 expressed  in  urothelial  tumor  cells  and  tumor  infiltrated  mononuclear  cells,  and  is 
 correlated  with  a  better  survival  in  some  studies  (Bellmunt  J  et  al,  2015).  The  binding  of 
 PD  L1  to  PD-1  on  activated  T  cells  delivers  an  inhibitory  signal  to  the  T  cells,  preventing 
 them  from  killing  target  TC,  and  protecting  the  tumor  from  immune  elimination  (Zou  and 
 Chen  2008).  PD-L1  may  also  inhibit  T  cells  through  binding  to  CD80,  although  the  exact 
 mechanism is still not elucidated (Butte et al, 2007; Paterson et al. 2011). 
 The  inhibitory  mechanism  described  above  is  co-opted  by  tumors  that  express  PD-L1  as  a 
 way  of  evading  immune  detection  and  elimination.  The  binding  of  an  anti-PD-L1  agent  to 
 the  PD-L1  receptor  inhibits  the  interaction  of  PD-L1  with  the  PD-1  and  CD80  receptors 
 expressed  on  immune  cells.  This  activity  overcomes  PD-L1–mediated  inhibition  of 
 antitumor  immunity.  While  functional  blockade  of  PD-L1  results  in  T-cell  reactivation, 
 this  mechanism  of  action  is  different  from  direct  agonism  of  a  stimulatory  receptor  such 
 as CD28 (Granier C et al, 2017). 
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 In  vivo  studies  have  shown  that  durvalumab  inhibits  tumor  growth  in  xenograft  models 
 via a T cell-dependent mechanism (Stewart et al 2015). 
 PD-L1  is  expressed  in  a  broad  range  of  cancers.  Based  on  these  findings,  an  anti-PD-L1 
 antibody  could  be  used  therapeutically  to  enhance  antitumor  immune  responses  in 
 patients  with  cancer.  Results  of  non-clinical  and  clinical  studies  of  monoclonal  antibodies 
 (mAbs)  targeting  the  PD-L1/PD-1  pathway  have  shown  evidence  of  clinical  activity  and 
 a  manageable  safety  profile,  supporting  the  hypothesis  that  an  anti-PD-L1  antibody  could 
 be  used  to  therapeutically  enhance  antitumor  immune  response  in  cancer  patients 
 (Brahmer  et  al.  2012;  Hirano  et  al.  2005;  Iwai  et  al.  2002;  Okudaira  et  al.  2009;  Topalian 
 et  al.  2012;  Zhang  et  al.  2008)  with  responses  that  tend  to  be  more  pronounced  in  patients 
 with  tumors  that  express  PD-L1  (Powles  et  al.  2014;  Rizvi  et  al  2015;  Segal  et  al  2016). 
 In  addition,  high  mutational  burden  e.g.,  in  bladder  carcinoma  (Alexandrov  et  al.  2013) 
 may contribute to the responses seen with immunotherapy. 
 In  contrast,  cytotoxic  T-lymphocyte-associated  antigen-4  (CTLA-4)  is  constitutively 
 expressed  by  regulatory  T  cells  and  upregulated  on  activated  T  cells.  CTLA-4  delivers  a 
 negative  regulatory  signal  to  T  cells  upon  binding  of  CD80  (B7.1)  or  CD86  (B7.2) 
 ligands  on  antigen-presenting  cells.  (Fife  and  Bluestone,  2008)  Blockade  of  CTLA-4 
 binding  to  CD80/86  by  anti-CTLA-4  antibodies  results  in  markedly  enhanced  T-cell 
 activation  and  antitumor  activity  in  animal  models,  including  killing  of  established 
 murine  solid  tumors  and  induction  of  protective  antitumor  immunity.  Therefore,  it  is 
 expected  that  treatment  with  an  anti  CTLA-4  antibody  will  lead  to  increased  activation  of 
 the  human  immune  system,  increasing  antitumor  activity  in  patients  with  solid  tumors  (Ni 
 L et al, 2017). 
 Pre-clinical  data  has  now  been  added  to  with  a  wealth  of  clinical  data  showing  that 
 blockade  of  negative  regulatory  signals  to  T-cells  such  as  cytotoxic  T-lymphocyte  antigen 
 4  (CTLA-4)  and  programmed  death  ligand  1  (PD-L1)  has  promising  clinical  activity 
 (Scott  Antonia,  Sarah  B  et  al,  2016).  Ipilimumab  was  granted  United  States  (US)  Food 
 and  Drug  Administration  (FDA)  approval  for  the  treatment  of  metastatic  melanoma  and 
 is  currently  under  investigation  for  several  other  malignancies  whilst  nivolumab  and 
 pembrolizumab,  two  anti-PD-1  agents  and  atezolizumab,  an  anti  PD-L1  agent  have  been 
 granted  approvals  by  agencies  such  as  the  United  States  of  America  Food  and  Drug 
 Administration  and  the  European  Medicines  Agency  approval  for  the  treatment  of  a 
 number  of  malignancies  including  metastatic  melanoma,  squamous  and  non-squamous 
 cell  non-small-cell  lung  cancer  and  urothelial  carcinoma.  In  addition,  data  from  agents  in 
 the  anti-PD-1/PD-L1  class  shows  clinical  activity  in  a  wide  range  of  tumor  types  (Homet 
 Moreno B, et al, 2015). 
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 1.1.2.  Durvalumab 
 Durvalumab  is  a  human  monoclonal  antibody  (mAb)  of  the  immunoglobulin  G  (IgG)  1 
 kappa  subclass  that  blocks  the  interaction  of  PD-L1  (but  not  programmed  cell  death 
 ligand-2)  with  PD-1  on  T  cells  and  CD80  (B7.1)  on  immune  cells  (IC).  It  is  being 
 developed  by  AstraZeneca/MedImmune  for  use  in  the  treatment  of  cancer  (MedImmune 
 is  a  wholly  owned  subsidiary  of  AstraZeneca;  AstraZeneca/MedImmune  will  be  referred 
 to  as  AstraZeneca  throughout  this  document.)  Durvalumab  has  been  engineered  to  reduce 
 antibody-dependent  cellular  cytotoxicity  and  complement-dependent  cytotoxicity.  In  vitro 
 studies  demonstrate  that  durvalumab  antagonizes  the  inhibitory  effect  of  PD-L1  on 
 primary  human  T  cells,  resulting  in  their  restored  proliferation  and  release  of  interferon 
 gamma (IFNγ; Stewart et al. 2015). 
 As  of  the  data  cut-off  (DCO)  date  (12  July  2017),  an  estimated  4067  patients  have  been 
 exposed  to  1  or  more  doses  of  durvalumab  in  ongoing  AstraZeneca-sponsored  Phase  I  to 
 III  studies,  either  as  monotherapy  or  in  combination,  and  5911  patients  where  the 
 treatment  arm  is  blinded.  Additionally,  approximately  4000  patients  have  been  exposed  to 
 1  or  more  doses  of  durvalumab  in  externally-sponsored/investigator-initiated  clinical 
 trials (ESR/IITs) (see Durvalumab IB version 12, Appendix B Table 46). 
 Estimates  of  overall  cumulative  patient  exposure  based  on  actual  exposure  data  from  any 
 completed  clinical  trials  and  the  enrolment/randomisation  schemes  for  ongoing  open 
 label  and  blinded  trials  are:  3723  patients  received  durvalumab  monotherapy  and  3372 
 received  durvalumab  in  combination  with  tremelimumab.  No  AstraZeneca  or 
 MedImmune  study  has  been  terminated  prematurely  due  to  toxicity.  Refer  to  the  current 
 durvalumab  Investigator’s  Brochure  for  a  complete  summary  of  non-clinical  and  clinical 
 information including safety, efficacy and pharmacokinetics. 
 1.1.3.  Tremelimumab 
 Tremelimumab  is  a  human  immunoglobulin  (Ig)G2  mAb  that  is  directed  against 
 CTLA-4;  cluster  of  differentiation  [CD]152),  a  cell  surface  receptor  that  is  expressed 
 primarily  on  activated  T  cells  and  acts  to  inhibit  their  activation.  Tremelimumab 
 completely  blocks  the  interaction  of  human  CTLA-4  with  CD80  and  CD86,  resulting  in 
 increased  release  of  cytokines  (interleukin  [IL]-2  and  interferon  [IFN]-γ)  from  human  T 
 cells,  peripheral  blood  mononuclear  cells  and  whole  blood  (Tarhini and Kirkwood 2008). 
 Tremelimumab is being developed by AstraZeneca for use in the treatment of cancer. 
 As  of  the  data  cutoff  date  (12  July  2017),  approximately  1617  patients  have  been  exposed 
 to  one  or  more  doses  of  tremelimumab  monotherapy  across  the  program;  574  patients 
 from  AstraZeneca/MedImmune  sponsored  studies  and  936  patients  from  legacy  studies 
 (monotherapy)  and  107  patients  from  externally  sponsored  studies.  Details  on  the  safety 
 profile  of  tremelimumab  monotherapy  are  summarized  in  Tremelimumab  IB,  section 
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 5.2.2.  Refer  to  the  current  tremelimumab  Investigator’s  Brochure  for  a  complete 
 summary  of  non-clinical  and  clinical  information  including  safety,  efficacy  and 
 pharmacokinetics. 
 1.1.4.  Durvalumab in combination with tremelimumab 
 Because  the  mechanisms  of  action  of  CTLA-4  and  PD-1  are  non-redundant  targeting  both 
 PD-1  and  CTLA-4  pathways  may  have  additive  or  synergistic  activity  (Pardoll  2012); 
 therefore,  in  addition  to  evaluating  both  agents  in  the  monotherapy  setting  in  a  number  of 
 cancer  indications  AstraZeneca  is  also  investigating  the  use  of  durvalumab  + 
 tremelimumab combination therapy for the treatment of cancer. 
 Study  D4190C00006  is  a  Phase  Ib  dose-escalation  study  to  establish  the  safety, 
 PK/pharmacodynamics,  and  preliminary  anti-tumor  activity  of  durvalumab  + 
 tremelimumab  combination  therapy  in  patients  with  advanced  NSCLC.  The  dosing 
 schedule  utilized  is  durvalumab  every  2  or  4  weeks  (Q2W,  Q4W)  up  to  12 months, 
 combined  with  tremelimumab  Q4W  up  to  Week  24  for  7 doses  then  every  12 weeks 
 (Q12W)  for  2  additional  doses  for  up  to  12 months.  The  study  is  ongoing  and  continues 
 to  accrue  (Scott  Antonia,  Sarah  B  2016).  In  addition,  other  clinical  studies  have  since 
 started looking at the combination in both NSCLC and other oncology indications. 
 To  date  more  than  1000  patients  have  received  the  combination  using  several  doses  and 
 dosing  schedules.  Details  on  the  safety  profile  of  durvalumab  +  tremelimumab 
 combination  therapy  are  summarized  in  Section 1.4.2.  Refer  to  the  current  editions  of  the 
 durvalumab  and  tremelimumab  IBs  for  a  complete  summary  of  non-clinical  and  clinical 
 information including safety, PK and efficacy. 
 1.1.5.  Combination with Radiotherapy 
 Nonclinical  studies  suggest  that  radiotherapy  may  sensitize  tumor  cells  to 
 immune-mediated  attack  (McFarland  2012)  by  prompting  release  of  soluble  tumor 
 antigens  from  killed  cells  as  well  as  by  increasing  tumor  cell  surface  expression  of 
 antigens  and  receptors  mediating  T-cell  recognition  and/or  killing  and  enhanced 
 efficiency  of  professional  antigen-presenting  cells  (Ferrara  2009,  Kershaw  2013). 
 Together  with  the  observation  that  radiation  may  induce  expression  of  chemokines 
 needed  for  T-cell  trafficking  (Kershaw  2013,  Hellevik  2014),  these  data  suggest  that 
 radiation  can  function  as  an  immune  adjuvant  to  help  reverse  the  suppression  of  tumor 
 immune responses. 
 As 
 a 
 crucial 
 tumor 
 immune-evasion 
 mechanism, 
 however, 
 Treg-mediated 
 immunosuppression  may  be  a  key  obstacle  for  successful  tumor  immunotherapy  in 
 general,  and  following  radiation  in  particular.  Following  sub-lethal  irradiation  of 
 antigen-primed  mice,  antigen-specific  immune  suppression  mediated  primarily  by  CD4+ 
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 CD25+  Tregs  develops  over  several  weeks.  The  proportion  of  Treg  to  T  effector 
 populations  is  skewed,  with  higher  numbers  of  Tregs  (McFarland  2012).  The  influx  of 
 Treg  cells  into  an  irradiated  tumor  microenvironment  therefore  may  counteract  any 
 benefit  obtained  from  increased  antigen  release,  enhanced  antigen  presentation,  or  influx 
 of  T  effector  cells.  Data  from  mice  also  suggest  that  tumor  cells  may  counterbalance  this 
 effect  by  upregulating  PD-L1  in  response  to  radiation  (Deng  2014).  Importantly, 
 administration  of  an  anti-PD-L1  antibody  could  greatly  enhance  radiation-induced  tumor 
 regression  and  survival  in  this  study,  providing  strong  support  to  the  notion  that 
 PD-1/PD-L1  blockade  may  overcome  immunosuppression  mediated  by  radiation-induced 
 PD-L1 upregulation 
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 1.2. 
 Research hypothesis 
 Combined-modality  treatment  of  localized  muscle  invasive  bladder  cancer  including 
 TUR,  radiotherapy  and  dual  checkpoint  inhibition  immunotherapy  could  achieve 
 pathological  complete  response  in  some  patients.  These  patients  could  avoid  to 
 undergone  radical  surgery  with  radical  cystectomy  and  preserve  their  bladder,  without  the 
 side-effects associated with chemotherapy. 
 1.3. 
 Rationale for conducting this study 
 Several  studies  have  shown  that  long-term  bladder  preservation  can  be  achieved  in  a 
 significant  proportion  of  patients  with  a  multimodal  treatment,  including  transurethral 
 resection  (TUR)  of  the  bladder  tumor  and  radiotherapy,  often  associated  with  neoadjuvant 
 or  concurrent  chemotherapy  (James  2012,  Milosevic  2007,  Mak  2014,  Ploussard  2014, 
 Shippley  1998).  In  these  studies,  only  patients  who  achieve  a  pathological  complete 
 response  of  the  muscle-invasive  bladder  tumor  with  the  treatment  are  considered 
 candidates  for  bladder  preservation.  In  the  rest  of  patients,  salvage  cystectomy  should  be 
 at  last  recommended  (Kaufman  1993,  Mitin  2016).  Interestingly,  the  survival  rates 
 observed  using  this  approach  are  comparable  to  those  expected  with  aggressive  surgery 
 (Mak  2014,  Efstathiou  2015,  Arcangeli  2016).  These  studies  showed  that  this  approach  is 
 clearly  feasible  and  therefore  constitutes  an  alternative  to  standard  radical  surgery  for 
 patients  with  surgical  contraindication,  cystectomy  refusal  or  patient’s  choice.  Bladder 
 preservation  via  combined-modality  treatment  provides  a  considerable  improvement  in 
 the  quality  of  life  of  selected  patients  by  allowing  them  to  avoid  radical  cystectomy  (Mak 
 2016,  Efstathiou  2009).  However,  given  the  complexity  of  this  multimodality  treatment, 
 it  can  only  be  performed  in  centers  with  experienced  multidisciplinary  teams  including 
 urologists,  oncologists  and  radiotherapists.  Our  center,  ICO-HUB,  has  a  large  experience 
 in  bladder  preservation  therapy  with  radiotherapy  alone  and  associated  with 
 chemotherapy  (Garcia  del  Muro  X  2004).  Recently,  we  conducted  also  a  clinical  trial  of 
 multimodal  bladder  preservation  using  a  targeted  agent,  sorafenib,  in  combination  with 
 radiotherapy (Garcia del Muro X 2011). 
 The  incorporation  of  immunotherapy,  especially  double-checkpoint  inhibition,  to  the 
 multimodality  therapy  of  localized  muscle-invasive  bladder  cancer  could  have  potential 
 important  advantages  over  the  current  regimens  including  cisplatin-based  chemotherapy. 
 Firstly,  immunotherapy  habitually  lack  the  strong  toxicity  of  this  chemotherapy,  and 
 could  substitute  it  in  the  bladder-sparing  regimen.  Furthermore,  the  potential  of 
 immunotherapy  might  be  optimal  being  used  in  a  very  early  stage,  in  non-previously 
 treated  patients  with  low  tumor  burden,  without  presence  of  metastases,  and  without 
 significant  repercussion  in  the  performance  status.  Therefore,  the  purpose  of  the  present 
 study  is  to  explore  feasibility,  toxicity  and  activity  of  the  integration  of  double-checkpoint 
 inhibition  immunotherapy,  associated  with  TUR  and  radiotherapy,  to  the  treatment  of 
 localized  muscle-invasive  bladder  cancer  with  selective  bladder-preservation  intent. 
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 Additionally,  the  availability  of  a  recent  histologic  sample  before  the  start  of  treatment, 
 and  a  second  sample  after  the  treatment  in  those  patients  without  response  to  the 
 treatment, constitutes a valuable model for an associated translational study. 
 1.3.1.  Durvalumab + tremelimumab combination therapy dose rationale 
 The  durvalumab  +  tremelimumab  doses  and  regimen  selected  for  this  study  are  based  on 
 evidence,  the  goal  of  selecting  an  optimal  combination  dose  of  durvalumab  and 
 tremelimumab  that  would  yield  sustained  target  suppression  (sPD-L1),  demonstrate 
 promising efficacy, and have an acceptable safety profile. 
 Pharmacokinetics/Pharmacodynamics data 
 Study  D4190C00006  included  dose  cohorts  with  both  a  Q4W  and  a  Q2W  schedule  of 
 durvalumab  in  combination  with  a  Q4W  schedule  of  tremelimumab.  The  Q4W  schedule 
 was  included  to  align  with  the  Q4W  dosing  of  tremelimumab.  PK  simulations  from 
 durvalumab  monotherapy  data  indicated  that  a  similar  area  under  the  plasma  drug 
 concentration-time  curve  at  steady  state  (AUC  ss  ;  4  weeks)  was  expected  following  both 
 10 mg/kg  Q2W  and  20 mg/kg  Q4W  dosing  with  durvalumab.  The  observed  durvalumab 
 PK  data  from  the  D4190C00006  study  were  in  line  with  the  predicted  monotherapy  PK 
 data  developed  pre-clinically  and  in  line  with  that  seen  in  the  first-time-in-human  (FTIH), 
 single  agent  study  (CD-ON-MEDI4736-1108)  in  patients  with  advanced  solid  tumors. 
 This  demonstrates  similar  exposure  of  durvalumab  20  mg/kg  Q4W  and  10 mg/kg  Q2W, 
 with  no  alterations  in  PK  when  durvalumab  and  tremelimumab  (doses  ranging  from  1  to 
 3  mg/kg)  are  dosed  together.  While  the  median  maximum  plasma  concentration  at  steady 
 state  (C  max,ss  )  is  expected  to  be  higher  with  20 mg/kg  Q4W  (approximately  1.5  fold)  and 
 median  trough  concentration  at  steady  state  (C  trough,ss  )  is  expected  to  be  higher  with  10 
 mg/kg  Q2W  (approximately  1.25  fold),  this  is  not  expected  to  impact  the  overall  safety 
 and  efficacy  profile,  based  on  existing  preclinical  and  clinical  data  (Scott  Antonia,  Sarah 
 B 2016) . 
 Monotonic  increases  in  PDx  activity  were  observed  with  increasing  doses  of 
 tremelimumab  relative  to  the  activity  observed  in  patients  treated  with  durvalumab 
 monotherapy.  There  was  evidence  of  augmented  PDx  activity  relative  to  durvalumab 
 monotherapy  with  combination  doses  containing  1  mg/kg  tremelimumab,  inclusive  of 
 both the 15 and 20 mg/kg durvalumab plus 1 mg/kg tremelimumab combinations. 
 Clinical data 
 In  Study  D4190C00006  various  dose  combinations  have  been  explored,  with  doses  of 
 tremelimumab  ranging  from  1  to  10  mg/kg  and  doses  of  durvalumab  ranging  from  3 to  20 
 mg/kg.  Tremelimumab  was  given  on  a  Q4W  schedule  whilst  durvalumab  was  explored  in 
 both  a  Q4W  and  Q2W  schedule,  with  the  goal  of  identifying  the  dose  combination  that 
 best  optimizes  the  benefit-risk  profile  in  an  acceptable  range  of  PK  and 
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 pharmacodynamic values (Scott Antonia, Sarah B 2016). 
 Patients  treated  with  doses  of  tremelimumab  above  1 mg/kg  had  a  higher  rate  of  adverse 
 events  (AEs),  including  discontinuations  due  to  AEs,  serious  AEs  (SAEs),  and  severe 
 AEs.  Between  the  10 mg/kg  durvalumab  +  1 mg/kg  tremelimumab  and  10 mg/kg 
 durvalumab  +  3 mg/kg  tremelimumab  cohorts  treated  at  the  q2w  schedule,  the  number  of 
 patients  reporting  any  AE,  Grade  3  AEs,  SAEs,  and  treatment-related  AEs  was  higher  in 
 the  10 mg/kg  durvalumab  +  3 mg/kg  tremelimumab  cohort  than  the  10 mg/kg 
 durvalumab  +  1 mg/kg  tremelimumab  cohort.  A  similar  pattern  was  noted  in  the  q4w 
 regimens,  suggesting  that,  as  the  dose  of  tremelimumab  increased  above  1  mg/kg,  a 
 higher  rate  of  treatment-related  events  may  be  anticipated.  Further,  the  SAEs  frequently 
 attributed  to  immunotherapy,  pneumonitis  and  colitis,  were  more  commonly  seen  in 
 cohorts  using  either  3  or  10  mg/kg  of  tremelimumab  compared  to  the  1-mg/kg  dose 
 cohorts.  Together,  these  data  suggest  that  a  combination  using  a  tremelimumab  dose  of  1 
 mg/kg  appeared  to  minimize  the  rate  of  toxicity  when  combined  with  durvalumab.  Thus, 
 all  combination  doses  utilizing  either  the  3  or  10  mg/kg  doses  of  tremelimumab  were 
 eliminated in the final dose selection (Scott Antonia, Sarah B 2016). 
 In  contrast,  cohorts  assessing  higher  doses  of  durvalumab  with  a  constant  dose  of 
 tremelimumab  did  not  show  an  increase  in  the  rate  of  AEs.  The  data  suggested  that 
 increasing  doses  of  durvalumab  may  not  impact  the  safety  of  the  combination  as  much  as 
 the  tremelimumab  dose.  Further,  safety  data  between  the  10-mg/kg  and  20-mg/kg  cohorts 
 were similar, with no change in safety events with increasing dose of durvalumab. 
 In  Study  D4190C00006,  of  all  treatment  cohorts,  the  cohort  of  patients  treated  in  the 
 20 mg/kg  durvalumab  +  1  mg/kg  tremelimumab  group  had  a  tolerable  safety  profile,  but 
 still  showed  strong  evidence  of  clinical  activity.  No  dose-limiting  toxicities  (DLTs)  were 
 reported in this cohort. 
 Preliminary  clinical  activity  of  the  durvalumab  and  tremelimumab  combination  did  not 
 appear  to  change  with  increasing  doses  of  tremelimumab.  The  15-  and  20-mg/kg 
 durvalumab  q4w  cohorts  demonstrated  objective  responses  at  all  doses  of  tremelimumab, 
 and increasing doses of tremelimumab did not provide deeper or more rapid responses. 
 Efficacy  data  suggested  that  the  20 mg/kg  durvalumab  +  1 mg/kg  tremelimumab  dose 
 cohort  may  demonstrate  equivalent  clinical  activity  to  other  dose  combinations.  Of  the  14 
 patients  in  this  cohort,  there  were  4  patients  (29%)  with  PR,  4 patients  (29%)  with  SD, 
 and  2 patients  (14%)  with  PD.  Two  patients  were  not  evaluable  for  response  (Scott 
 Antonia, Sarah B 2016). 
 Altogether,  the  data  suggested  that  a  20 mg/kg  durvalumab  +  1 mg/kg  tremelimumab 
 dose combination should be selected for further development. 
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 Refer  to  the  current  durvalumab  Investigator’s  Brochure  for  a  complete  summary  of 
 non-clinical  and  clinical  information  on  the  durvalumab  +  tremelimumab  combination, 
 including safety, efficacy and pharmacokinetics. 
 1.3.2.  Rationale for fixed dosing 
 A  population  PK  model  was  developed  for  durvalumab  using  monotherapy  data  from  a 
 Phase  I  study  (study  1108;  N=292;  doses=0.1  to  10  mg/kg  Q2W  or  15  mg/kg  Q3W;  solid 
 tumors).  Population  PK  analysis  indicated  only  minor  impact  of  body  weight  (WT)  on  the 
 PK  of  durvalumab  (coefficient  of  ≤0.5).  The  impact  of  body  WT-based  (10  mg/kg  Q2W) 
 and  fixed  dosing  (750  mg  Q2W)  of  durvalumab  was  evaluated  by  comparing  predicted 
 steady  state  PK  concentrations  (5th,  median  and  95th  percentiles)  using  the  population 
 PK  model.  A  fixed  dose  of  750  mg  was  selected  to  approximate  10  mg/kg  (based  on 
 median  body  WT  of  ~75  kg).  A  total  of  1000  patients  were  simulated  using  body  WT 
 distribution  of  40–120  kg.  Simulation  results  demonstrate  that  body  WT-based  and  fixed 
 dosing  regimens  yield  similar  median  steady  state  PK  concentrations  with  slightly  less 
 overall between-patient variability with fixed dosing regimen. 
 Similarly,  a  population  PK  model  was  developed  for  tremelimumab  using  data  from 
 Phase  1  through  Phase  3  (N=654;  doses=0.01  to  15  mg/kg  Q4W  or  Q90D;  metastatic 
 melanoma)  (Wang  et al 2014).  Population  PK  model  indicated  minor  impact  of  body  WT 
 on  PK  of  tremelimumab  (coefficient  of  ≤0.5).  The  WT-based  (1  mg/kg  Q4W)  and  fixed 
 dosing  (75  mg/kg  Q4W;  based  on  median  body  WT  of  ~75  kg)  regimens  were  compared 
 using  predicted  PK  concentrations  (5th,  median  and  95th  percentiles)  using  population 
 PK  model  in  a  simulated  population  of  1000  patients  with  body  weight  distribution  of  40 
 kg  to  120  kg.  Similar  to  durvalumab,  simulations  indicated  that  both  body  WT-based  and 
 fixed  dosing  regimens  of  tremelimumab  yield  similar  median  steady  state  PK 
 concentrations with slightly less between-patient variability with fixed dosing regimen. 
 Similar  findings  have  been  reported  by  others  (Ng  et  al  2006;  Wang  et al 2009;  Zhang 
 et al 2012;  Narwal  et  al  2013).  Wang  and  colleagues  investigated  12  monoclonal 
 antibodies  and  found  that  fixed  and  body  size-based  dosing  perform  similarly,  with  fixed 
 dosing  being  better  for  7  of  12  antibodies  (Wang  et al 2009).  In  addition,  they 
 investigated  18  therapeutic  proteins  and  peptides  and  showed  that  fixed  dosing  performed 
 better  for  12  of  18  in  terms  of  reducing  the  between-patient  variability  in 
 pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012). 
 A  fixed  dosing  approach  is  preferred  by  the  prescribing  community  due  to  ease  of  use 
 and  reduced  dosing  errors.  Given  expectation  of  similar  pharmacokinetic  exposure  and 
 variability,  we  considered  it  feasible  to  switch  to  fixed  dosing  regimens.  Based  on 
 average  body  WT  of  75  kg,  a  fixed  dose  of  1500  mg  Q4W  durvalumab  (equivalent  to  20 
 mg/kg  Q4W)  and  a  fixed  dose  of  75  mg  Q4W  tremelimumab  (equivalent  to  1  mg/kg 
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 Q4W) is included in the current study. 
 1.3.3.  Radiotherapy dose 
 Radiotherapy  will  be  administered  at  standard  doses  for  radical  treatment  of  the  bladder 
 with  bladder-sparing  intent.  The  radiotherapy  schedule  selected  for  this  study  has  been 
 widely  used  in  several  bladder  preservation  studies  (James  ND1,  Hussain  SA,  Hall  E,  et 
 al.  Radiotherapy  with  or  without  chemotherapy  in  muscle-invasive  bladder  cancer.  N 
 Engl  J  Med.  2012  Apr  19;366(16):1477-88).  64  Gy  in  32  fractions,  given  as  2  Gy/day  (5 
 doses/week)  at  doses  of  46  Gy  to  the  minor  pelvis  (23  doses)  and  64-66  Gy  to  the  bladder 
 (32 doses) will be administered. 
 1.4. 
 Benefit-risk and ethical assessment 
 1.4.1.  Durvalumab + tremelimumab 
 1.4.1.1.  Overall risks 
 Monoclonal  antibodies  directed  against  immune  checkpoint  proteins,  such  as 
 programmed  cell  death  ligand  1  (PD-L1)  as  well  as  those  directed  against  programmed 
 cell  death-1  (PD-1)  or  cytotoxic  T-lymphocyte  antigen-4  (CTLA-4),  aim  to  boost 
 endogenous  immune  responses  directed  against  tumor  cells.  By  stimulating  the  immune 
 system however, there is the potential for adverse effects on other tissues. 
 Most  adverse  drug  reactions  seen  with  the  immune  checkpoint  inhibitor  class  of  agents 
 are  thought  to  be  because  of  inflammatory  cells  on  specific  tissues.  These  risks  are 
 generally  events  with  a  potential  inflammatory  mechanism  and  which  may  require  more 
 frequent  monitoring  and/or  unique  interventions  such  as  immunosuppressants  and/or 
 endocrine  replacement  therapy.  These  risks  include  gastrointestinal  AEs  such  as  colitis 
 and  diarrhoea,  pneumonitis  /interstitial  lung  disease  (ILD),  renal  AEs  such  as,  nephritis 
 and  increases  in  creatinine,  hepatic  AEs  such  as  hepatitis  and  liver  enzyme  elevations, 
 skin  events  such  as  rash  and  dermatitis,  endocrinopathies  such  as  hypo-  and 
 hyperthyroidism,  hypophysitis,  adrenal  insufficiency.  diabetes  mellitus  type  I  and 
 diabetes  insipidus,  and  neurotoxicities  such  as  myasthenia  gravis  and  Guillain-Barre 
 syndrome. 
 1.4.1.2.  Durvalumab 
 ADRs in durvalumab monotherapy 
 The 
 identified 
 risks 
 with 
 durvalumab 
 monotherapy 
 include 
 the 
 following: 
 cough/productive  cough,  pneumonitis,  ILD,  dysphonia,  ALT/AST  increased,  hepatitis, 
 diarrhoea,  abdominal  pain,  colitis,  hypothyroidism,  hyperthyroidism,  blood  TSH 
 increased,  blood  TSH  decreased,  adrenal  insufficiency,  Type  1  diabetes  mellitus, 
 hypophysitis/hypopituitarism,  diabetes  insipidus,  blood  creatinine  increased,  dysuria, 
 nephritis,  rash,  pruritus,  night  sweats,  dermatitis,  myocarditis,  pyrexia,  oedema 
 peripheral,  upper  respiratory  tract  infections,  pneumonia,  oral  candidiasis,  dental  and  oral 
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 soft  tissue  infections,  influenza,  myalgia,  myositis,  polymyositis  and  infusion-related 
 reaction. 
 ●  Potential  imAEs  for  durvalumab  and  durvalumab  in  combination  with 
 tremelimumab include 
 ○  Pancreatitis 
 ○  Other  rare  or  less  frequent  events  with  a  potential  immune-mediated 
 aetiology,  eg,  pericarditis,  sarcoidosis,  uveitis,  and  other  events  involving 
 the  eye  (eg,  keratitis  and  optic  neuritis),  skin  (eg,  scleroderma  and 
 vitiligo),  and  haematological  (eg,  haemolytic  anaemia  and  immune 
 thrombocytopenic 
 purpura), 
 rheumatological 
 events 
 (polymyalgia 
 rheumatica  and  autoimmune  arthritis)  and  neuropathy/neuromuscular 
 toxicities (eg, myasthenia gravis, Guillain Barre syndrome) 
 ●  Hypersensitivity reactions including: 
 ○  Anaphylaxis and allergic reaction 
 ○  Cytokine release syndrome 
 ○  Immune complex disease 
 ●  Other infections 
 A  detailed  summary  of  durvalumab  monotherapy  AE  data  can  be  found  in  the  current 
 version of the durvalumab IB. 
 In  monotherapy  clinical  studies  AEs  (all  grades)  reported  very  commonly  (≥10%  of 
 patients)  are  fatigue,  nausea,  decreased  appetite,  dyspnea,  cough,  constipation,  diarrhea, 
 vomiting,  back  pain,  pyrexia,  abdominal  pain,  anemia,  arthralgia,  peripheral  edema, 
 headache,  rash,  and  pruritus.  Approximately  8%  of  patients  experienced  an  AE  that 
 resulted  in  permanent  discontinuation  of  durvalumab.  and  approximately  5%  of  patients 
 experienced an SAE that was related to durvalumab by the study investigator. 
 The  majority  of  treatment-related  AEs  were  manageable  with  dose  delays,  symptomatic 
 treatment,  and  in  the  case  of  events  suspected  to  have  an  immune  basis,  the  use  of 
 established  treatment  guidelines  for  immune-mediated  toxicity  (see  the  Dosing 
 Modification and Toxicity Management Guidelines in appendix 1). 
 A  detailed  summary  of  durvalumab  monotherapy  AE  data  can  be  found  in  the  current 
 version of the durvalumab IB. 
 1.4.1.3.  Tremelimumab 
 Risks  with  tremelimumab  monotherapy  are  GI  effects  (colitis,  diarrhoea,  enterocolitis  and 
 intestinal  perforation),  endocrine  disorders  (hypo  and  hyperthyroidism,  hypophysitis  and 
 adrenal  insufficiency),  skin  effects  (rash,  and  pruritus),  elevations  in  lipase  and  amylase, 
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 other  gastrointestinal  events  e.g.  ulcerative  colitis,  dehydration,  nausea  and  vomiting; 
 hepatic  events  including  hepatitis,  and  liver  enzyme  elevations;  pneumonitis  and  ILD; 
 clinical  manifestations  of  pancreatitis;  nervous  system  events  including  encephalitis, 
 peripheral  motor  and  sensory  neuropathies,  Guillain-Barre  and  proximal  muscle 
 weakness; 
 cytopenias 
 including 
 thrombocytopenia, 
 anemia 
 and 
 neutropenia; 
 infusion-related  reactions,  anaphylaxis,  and  allergic  reactions;  renal  events  including 
 renal  failure,  acute  kidney  injury,  nephritis,  nephrotic  syndrome,  autoimmune  nephritis 
 and  electrolyte  abnormalities  such  as  hypokalemia;  autoimmune  diseases  including 
 autoimmune 
 arthritis, 
 Sjögren’s  syndrome  and  giant  cell  temporal  arteritis; 
 hyperglycemia  and  diabetes  mellitus;  and  pyrexia  (Comin-Anduix  B,  Escuin-Ordinas  H., 
 2016). 
 Further  information  on  these  risks  can  be  found  in  the  current  version  of  the 
 tremelimumab IB. 
 Using  pooled  data  from  monotherapy  clinical  studies  AEs  (all  grades)  reported  very 
 commonly  (≥10%  of  patients)  were  diarrhea,  nausea,  fatigue,  pruritus,  decreased  appetite, 
 rash,  vomiting,  dyspnea,  constipation,  cough,  pyrexia,  abdominal  pain,  decreased  weight, 
 headache,  asthenia,  and  anaemia.  Approximately  16%  of  patients  experienced  an  AE  that 
 resulted  in  permanent  discontinuation  of  tremelimumab  and  approximately  45%  of 
 patients experienced an SAE. 
 A  detailed  summary  of  tremelimumab  monotherapy  AE  data  can  be  found  in  the  current 
 version of the tremelimumab IB. 
 1.4.2.  Durvalumab + tremelimumab 
 The  safety  of  durvalumab  +  tremelimumab  combination  therapy  is  being  evaluated  in  the 
 ongoing  dose  escalation  and  dose  expansion  Study  006,  in  patients  with  NSCLC,  and  has 
 so far shown a manageable safety and tolerability profile. 
 The  potential  risks  with  the  combination  of  durvalumab  +  tremelimumab  are  similar  to 
 those  for  durvalumab  and  tremelimumab  monotherapy.  Emerging  data  from  study  006 
 and  from  combinations  of  other  agents  in  the  same  class  indicate  an  increased  frequency 
 and/or severity of some of these potential immune-mediated toxicities. 
 In  durvalumab+tremelimumab  combination  studies  at  the  dose  of  durvalumab  20  mg/kg 
 and  tremelimumab  1  mg/kg  AEs  (all  grades)  reported  very  commonly  (≥10%  of  patients) 
 are  fatigue,  diarrhoea,  nausea,  dyspnea,  decreased  appetite,  pruritus,  vomiting,  anaemia, 
 constipation, cough, abdominal pain, pyrexia, back pain, hyponatremia and rash. 
 Approximately  13%  of  patients  experienced  an  AE  that  resulted  in  permanent 
 discontinuation  of  study  drug  and  approximately  13%  of  patients  experienced  an  SAE 
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 that  was  related  to  durvalumab  and  tremelimumab  by  the  study  investigator  (Scott 
 Antonia, Sarah B 2016). 
 A  detailed  summary  of  durvalumab  +  tremelimumab  combination  AE  data  can  be  found 
 in the current version of the durvalumab IB. 
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 2. 
 STUDY OBJECTIVE 
 2.1. 
 Primary objective(s) 
 To  determine  the  efficacy  of  durvalumab  plus  tremelimumab  with  concurrent 
 radiotherapy  in  terms  of  pathological  response  rate  in  patients  with  localized  muscle 
 invasive bladder cancer treated with bladder preservation intent. 
 2.2. 
 Secondary objective(s) 
 • 
 To  determine  the  rate  of  patients  with  bladder  preserved,  the  rate  of  immediate  and 
 late  salvage  cystectomies  and  the  survival  with  bladder  preserved  free  of  tumor, 
 defined  as  the  time  from  the  start  of  immunotherapy  to  either  the  date  of  cystectomy 
 or the date of recurrence of muscle- invasive bladder carcinoma or metastasis. 
 • 
 To  determine  the  disease-free  survival,  defined  as  the  time  from  the  start  of  therapy 
 to  the  date  of  recurrence  of  muscle  invasive  bladder  carcinoma  or  metastases,  and 
 overall  survival,  defined  as  the  time  from  the  start  of  immunotherapy  to  the  date  of 
 death due to any cause 
 • 
 To  assess  the  safety  profile  and  tolerability  of  the  combination  of  durvalumab  plus 
 tremelimumab with concurrent radiotherapy 
 • 
 To  evaluate  the  long-term  functionalism  and  late  sequelae  of  the  treatment  in  the 
 preserved bladders 
 2.3. 
 Exploratory objective(s) 
 An  associated  translational  study  will  be  performed  to  analyze  and  characterize  changes 
 in  the  tumor  cell  and  inflammatory  stroma  induced  by  the  study  treatment,  in  patients 
 with  poor  response.  Additionally,  the  predictive  value  of  immune  biomarkers  on  response 
 and bladder preservation will be explored. 
 3. 
 STUDY DESIGN 
 3.1. 
 Overview of study design 
 This  is  an  open-label,  multicenter,  phase  II  trial  of  the  combination  of  durvalumab  plus 
 tremelimumab  with  concurrent  normofractionated  radiotherapy  in  patients  with  localized 
 muscle  invasive  bladder  cancer  treated  with  a  selective  multimodality  bladder 
 conservative  approach.  The  study  will  be  conducted  in  a  small  group  of  centers  with 
 multidisciplinary  teams  with  wide  experience  in  multimodality  bladder  preservation 
 therapy (7 centers belonging to SOGUG). 
 The  treatment  consisted  of  initial  transurethral  resection  (TUR)  of  the  tumor,  with 
 multiple  random  biopsies  of  normal-appearing  bladder  urothelium,  followed  by 
 durvalumab  1500  mg  i.v.  plus  tremelimumab  75  mg  i.v.,  every  4  weeks  for  a  total  of  3 
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 doses.  Two  weeks  after  the  initiation  of  immunotherapy,  normofractionated 
 external-beam  radiotherapy  with  high-energy  photons  will  be  started.  Radiotherapy  will 
 be  administered  concurrently  with  immunotherapy  at  doses  of  46  Gy  to  the  minor  pelvis 
 and  64-66  Gy  to  the  bladder. 
 Six  weeks  after  the  end  of  radiotherapy  as  an  efficacy 
 determination,  ALL  patients  will  undergo  a  new  cystoscopy  with  biopsies  of  the  tumor 
 bed  and  all  residual  present  lesions.  Response  is  defined  as  an  absence  of  invasive  cancer 
 at  post  immunotherapy  biopsy  (≤cT1).  Patients  with  response  to  immunotherapy  will  be 
 candidates  to  bladder  preservation,  whereas  in  those  with  residual  muscle  invasive  tumor 
 the  possibility  of  salvage  radical  cystectomy  must  be  evaluated.  Patients  developing  an 
 isolated  bladder  invasive  relapse  during  follow-up  will  be  also  possible  candidates  to 
 salvage  cystectomy,  whereas  those  developing  a  superficial  relapse  in  the  preserved 
 bladder will be managed with TUR and intravesical BCG. 
 To  monitor  accurately  the  potential  toxicity  of  radiotherapy  associated  with  durvalumab 
 and  tremelimumab,  an  initial  cohort  of  5  patients  of  first  Simon  Optimax  stage  of  12 
 patients,  will  be  treated.  If  no  dose  limiting  toxicity  is  observed  in  ≥2  of  these  patients  in 
 the  12  weeks  of  observation  period,  the  rest  of  patients  will  be  treated  at  full  doses.  In 
 contrast,  if  severe  toxicity  is  observed  in  ≥2  of  these  patients,  3  additional  patients  will  be 
 treated.  If  dose  limiting  toxicity  is  seen  in  one  of  these  additional  patients,  the  therapeutic 
 regimen  will  be  modified  in  the  subsequent  ones,  administering  full  doses  of  durvalumab 
 but discontinuing tremelimumab after the first dose. 
 Patients  will  be  followed  up  every  3  months  the  first  year,  every  4  months  the  second 
 year  and  every  6  months  thereafter  with  abdomen  and  pelvis  CT  scan,  Rx  thorax,  urine 
 cytology.  Additional  cystoscopy  and  bladder  biopsy  will  be  performed  anytime  in  case  of 
 detection  abnormalities  in  the  cytology  or  imaging  studies.  The  study  will  be  closed  2 
 years after the last patient inclusion. 
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 3.2. 
 Study schema 
 Protocol Activities 
 Screening 
 (≤28 Days Prior 
 to 
 Randomization) 
 Treatment Period (treatment period for durvalumab + 
 tremelimumab and radiotherapy). 
 Response 
 evaluation to 
 therapy  j 
 Follow-up  k 
 W 
 1 
 W 
 2 
 W 
 3 
 W 
 4 
 W 
 5 
 W 
 6 
 W 
 7 
 W 
 8 
 W 
 9 
 W1 
 0 
 W1 
 1 
 W12 
 (End of 
 treatment 
 visit) 
 Written informed 
 consent/assignment of 
 patient identification 
 number 
 X 
 Preliminary eligibility 
 fulfillment (investigator’s 
 opinion) 
 X 
 Demography and history of 
 tobacco and alcohol use 
 X 
 Previous treatments for 
 bladder cancer 
 X 
 Recent formalin-fixed 
 tumour biopsy 
 X 
 Formal verification of 
 eligibility criteria 
 X 
 Medical and surgical 
 history 
 X 
 Hepatitis B and C; HIV 
 X 
 Urine hCG or serum 
 βhCG  a 
 X 
 X 
 Durvalumab 
 administration 
 X 
 X 
 X 
 Tremelimumab 
 administration 
 X 
 X 
 X 
 Radiotherapy 
 administration 
 X 
 X 
 X 
 X 
 X 
 X 
 Physical examination  b 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Vital signs (pre-, during 
 and post-infusion vital 
 signs assessments)  c 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Weight 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 12- lead ECG  d 
 X 
 X 
 Adverse event/serious 
 adverse event assessment 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Concomitant medications 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 ECOG 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Serum chemistry (complete 
 clin. chem. panel including 
 liver enzymes)  e 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Thyroid function tests 
 (TSH and fT3 and fT4)  f 
 X 
 X 
 X 
 X 
 X 
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 Hematology  e 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Urinalysis  g 
 X 
 X 
 X 
 X 
 X 
 Coagulation parameters  h 
 X 
 X 
 Cystoscopy and random 
 biopsies 
 X 
 X 
 Tumour assessment (CT 
 scan)  i 
 X 
 X 
 Biomarker/pharmacodyna 
 mic sampling 
 Peripheral blood  l 
 X 
 X 
 X 
 X 
 Fresh tumor biopsies  m 
 X 
 Urine samples  n 
 X 
 X 
 a  Pre-menopausal female patients of childbearing potential  only 
 b  Full physical examination at baseline; targeted  physical examination at other time points 
 c  Patients  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  (i.e.,  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  follow  the  principles 
 as described above or more frequently if clinically indicated. 
 d  ECG  during  screening  and  on  cycle  1  Day  1  within  1  hr  prior  to  the  start  of  the  first  study  treatment.  Thereafter  as 
 clinically indicated. 
 e  According  what  is  detailed  on  tables  4  and  5.  If  screening  laboratory  assessments  are  performed  within  3  days  prior  to 
 Day  1  they  do  not  need  to  be  repeated  at  Day  1.  Results  for  safety  bloods  must  be  available  and  reviewed  before 
 commencing  an  infusion.  Gamma  glutamyltransferase  tested  at  Screening,  Day  1  and  as  clinically  indicated.  Depending 
 on  the  profile  of  the  combination  agent,  the  frequency  of  the  hematology,  serum  chemistry  and  LFT  testing  may  need  to 
 be increased to every two weeks. 
 f  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. 
 g  Urinalysis performed at Screening, Day 1, every  4 weeks and as clinically indicated. 
 h  Coagulation  tests:  prothrombin  time,  APTT  and  INR  –  to  be  only  performed  at  screening  and  EoT  visit,  and  only  as 
 clinically indicated thereafter. 
 i  Timing of CT scans: 
 - Initial Staging: thorax and , abdomen and pelvis CT scan 
 - Post-therapy re-staging (week 12): thorax, and abdomen CT scan and when applicable pelvis 
 j  Six  weeks  since  the  end  of  radiotherapy.  Cystoscopy  and  bladder  biopsy  will  be  performed  for  all  patients  as  a  efficacy 
 determination 
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 k  Follow-up:  Pelvis  and  abdomen  CT  scan,  urine  cytology  and  Rx  Thorax  every  3  months  the  first  year,  every  4  months 
 the  second  year  and  every  6  months  thereafter.  Additional  cystoscopy  and  bladder  biopsy  will  be  performed  in  case  of 
 detection abnormalities in the symptomatology, cytology or imaging studies 
 l  Peripheral  blood:  Week  1  prior  to  the  administration  of  durvalumab  and  tremelimumab,  W2  before  initiation  of  RT, 
 W8 at the end of RT, and W12 at the time of tumor response 
 m  Fresh  tumor  biopsies:  A  fresh  biopsy  sample,  optional,  at  the  time  of  initial  TUR.  Those  patients  who  have  not 
 achieved  complete  response  will  be  submitted  to  a  new  fresh  biopsy,  if  not  clinically  contraindicated.  It  will  be  required 
 to  send  fresh  and  formalin  fixed  samples  of  the  pathological  surgical  specimen  from  patients  who  are  candidate  to 
 salvage cystectomy. 
 n  Urine  samples  (Optional):  only  for  patients  included  in  ICO  L’Hospitalet.  The  samples  will  be  collected  at  the  time  of 
 screening  periode  and  the  end  of  treatment  visit.  The  first  urine  in  the  morning  would  be  collected  using  a  standard 
 testing tube of 50 ml. 
 3.3. 
 Study oversight for safety evaluation 
 It  should  be  documented  whether  or  not  the  patient  ends  the  trial.  If  for  some  reason 
 abandoned,  the  investigator  should  register  the  reason  for  premature  termination  in  the 
 eCRF.  The  reasons  why  a  patient  may  drop  out  or  be  removed  from  the  trial  are  as  listed 
 in section 4.4. 
 4. 
 PATIENT 
 SELECTION, 
 ENROLLMENT, 
 RANDOMIZATION, 
 RESTRICTIONS, 
 DISCONTINUATION AND WITHDRAWAL 
 Each  patient  must  meet  all  inclusion  criteria  (Section  4.1 )  and  none  of  the  exclusion 
 criteria  (Section  4.2 )  for  this  study.  Under  no  circumstances  will  there  be  exceptions  to 
 this rule. 
 4.1. 
 Inclusion criteria 
 For inclusion in the study, patients should fulfill the following criteria: 
 1. 
 Patients  diagnosed  with  urothelial  carcinoma  of  the  bladder,  in  clinical  stages 
 T2-4a  N0  M0,  who  are  not  candidates  for  radical  cystectomy  by  medical  reasons,  refusal 
 or patient’s choice. 
 2. 
 Written  informed  consent  obtained  from  the  patient  prior  to  performing  any 
 protocol-related procedures, including screening evaluations 
 3. 
 Age  >18  years  at  time  of  study  entry  or  Adult  male  or  female  (according  to  age  of 
 majority as defined as ≥18 years) 
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 4. 
 Patients must have ECOG performance status 0 or 1. 
 5. 
 A  paraffin-embedded  tumor  sample  must  be  available  for  the  associate  molecular 
 study. 
 6. 
 Body weight >30 Kg. 
 7. 
 Adequate normal organ and marrow function as defined below: 
 ●  Haemoglobin ≥9 g/dL 
 ●  Absolute neutrophil count (ANC ≥1.5 (or 1.0) x (> 1500 per mm3) 
 ●  Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3) 
 ●  Serum  bilirubin  ≤1.5  x  institutional  upper  limit  of  normal  (ULN).  This  will  not 
 apply  to  patients  with  confirmed  Gilbert’s  syndrome  (persistent  or  recurrent 
 hyperbilirubinemia  that  is  predominantly  unconjugated  in  the  absence  of 
 hemolysis  or  hepatic  pathology),  who  will  be  allowed  only  in  consultation  with 
 their physician. 
 ●  AST  (SGOT)/ALT  (SGPT)  ≤2.5  x  institutional  upper  limit  of  normal  unless  liver 
 metastases are present, in which case it must be ≤5x ULN 
 ●  Measured  creatinine  clearance  (CL)  >40  mL/min  or  Calculated  creatinine 
 clearance  CL>40  mL/min  by  the  Cockcroft-Gault  formula  (Cockcroft  and  Gault 
 1976) or by 24-hour urine collection for determination of creatinine clearance: 
Males: 
Creatinine 
 CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
72 x serum creatinine (mg/dL) 
Females: 
Creatinine 
 CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
 x 0.85 
72 x serum creatinine (mg/dL) 
 8. 
 Evidence  of  post-menopausal  status  or  negative  urinary  or  serum  pregnancy  test 
 for  female  pre-menopausal  patients.  Women  will  be  considered  post-menopausal  if  they 
 have  been  amenorrheic  for  12  months  without  an  alternative  medical  cause.  The 
 following age-specific requirements apply: 
 ●  Women  <50  years  of  age  would  be  considered  post-menopausal  if  they  have  been 
 amenorrheic  for  12  months  or  more  following  cessation  of  exogenous  hormonal 
 treatments  and  if  they  have  luteinizing  hormone  and  follicle-stimulating  hormone 
 levels  in  the  post-menopausal  range  for  the  institution  or  underwent  surgical 
 sterilization (bilateral oophorectomy or hysterectomy). 
 ●  Women  ≥50  years  of  age  would  be  considered  post-menopausal  if  they  have  been 
 amenorrheic  for  12  months  or  more  following  cessation  of  all  exogenous 
 hormonal  treatments,  had  radiation-induced  menopause  with  last  menses  >1  year 
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 ago,  had  chemotherapy-induced  menopause  with  last  menses  >1  year  ago,  or 
 underwent  surgical  sterilization  (bilateral  oophorectomy,  bilateral  salpingectomy 
 or hysterectomy). 
 9. 
 Patient  is  willing  and  able  to  comply  with  the  protocol  for  the  duration  of  the 
 study  including  undergoing  treatment  and  scheduled  visits  and  examinations  including 
 follow up. 
 4.2. 
 Exclusion criteria 
 Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
 1. 
 Involvement  in  the  planning  and/or  conduct  of  the  study  (applies  to  both  sponsor 
 staff and/or staff at the study site) 
 2. 
 Participation  in  another  clinical  study  with  an  investigational  product  during  the 
 last 30 days. 
 3. 
 Concurrent  enrolment  in  another  clinical  study,  unless  it  is  an  observational 
 (non-interventional)  clinical  study  or  during  the  follow-up  period  of  an  interventional 
 study. 
 4. 
 Previous  treatment  with  radiotherapy  to  the  bladder,  systemic  chemotherapy  or 
 immune  checkpoint  inhibitors.  Prior  intravesical  BCG  treatment  for  non-muscle  invasive 
 bladder cancer is allowed, 28 days prior to study. 
 5. 
 Presence of regional lymph node or metastatic extension of the disease. 
 6. 
 Any  unresolved  toxicity  NCI  CTCAE  Grade  ≥2  from  previous  anticancer  therapy 
 with  the  exception  of  alopecia,  vitiligo,  and  the  laboratory  values  defined  in  the  inclusion 
 criteria.  Patients  with  Grade  ≥2  neuropathy  will  be  evaluated  on  a  case-by-case  basis  after 
 consultation  with  the  Study  Physician.  Patients  with  irreversible  toxicity  not  reasonably 
 expected  to  be  exacerbated  by  treatment  with  durvalumab  or  tremelimumab  may  be 
 included only after consultation with the Study Physician. 
 7. 
 Any  concurrent  chemotherapy,  investigational  product  ( IP)  other  than  studied  in  this 
 protocol ,  biologic,  or  hormonal  therapy  for  cancer  treatment.  Concurrent  use  of  hormonal 
 therapy  for  non–cancer-related  conditions  (e.g.,  hormone  replacement  therapy)  is 
 acceptable. 
 8. 
 Major  surgical  procedure  (as  defined  by  the  Investigator)  within  28  days  prior  to 
 the  first  dose  of  IP.  Note:  Local  surgery  of  isolated  lesions  for  palliative  intent  is 
 acceptable. 
 9. 
 History of allogeneic organ transplantation. 
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 10. 
 Active  or  prior  documented  autoimmune  or  inflammatory  disorders  (including 
 inflammatory  bowel  disease  [e.g.,  colitis  or  Crohn's  disease],  diverticulitis  [with  the 
 exception  of  diverticulosis],  systemic  lupus  erythematosus,  Sarcoidosis  syndrome,  or 
 Wegener  syndrome  [granulomatosis  with  polyangiitis,  Graves'  disease,  rheumatoid 
 arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: 
 ●  Patients with vitiligo or alopecia 
 ●  Patients  with  hypothyroidism  (e.g.,  following  Hashimoto  syndrome)  stable  on 
 hormone replacement 
 ●  Any chronic skin condition that does not require systemic therapy 
 ●  Patients  without  active  disease  in  the  last  5  years  may  be  included  but  only  after 
 consultation with the study physician 
 ●  Patients with celiac disease controlled by diet alone 
 11. 
 Uncontrolled  intercurrent  illness,  including  but  not  limited  to,  ongoing  or  active 
 infection,  symptomatic  congestive  heart  failure,  uncontrolled  hypertension,  unstable 
 angina  pectoris,  cardiac  arrhythmia,  interstitial  lung  disease,  serious  chronic 
 gastrointestinal  conditions  associated  with  diarrhea,  or  psychiatric  illness/social  situations 
 that  would  limit  compliance  with  study  requirement,  substantially  increase  risk  of 
 incurring AEs or compromise the ability of the patient to give written informed consent 
 12. 
 History of another primary malignancy, except for: 
 ●  Malignancy  treated  with  curative  intent  and  with  no  known  active  disease  ≥5 
 years before the first dose of IP and of low potential risk for recurrence . 
 ●  Adequately  treated  non-melanoma  skin  cancer  or  lentigo  maligna  without 
 evidence of disease. 
 ●  Adequately treated carcinoma in situ without evidence of disease. 
 ●  Non-muscle invasive bladder cancer. 
 ●  Incidental prostate carcinoma 
 13. 
 History of active primary immunodeficiency 
 14. 
 Active  infection  including  tuberculosis  (clinical  evaluation  that  includes  clinical 
 history,  physical  examination  and  radiographic  findings,  and  TB  testing  in  line  with  local 
 practice),  hepatitis  B  (known  positive  HBV  surface  antigen  (HBsAg)  result),  hepatitis  C, 
 or  human  immunodeficiency  virus  (positive  HIV  1/2  antibodies).  Patients  with  a  past  or 
 resolved  HBV  infection  (defined  as  the  presence  of  hepatitis  B  core  antibody  [anti-HBc] 
 and  absence  of  HBsAg)  are  eligible.  Patients  positive  for  hepatitis  C  (HCV)  antibody  are 
 eligible only if polymerase chain reaction is negative for HCV RNA. 
 15. 
 Current  or  prior  use  of  immunosuppressive  medication  within  14  days  before  the 
 first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: 
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 ●  Intranasal,  inhaled,  topical  steroids,  or  local  steroid  injections  (e.g.,  intra  articular 
 injection) 
 ●  Systemic  corticosteroids  at  physiologic  doses  not  to  exceed  10  mg/day  of 
 prednisone or its equivalent 
 ●  Steroids  as  premedication  for  hypersensitivity  reactions  (e.g.,  CT  scan 
 premedication) 
 16. 
 Receipt  of  live  attenuated  vaccine  within  30  days  prior  to  the  first  dose  of  IP. 
 Note:  Patients,  if  enrolled,  should  not  receive  live  vaccine  whilst  receiving  IP  and  up  to 
 30 days after the last dose of IP. 
 17. 
 Female  patients  who  are  pregnant  or  breastfeeding  or  male  or  female  patients  of 
 reproductive  potential  who  are  not  willing  to  employ  effective  birth  control  from 
 screening  to  90  days  after  the  last  dose  of  durvalumab  monotherapy  or  180  days  after  the 
 last dose of durvalumab + tremelimumab combination therapy. 
 18. 
 Known  allergy  or  hypersensitivity  to  any  of  the  study  drugs  or  any  of  the  study 
 drug excipients. 
 19. 
 Prior  randomisation  or  treatment  in  a  previous  durvalumab  and/or  tremelimumab 
 clinical study. 
 20. 
 Judgment  by  the  investigator  that  the  patient  is  unsuitable  to  participate  in  the 
 study  and  the  patient  is  unlikely  to  comply  with  study  procedures,  restrictions  and 
 requirements. 
 21. 
 Known allergy or hypersensitivity to IP or any excipient 
 Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.5 
 If  a  patient  withdraws  from  participation  in  the  study,  then  his  or  her 
 enrollment/randomization code cannot be reused. 
 4.3. 
 Study oversight for safety evaluation 
 It  should  be  documented  whether  or  not  the  patient  ends  the  trial.  If  for  some  reason 
 abandoned  the  treatment  should  register  the  reason  for  premature  termination  in  the 
 eCRF.  The  reasons  why  a  patient  may  drop  out  from  treatment  or  be  removed  from  the 
 trial are described in the following sections. 
 4.4. 
 Withdrawal of patients from study treatment 
 An  individual  patient  will  not  receive  any  further  investigational  product  if  any  of  the 
 following occurs: 
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 • 
 An  individual  patient  will  not  receive  any  further  durvalumab  + 
 tremelimumab combination therapy. 
 • 
 Patient will not receive tremelimumab monotherapy in any case. 
 • 
 Withdrawal of consent or lost to follow-up. 
 • 
 Adverse  event  that,  in  the  opinion  of  the  investigator  or  the  sponsor, 
 contraindicates further dosing. 
 • 
 Any AE that meets criteria for discontinuation, as defined in Section 10. 
 • 
 Patient  is  determined  to  have  met  one  or  more  of  the  exclusion  criteria  for 
 study  participation  at  study  entry  and  continuing  investigational  therapy 
 might constitute a safety risk. 
 • 
 Consumption  of  illicit  drugs  or  other  substances  by  the  patient  which,  at  the 
 discretion  of  the  investigator,  may  reasonably  contribute  to  the  toxicity  or 
 otherwise, interfere in some with the results. 
 • 
 Pregnancy  (proof  of  beta-HCG  compatible  with  pregnancy,  communicating 
 pregnancy as a serious adverse event), or intent to become pregnant. 
 • 
 Grade ≥3 infusion reaction. 
 • 
 Request to discontinue treatment by the patient or a legal representative. 
 • 
 At  the  specific  request  of  the  sponsor  and  /  or  research  coordinators  of  the 
 trial. 
 • 
 Patient  noncompliance  that,  in  the  opinion  of  the  investigator  or  sponsor, 
 warrants withdrawal; e.g., refusal to adhere to scheduled visits. 
 • 
 Initiation  of  alternative  anticancer  therapy  including  another  investigational 
 agent. 
 • 
 Development of a secondary malignant tumor requiring treatment. 
 • 
 Confirmation  of  PD  and  investigator  determination  that  the  patient  is  no 
 longer  benefiting  from  treatment  with  durvalumab  +  tremelimumab.  Patients 
 who  are  permanently  discontinued  from  further  receipt  of  investigational 
 product,  regardless  of  the  reason  (withdrawal  of  consent,  due  to  an  AE, 
 other), will be identified as having permanently discontinued treatment 
 Patients  who  are  permanently  discontinued  from  receiving  investigational  product  will  be 
 followed  for  safety  per  Section  10  and  Appendix  1,  including  the  collection  of  any 
 protocol-specified  blood  specimens,  unless  consent  is  withdrawn  or  the  patient  is  lost  to 
 follow-up  or  enrolled  in  another  clinical  study.  All  patients  will  be  followed  for  survival. 
 Patients  who  decline  to  return  to  the  site  for  evaluations  will  be  offered  follow-up  by 
 phone every 3 months as an alternative. 
 The date and reason for treatment discontinuation should be recorded in the eCRF. 
 4.5. 
 Withdrawal of patients from study 
 Criteria for withdrawal of the study: 
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 1.  Withdrawal of informed consent 
 2.  Death of the patient 
 3.  Loss of follow-up 
 The  investigator  will  do  everything  possible  to  keep  all  patients  in  the  study  unless  it  is 
 considered  that  the  most  appropriate  option  for  the  patient  is  to  interrupt  his/her 
 participation. 
 If  a  patient  refuses  to  continue  his/her  participation  in  the  study,  all  end-of-study 
 evaluations  should  be  performed  if  the  patient  accepts  or  can  be  evaluated.  The  date  and 
 reason for withdrawal should be recorded in the eCRF. 
 4.6. 
 Withdrawal of consent 
 Patients  are  free  to  withdraw  from  the  study  at  any  time  (IP  and  assessments)  without 
 prejudice to further treatment. 
 Patients  who  withdraw  consent  for  further  participation  in  the  study  will  not  receive  any 
 further  IP  or  further  study  observation,  apart  from  follow-up  for  survival,  which  will 
 continue  until  the  end  of  the  study  unless  the  patient  has  expressly  withdrawn  their 
 consent  to  survival  follow-up.  Note  that  the  patient  may  be  offered  additional  tests  or 
 tapering of treatment to withdraw safely. 
 A  patient  who  withdraws  consent  will  always  be  asked  about  the  reason(s)  for  withdrawal 
 and  the  presence  of  any  AE.  The  Investigator  will  follow  up  AEs  outside  of  the  clinical 
 study. 
 If  a  patient  withdraws  consent,  they  will  be  specifically  asked  if  they  are  withdrawing 
 consent to: 
 • 
 all  further  participation  in  the  study  including  any  further  follow  up  (e.g., 
 survival contact telephone calls) 
 • 
 withdrawal of consent to the use of their study generated data 
 • 
 withdrawal to the use of any samples 
 5. 
 INVESTIGATIONAL PRODUCTS 
 5.1. 
 Durvalumab and tremelimumab 
 AstraZeneca/MedImmune  will  supply  durvalumab  and  tremelimumab  to  the  sponsor  as  a 
 solution  for  infusion  after  dilution.  The  sponsor  will  supply  durvalumab  and 
 tremelimumab to the site pharmacies as a solution for infusion after dilution. 
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 5.2. 
 Durvalumab (MEDI4736) 
 Durvalumab  (MEDI4736)  will  be  supplied  as  a  500-mg  vial  solution  for  infusion  after 
 dilution.  The  solution  contains  50  mg/mL  durvalumab  (MEDI4736),  26  mM 
 histidine/histidine  hydrochloride,  275  mM  trehalose  dihydrate,  and  0.02%  weight/volume 
 (w/v)  polysorbate  80;  it  has  a  pH  of  6.0.  The  nominal  fill  volume  is  10.0 mL. 
 Investigational  product  vials  are  to  be  stored  at  2°C  to  8°C  (36°F  to  46°F)  and  must  not 
 be  frozen.  Drug  product  should  be  kept  in  secondary  packaging  until  use  to  prevent 
 excessive light exposure . 
 5.3. 
 Tremelimumab 
 Tremelimumab  will  be  supplied  as  a  400-mg  or  a  25-mg  vial  solution  for  infusion  after 
 dilution.  The  solution  contains  20  mg/mL  tremelimumab,  20  mM  histidine/histidine 
 hydrochloride,  222  mM  trehalose  dihydrate,  0.27  mM  disodium  edetate  dihydrate,  and 
 0.02%  weight/volume  (w/v)  polysorbate  80;  it  has  a  pH  of  5.5  and  density  of  1.034  g/mL. 
 The  nominal  fill  volume  is  20.0  mL  for  the  400-mg  vial  and  1.25  mL  for  the  25-mg  vial. 
 Investigational  product  vials  are  stored  at  2°C  to  8°C  (36°F  to  46°F)  and  must  not  be 
 frozen.Drug  product  should  be  kept  in  secondary  packaging  until  use  to  prevent  excessive 
 light exposure . 
 5.4. 
 Formulation/packaging/storage 
 The  trial  medication  (i.e.,  Durvalumab  and  Tremelimumab)  and  its  packaging  will  be 
 labeled  in  accordance  with  annex  13  of  EU  to  Good  Manufacturing  Practice.  Storage  will 
 be done according IB and labeling specifications. 
 5.5 
 Dose and treatment regimens 
 5.5.1.  Treatment regimens 
 Durvalumab + tremelimumab combination therapy 
 All  patients  will  receive  durvalumab  (MEDI4736)  (1500mg  Q4W)  in  combination  with 
 tremelimumab  (75 mg  IV  Q4W)  for  up  to  3 doses/cycles  each,  unless  there  is 
 unacceptable  toxicity,  withdrawal  of  consent,  or  another  discontinuation  criterion  is  met. 
 If  a  patient’s  weight  falls  to  30kg  or  below  the  patient  should  receive  weight-based  dosing 
 equivalent  to  20  mg/kg  of  durvalumab  Q4W  and  1mg/kg  tremelimumab  Q4W  until  the 
 weight  improves  to  >30  kg,  at  which  point  the  patient  should  start  receiving  the  fixed 
 dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W. 
 Tremelimumab  will  be  administered  first;  the  durvalumab  (MEDI4736)  infusion  will  start 
 approximately  1 hour  (maximum  2 hours)  after  the  end  of  the  tremelimumab  infusion. 
 Standard  infusion  time  for  each  is  one  hour.  If  there  are  interruptions  during  infusion,  the 
 total  allowed  infusion  time  for  each  should  not  exceed  8  hours  at  room  temperature.  If 
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 there  are  no  clinically  significant  concerns  after  the  first  cycle,  then,  at  the  discretion  of 
 the  Investigator,  all  other  cycles  of  durvalumab  (MEDI4736)  can  be  given  immediately 
 after the tremelimumab infusion has finished. 
 5.5.2.  Study drug preparation of durvalumab and tremelimumab 
 Based  on  average  body  WT  of  75  kg,  1500  mg  Q4W  durvalumab  (equivalent  to  20  mg/kg 
 Q4W)  and  75  mg  Q4W  tremelimumab  (equivalent  to  1  mg/kg  Q4W)  is  included  in  the 
 current study. 
 5.5.2.1.  Preparation of durvalumab doses for administration with an IV bag 
 The  dose  of  durvalumab  (MEDI4736)  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  (MEDI4736)  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 
 ●  A  dose  of  1500mg  (for  patients  >30kg  in  weight)  will  be  administered  using  an 
 IV  bag  containing  0.9%  (w/v)  saline  or  5%  (w/v)  dextrose,  with  a  final 
 durvalumab  (MEDI4736)  concentration  ranging  from  1  to  20  mg/mL,  and 
 delivered  through  an  IV  administration  set  with  a  0.2-  or  0.22-μm  in-line  filter. 
 Add  30.0 mL  of  durvalumab  (MEDI4736)  (i.e.,  1500mg  of  durvalumab 
 [MEDI4736])  to  the  IV  bag.  The  IV  bag  size  should  be  selected  such  that  the  final 
 concentration  is  within  1  to  20  mg/mL.  Mix  the  bag  by  gently  inverting  to  ensure 
 homogeneity of the dose in the bag. 
 If  patient  weight  falls  to  ≤  30  kg  weight-based  dosing  at  20  mg/kg  will  be  administered 
 using  an  IV  bag  containing  0.9%  (w/v)  saline  or  5%  (w/v)  dextrose,  with  a  final 
 durvalumab  (MEDI4736)  concentration  ranging  from  1  to  20  mg/mL,  and  delivered 
 through an IV  administration set with a 0.2- or 0.22-μm  in-line filter. 
 Standard  infusion  time  is  1  hour.  However,  if  there  are  interruptions  during  infusion,  the 
 total allowed infusion time should not exceed 8 hours at room temperature. 
 Do not co-administer other drugs through the same infusion line. 
 The  IV  line  will  be  flushed  with  a  volume  of  IV  diluent  equal  to  the  priming  volume  of 
 the  infusion  set  used  after  the  contents  of  the  IV  bag  are  fully  administered,  or  complete 
 the  infusion  according  to  institutional  policy  to  ensure  the  full  dose  is  administered  and 
 document if the line was not flushed. 
 If  either  preparation  time  or  infusion  time  exceeds  the  time  limits  a  new  dose  must  be 
 prepared  from  new  vials.   Durvalumab  (MEDI4736)  does  not  contain  preservatives,  and 
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 any unused portion must be discarded. 
 5.5.2.2.  Preparation of tremelimumab doses for administration with an IV bag 
 The  dose  of  tremelimumab  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 tremelimumab 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 
 ●  A  dose  of  75  mg  (for  patients  >30kg  in  weight)  will  be  administered  using  an  IV 
 bag  containing  0.9%  (w/v)  saline  or  5%  (w/v)  dextrose,  with  a  final 
 tremelimumab  concentration  ranging  from  0.10  to  10  mg/mL,  and  delivered 
 through  an  IV  administration  set  with  a  0.2-  or  0.22-μm  in-line  filter.  Add  3.8  mL 
 (i.e.,75  mg  of  tremelimumab,  with  the  dose  volume  rounded  to  the  nearest  tenth 
 mL)  to  the  IV  bag.  The  IV  bag  size  should  be  selected  such  that  the  final 
 concentration  is  within  0.10  to  10  mg/mL.  Mix  the  bag  by  gently  inverting  to 
 ensure homogeneity of the dose in the bag. 
 If  weight  falls  to  ≤  30  kg,  weight-based  dosing  at  1  mg/kg  Weight-based  dosing  (for 
 patients  ≤30  kg)  will  be  a  administered  using  an  IV  bag  containing  0.9%  (w/v)  saline  or 
 5%  (w/v)  dextrose,  with  a  final  tremelimumab  concentration  ranging  from  0.10  to  10 
 mg/mL,  and  delivered  through  an  IV  administration  set  with  a  0.2-  or  0.22-μm  in-line 
 filter. Appendix 2 includes an example of a weight-based dose calculation. 
 Standard  infusion  time  is  one  hour,  however  if  there  are  interruptions  during  infusion,  the 
 total allowed infusion time should not exceed 8 hours at room temperature. 
 Do not co-administer other drugs through the same infusion line. 
 The  IV  line  will  be  flushed  with  a  volume  of  IV  diluent  equal  to  the  priming  volume  of 
 the  infusion  set  used  after  the  contents  of  the  IV  bag  are  fully  administered,  or  complete 
 the  infusion  according  to  institutional  policy  to  ensure  the  full  dose  is  administered  and 
 document if the line was not flushed. 
 If  either  preparation  time  or  infusion  time  exceeds  the  time  limits  a  new  dose  must  be 
 prepared  from  new  vials.  Tremelimumab  does  not  contain  preservatives,  and  any  unused 
 portion must be discarded. 
 5.5.3.  Monitoring of dose administration 
 Patients  will  be  monitored  during  and  after  the  infusion  with  assessment  of  vital  signs  at 
 the times specified in the Study Protocol. 
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 In  the  event  of  a  ≤Grade 2  infusion-related  reaction,  the  infusion  rate  of  study  drug  may 
 be  decreased  by  50%  or  interrupted  until  resolution  of  the  event  and  re-initiated  at  50%  of 
 the  initial  rate  until  completion  of  the  infusion.  For  patients  with  a  ≤Grade  2 
 infusion-related  reaction,  subsequent  infusions  may  be  administered  at  50%  of  the  initial 
 rate.  Acetaminophen  and/or  an  antihistamine  (e.g.,  diphenhydramine)  or  equivalent 
 medications  per  institutional  standard  may  be  administered  at  the  discretion  of  the 
 investigator.  If  the  infusion  related  reaction  is  ≥Grade  3  in  severity,  study  drug  will  be 
 discontinued.  For  management  of  patients  who  experience  an  infusion  reaction,  please 
 refer to the toxicity and management guidelines in Appendix 1. 
 As  with  any  antibody,  allergic  reactions  to  dose  administration  are  possible.  Appropriate 
 drugs  and  medical  equipment  to  treat  acute  anaphylactic  reactions  must  be  immediately 
 available,  and  study  personnel  must  be  trained  to  recognize  and  treat  anaphylaxis.  The 
 study  site  must  have  immediate  access  to  emergency  resuscitation  teams  and  equipment 
 in addition to the ability to admit patients to an intensive care unit if necessary. 
 5.5.4.  Accountability and dispensation of IMPs 
 The  trial  medication  will  be  sent  to  the  investigator's  site  pharmacy  preceded  by  the 
 Regulatory  Green  Light.  The  medication  is  to  be  used  exclusively  in  the  clinical  trial 
 according to the instructions of this trial protocol. 
 When  a  drug  shipment  is  received,  the  Investigator  or  designee  will  check  the  amount 
 and  condition  of  the  delivery,  drug  expiration  date,  and  sign  the  Receipt  of  Shipment 
 Form  provided.  The  Receipt  of  Shipment  Form  should  be  faxed  or  emailed  to  the  CRO. 
 The  original  form  will  preliminarily  be  retained  at  the  site  and  will  be  collected  at  the 
 next  monitoring  visit  by  the  monitor  and  stored  in  the  Trial  Master  File  at  CRO.  A  copy 
 remains  in  the  Investigator  File  at  the  site.  In  case  of  shipment  problems  the  Investigator 
 or designee shall contact the CRA as soon as possible. 
 For  this  trial  a  IWRS  system  will  be  used  for  IMP  stock  management,  Pharmacy  or  PI 
 designee  properly  identified  in  the  personnel  list  and  tasks  delegation  log,  will  get  access 
 to  the  web  based  platform  to  update  receptions,  destructions  and  dispensing  of  IMPs.  The 
 record  must  be  continuously  updated  and  contain  the  dates,  quantities  and  compounds  of 
 drugs  received,  medication  identification  number(s),  the  patient  identification  number  to 
 whom  the  trial  medication  was  dispensed,  date  and  quantity  of  medication  dispensed.  The 
 system  includes  an  audit  trail  that  allow  to  unequivocal  identify  the  staff  member  and  the 
 field modify at any time. 
 5.5.5.  Disposition of unused investigational study drug 
 Trial  medication  will  be  monitored  by  the  CRA  at  the  respective  hospital  pharmacy  prior 
 to  destruction  after  having  completed  a  final  inventory,  when  applicable.  Local  or 
 institutional  regulations  may  require  immediate  destruction  of  the  study  drug  used  for 
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 safety  reasons,  e.g.,  cytotoxicity  or  to  maintain  the  storage  capacity  and  functionality  of 
 the  storage  at  the  site.  In  these  cases,  it  may  be  acceptable  to  destroy  it  by  the  research 
 staff,  including  partially  used  and  empty  vials,  dispensed  before  a  monitoring  inspection, 
 if  the  verification  of  original  documents  of  empty  boxes  that  indicate  the  information  of 
 batch  number  and  dispensing  date  to  the  patient  on  the  label.  This  documentation  will  be 
 verified against the quantity shipped, dispensed, returned and destroyed. 
 Prior  to  the  destruction  a  final  trial  medication  reconciliation  statement  must  be 
 completed. 
 Drug supplies will be destroyed according to the legal requirements in Spain. 
 All  trial  medication  inventory  forms  must  be  made  available  for  inspection  by  a  Sponsor 
 authorized  representative  or  designee  and  regulatory  agency  inspectors.  The  Investigator 
 is responsible for the accountability of all used and unused study supplies at the site. 
 6. 
 TREATMENT PLAN 
 The  treatment  consisted  of  initial  TUR  of  the  tumor,  with  multiple  random  biopsies  of 
 normal-appearing  bladder  urothelium,  followed  by  durvalumab  1500  mg  i.v.  plus 
 tremelimumab 75 mg i.v., every 4 weeks for a total of 3 doses. 
 Two  weeks  after  the  initiation  of  immunotherapy,  normofractionated  external-beam 
 radiotherapy  with  high-energy  photons  will  be  started.  Radiotherapy  will  be  administered 
 concurrently  with  immunotherapy  at  doses  of  46  Gy  to  the  minor  pelvis  and  64-66  Gy  to 
 the bladder. 
 Six  weeks  after  the  end  of  radiotherapy,  ALL  patients  will  undergo  a  new  cystoscopy 
 with  biopsies  of  the  tumor  bed  and  all  residual  present  lesions  as  an  efficacy 
 determination.  In  patients  with  persistent  prominent  inflammatory  reaction  at  this 
 moment,  the  cystoscopy  can  be  performed  1-2  weeks  later  (6  to  8  weeks  after  the  end  of 
 radiotherapy).  Response  is  defined  as  an  absence  of  invasive  cancer  at  post 
 immunotherapy  biopsy  (≤cT1).  Patients  with  response  to  immunotherapy  will  be 
 candidates  to  bladder  preservation,  whereas  in  those  with  residual  muscle  invasive  tumor 
 the  possibility  of  salvage  radical  cystectomy  must  be  evaluated.  Patients  developing  an 
 isolated  bladder  invasive  relapse  during  follow-up  will  be  also  possible  candidates  to 
 salvage  cystectomy,  whereas  those  developing  a  superficial  relapse  in  the  preserved 
 bladder will be managed with TUR and intravesical BCG. 
 Patients  will  be  followed  up  every  3  months  the  first  year,  every  4  months  the  second 
 year  and  every  6  months  thereafter  with  abdomen  and  pelvis  CT  scan,  Rx  thorax,  urine 
 cytology.  Additionally  of  the  mandatory  efficacy  cystoscopy  and  bladder  biopsy  (6w  post 
 RT),  other  cystoscopy  and  bladder  biopsy  will  be  performed  in  case  of  detection 
 abnormalities  in  the  cytology  or  imaging  studies.  The  study  will  be  closed  2  years  after 
 the last patient inclusion. 
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 Replacement of patients 
 It  is  planned  to  replace  those  patients  who  interrupt  the  trial  in  advance  (without  having 
 completed 12 weeks of treatment) and have not presented dose-limiting toxicity. 
 Patients  who  have  not  been  taking  durvalumab  and  tremelimumab  for  more  than  21  days 
 or  who  discontinue  treatment  with  radiotherapy  for  more  than  2  weeks  will  also  be 
 replaced. 
 6.1. 
 Dose modification and toxicity management 
 6.1.1.  Radiotherapy 
 Patients  who,  for  reasons  unrelated  to  toxicity,  discontinue  radiotherapy  for  more  than  2 
 weeks  will  be  excluded  from  the  study.  In  the  case  of  interruptions  of  less  than  2  weeks, 
 the patient will resume treatment from the point where he was interrupted. 
 A  severe  toxicity  (G3-4)  related  to  radiotherapy  or  due  to  combination  of  the 
 RT+durvalumab/tremelimumab,  RT  will  be  suspended  until  recovery  to  G1. 
 However, if it is toxicity unrelated to the RT, it will continue without variations. 
 6.1.2.  Durvalumab and tremelimumab 
 Guidelines  for  the  management  of  immune-mediated  reactions,  infusion-related  reactions, 
 and  non-immune-mediated  reactions  for  durvalumab  monotherapy  and  durvalumab  + 
 tremelimumab  are  provided  in  the  Dosing  Modification  and  Toxicity  Management 
 Guidelines  in  Appendix  1.  Patients  should  be  thoroughly  evaluated  and  appropriate 
 efforts  should  be  made  to  rule  out  neoplastic,  infectious,  metabolic,  toxin,  or  other 
 etiologic  causes  of  the  imAE.  Serologic,  immunologic,  and  histologic  (biopsy)  data,  as 
 appropriate,  should  be  used  to  support  an  imAE  diagnosis.  In  the  absence  of  a  clear 
 alternative etiology, events should be considered potentially immune related. 
 In  addition,  there  are  certain  circumstances  in  which  durvalumab  and  tremelimumab 
 should  be  permanently  discontinued  (see  Section  4.4  of  this  protocol  and  the  Dosing 
 Modification and Toxicity Management Guidelines in Appendix 1). 
 Following  the  first  dose  of  IP,  subsequent  administration  of  durvalumab  and 
 tremelimumab  can  be  modified  based  on  toxicities  observed  as  described  in  the  Dosing 
 Modification  and  Toxicity  Management  Guidelines  in  Appendix  1.  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  durvalumab  monotherapy  and  the  durvalumab  +  tremelimumab 
 regimen by the reporting investigator. 
 Dose  reductions  are  not  permitted.  In  case  of  doubt,  the  Investigator  should  consult 
 with  the  Study  Physician.  In  case  of  severe  grade  3-4  toxicity,  the  possibility  to 
 discontinue  tremelimumab,  following  the  administration  of  durvalumab  alone 
 concurrently with radiotherapy, when the toxicity will recover, should be considered. 
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 It  is  planned  to  replace  those  patients  who  interrupt  the  trial  in  advance  (without  having 
 completed  12  weeks  of  treatment)  and  have  not  presented  dose-limiting  toxicity.  Patients 
 who  have  not  been  taking  durvalumab  and  tremelimumab  for  more  than  21  days  or  who 
 discontinue treatment with radiotherapy for more than 2 weeks will also be replaced. 
 Patients  should  be  thoroughly  evaluated  and  appropriate  efforts  should  be  made  to  rule 
 out  neoplastic,  infectious,  metabolic,  toxin,  or  other  etiologic  causes  of  the  imAE. 
 Serologic,  immunologic,  and  histologic  (biopsy)  data,  as  appropriate,  should  be  used  to 
 support  an  imAE  diagnosis.  In  the  absence  of  a  clear  alternative  etiology,  events  should 
 be considered potentially immune related. 
 All  toxicities  will  be  graded  according  to  NCI  CTCAE,  Version  4.03  and  RTOG/EORTC 
 grading system. 
 7. 
 RESTRICTIONS 
 DURING 
 THE 
 STUDY 
 AND 
 CONCOMITANT TREATMENTS 
 7.1. 
 Restrictions during the study 
 The  following  restrictions  apply  while  the  patient  is  receiving  study  treatment  and  for  the 
 specified times before and after: 
 Female patient of child-bearing potential 
 ●  Females  of  childbearing  potential  who  are  sexually  active  with  a  non  sterilized 
 male  partner  must  use  at  least  1  highly  effective  method  of  contraception  (Table 
 1)  from  the  time  of  screening  and  must  agree  to  continue  using  such  precautions 
 for  180 days  after  the  last  dose  of  durvalumab  +  tremelimumab  combination 
 therapy  or  90 days  after  the  last  dose  of  durvalumab  monotherapy.  Non-sterilized 
 male  partners  of  a  female  patient  must  use  male  condom  plus  spermicide 
 throughout  this  period.  Cessation  of  birth  control  after  this  point  should  be 
 discussed  with  a  responsible  physician.  Not  engaging  in  sexual  activity  for  the 
 total  duration  of  the  drug  treatment  and  the  drug  washout  period  is  an  acceptable 
 practice;  however,  periodic  abstinence,  the  rhythm  method,  and  the  withdrawal 
 method  are  not  acceptable  methods  of  birth  control.  Female  patients  should  also 
 refrain from breastfeeding throughout this period. 
 Male patients with a female partner of childbearing potential 
 ●  Non-sterilized  males  who  are  sexually  active  with  a  female  partner  of 
 childbearing  potential  must  use  a  male  condom  plus  spermicide  from  screening 
 through  180 days  after  receipt  of  the  final  dose  of  durvalumab  +  tremelimumab 
 combination  therapy  or  90 days  after  receipt  of  the  final  dose  of  durvalumab 
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 monotherapy.  Not  engaging  in  sexual  activity  is  an  acceptable  practice;  however, 
 occasional  abstinence,  the  rhythm  method,  and  the  withdrawal  method  are  not 
 acceptable  methods  of  contraception.  Male  patients  should  refrain  from  sperm 
 donation throughout this period. 
 ●  Female  partners  (of  childbearing  potential)  of  male  patients  must  also  use  a  highly 
 effective method of contraception throughout this period (Table 1). 
 N.B  Females  of  childbearing  potential  are  defined  as  those  who  are  not  surgically  sterile 
 (i.e.,  bilateral  tubal  ligation,  bilateral  oophorectomy,  or  complete  hysterectomy)  or 
 post-menopausal. 
 Women  will  be  considered  post-menopausal  if  they  have  been  amenorrheic  for  12  months 
 without an alternative medical cause. The following age-specific requirements apply: 
 ●  Women  <50  years  of  age  would  be  considered  post-menopausal  if  they  have  been 
 amenorrheic  for  12  months  or  more  following  cessation  of  exogenous  hormonal 
 treatments  and  if  they  have  luteinizing  hormone  and  follicle-stimulating  hormone 
 levels  in  the  post-menopausal  range  for  the  institution  or  underwent  surgical 
 sterilization (bilateral oophorectomy or hysterectomy). 
 ●  Women  ≥50  years  of  age  would  be  considered  post-menopausal  if  they  have  been 
 amenorrheic  for  12  months  or  more  following  cessation  of  all  exogenous 
 hormonal  treatments,  had  radiation-induced  menopause  with  last  menses  >1  year 
 ago,  had  chemotherapy-induced  menopause  with  last  menses  >1  year  ago,  or 
 underwent  surgical  sterilization  (bilateral  oophorectomy,  bilateral  salpingectomy 
 or hysterectomy). 
 Highly  effective  methods  of  contraception,  defined  as  one  that  results  in  a  low  failure  rate 
 (i.e.,  less  than  1%  per  year)  when  used  consistently  and  correctly  are  described  in  Table  1. 
 Note  that  some  contraception  methods  are  not  considered  highly  effective  (e.g.,  male  or 
 female  condom  with  or  without  spermicide;  female  cap,  diaphragm,  or  sponge  with  or 
 without  spermicide;  non-copper  containing  intrauterine  device;  progestogen-only  oral 
 hormonal  contraceptive  pills  where  inhibition  of  ovulation  is  not  the  primary  mode  of 
 action  [excluding  Cerazette/desogestrel  which  is  considered  highly  effective];  and 
 triphasic combined oral contraceptive pills). 
 Table 1.  Highly effective methods of contraception  (<1% failure rate) 
 Barrier/Intrauterine methods 
 Hormonal Methods 
 ● 
 Copper T intrauterine 
 device 
 ● 
 Levonorgestrel-releasing 
 intrauterine system (e.g., 
 Mirena®)  a 
 ● 
 Implants: Etonogestrel-releasing implants: e.g. Implanon® or Norplant® 
 ● 
 Intravaginal: 
 Ethinylestradiol/etonogestrel-releasing 
 intravaginal 
 devices: 
 e.g. 
 NuvaRing® 
 ● 
 Injection: Medroxyprogesterone injection: e.g. Depo-Provera® 
 ● 
 Combined Pill: Normal and low dose combined oral contraceptive pill 
 ● 
 Patch: Norelgestromin/ethinyl estradiol-releasing transdermal system: e.g. Ortho Evra® 
 ● 
 Minipill:  Progesterone  based  oral  contraceptive  pill  using  desogestrel:  Cerazette®  is 
 currently the only highly effective progesterone based pill 
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 a 
 This is also considered a hormonal method 
 Blood donation 
 Patients  should  not  donate  blood  while  participating  in  this  study,  or  for  at  least  90  days 
 following  the  last  infusion  of  durvalumab  or  tremelimumab  or  90 days  after  receipt  of  the 
 final dose of durvalumab. 
 7.2. 
 Concomitant treatment(s) 
 The  Principal  Investigator  must  be  informed  as  soon  as  possible  about  any  medication 
 taken  from  the  time  of  screening  until  the  end  of  the  clinical  phase  of  the  study  (final 
 study  visit).  Any  concomitant  medication(s),  including  herbal  preparations,  taken  during 
 the study will be recorded in the CRF. 
 Restricted,  prohibited,  and  permitted  concomitant  medications  are  described  in  the 
 following  tables.  Refer  to  IB’s  Section 6.6  for  guidance  on  management  of  IP-related 
 toxicities. 
 7.2.1.  Permitted concomitant medications 
 Table 2 .  Supportive medications 
 Supportive medication/class of drug 
 Usage 
 Concomitant medications or treatments (e.g., acetaminophen or diphenhydramine) deemed 
 necessary to provide adequate prophylactic or supportive care, except for those medications 
 identified as “prohibited,” as listed above 
 To be administered as 
 prescribed by the 
 Investigator 
 Best supportive care (including antibiotics, nutritional support, correction of metabolic disorders, 
 optimal symptom control, and pain management [including palliative radiotherapy to non-target 
 lesions, etc]) 
 Should be used, when 
 necessary, for all patients 
 Inactivated viruses, such as those in the influenza vaccine 
 Permitted 
 7.2.2.  Excluded concomitant medications 
 Table 3 .  Prohibited concomitant medications 
 Prohibited medication/class of drug 
 Usage 
 Any investigational anticancer therapy 
 other than those under investigation in this 
 study 
 Should not be given concomitantly whilst the patient is on study treatment 
 mAbs against CTLA-4, PD-1, or PD-L1 
 other than those under investigation in this 
 study 
 Should not be given concomitantly whilst the patient is on study treatment 
 Any concurrent chemotherapy, 
 Should  not  be  given  concomitantly  whilst  the  patient  is  on  study  treatment. 
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 radiotherapy, immunotherapy, or biologic 
 or hormonal therapy for cancer treatment 
 other than those under investigation in this 
 study 
 (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]) 
 Immunosuppressive medications 
 including, but not limited to, systemic 
 corticosteroids at doses exceeding 10 
 mg/day of prednisone or equivalent, 
 methotrexate, azathioprine, and tumor 
 necrosis factor-α blockers 
 Should  not  be  given  concomitantly,  or  used  for  premedication  prior  to  the  I-O 
 infusions. The following are allowed exceptions: 
 ● 
 Use  of  immunosuppressive  medications  for  the  management  of 
 IP-related AEs , 
 ● 
 Use in patients with contrast allergies. 
 ● 
 In  addition,  use  of  inhaled,  topical,  and  intranasal  corticosteroids  is 
 permitted . 
 A  temporary  period  of  steroids  will  be  allowed  if  clinically  indicated  and 
 considered  to  be  essential  for  the  management  of  non-immunotherapy  related 
 events  experienced  by  the  patient  (e.g.,  chronic  obstructive  pulmonary  disease, 
 radiation, nausea, etc). 
 Drugs with laxative properties and herbal 
 or natural remedies for constipation 
 Should  be  used  with  caution  through  to  90 days  after  the  last  dose  of 
 tremelimumab during the study 
 Sunitinib 
 Should  not  be  given  concomitantly  or  through  90  days  after  the  last  dose  of 
 tremelimumab  (acute  renal  failure  has  been  reported  with  combination  therapy 
 of tremelimumab and sunitinib) 
 EGFR TKIs 
 Should not be given concomitantly. 
 Should be used with caution in the 90 days post last dose of durvalumab. 
 Increased  incidences  of  pneumonitis  (with  third  generation  EGFR  TKIs)  and 
 increased  incidence  of  transaminase  increases  (with  1  st  generation  EGFR  TKIs) 
 has been reported when durvalumab has been given concomitantly. 
 Live attenuated vaccines 
 Should not be given through 30 days after the last dose of IP (including SoC) 
 Herbal and natural remedies which may 
 have immune-modulating effects 
 Should not be given concomitantly unless agreed by the sponsor 
 8. 
 STUDY PROCEDURES 
 8.1. 
 Schedule of study procedures 
 Before  study  entry,  throughout  the  study,  and  following  study  drug  discontinuation, 
 various  clinical  and  diagnostic  laboratory  evaluations  are  outlined.  The  purpose  of 
 obtaining  these  detailed  measurements  is  to  ensure  adequate  safety  and  tolerability 
 assessments.  Clinical  evaluations  and  laboratory  studies  may  be  repeated  more  frequently 
 if  clinically  indicated.  The  Schedules  of  Assessments  during  the  screening  and  treatment 
 period is provided following the Protocol Synopsis 
 For durvalumab + tremelimumab combination+radiotherapy 
 ●  Tumor  efficacy  (RECIST)  assessment  dates  are  not  affected  by  dose  delays  and 
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 remain  as  originally  scheduled,  as  they  are  based  on  the  date  of  enrollment  (not  the 
 date of therapy). 
 ●  All  other  scheduled  assessments  must  be  performed  relative  to  the  start  of  the  dosing 
 cycle  such  that  all  laboratory  procedures,  etc  required  for  dosing  should  be  performed 
 within 3 days prior to dosing 
 ●  Patients may delay dosing under certain circumstances. 
 ●  Dosing  may  be  delayed  per  Toxicity  Management  Guidelines,  due  to  either  an 
 immune or a non-immune-related AE. 
 ●  If  dosing  must  be  delayed  for  reasons  other  than  treatment-related  toxicity,  dosing 
 will resume as soon as feasible 
 ●  Dosing  intervals  of  subsequent  cycles  may  be  shortened  as  clinically  feasible  in  order 
 to  gradually  align  treatment  cycles  with  the  schedule  of  tumor  efficacy  (RECIST)  . 
 Subsequent  time  between  2  consecutive  doses  cannot  be  less  than  22  days,  based  on 
 the  half-lives  of  durvalumab  and  tremelimumab  (see  current  Investigator  Brochures 
 for durvalumab and tremelimumab. 
 8.1.1.  Screening phase 
 Screening  procedures  will  be  performed  up  to  28  days  before  Day  1  of  Week  1,  unless 
 otherwise  specified.  All  patients  must  first  read,  understand,  and  sign  the  IEC-approved 
 ICF  before  any  study-specific  screening  procedures  are  performed.  After  signing  the  ICF, 
 completing  all  screening  procedures,  and  being  deemed  eligible  for  entry,  patients  will  be 
 enrolled  in  the  study.  Procedures  that  are  performed  prior  to  the  signing  of  the  ICF  and 
 are  considered  standard  of  care  may  be  used  as  screening  assessments  if  they  fall  within 
 the 28-day screening window. 
 The following procedures will be performed during the Screening Visit: 
 ● 
 Informed Consent 
 ● 
 Review of eligibility criteria 
 ● 
 Medical history and demographics 
 ● 
 Complete physical exam 
 ● 
 ECOG Performance Status 
 ● 
 Vitals signs, weight and height 
 ● 
 12-lead ECG (in triplicate [2-5 minutes apart]) 
 ● 
 Confirm collection of tumor biopsy 
 ● 
 Review of prior/concomitant medications 
 ● 
 Imaging by CT scan 
 ● 
 Clinical laboratory tests for: 
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 ● 
 Clinical chemistry (see Table 4) 
 ● 
 Hematology (see Table 5) 
 ● 
 Urinalysis (see Table 6) 
 ● 
 Coagulation (PT, PTT, INR) 
 ● 
 Serum pregnancy test (for women of childbearing potential only) 
 ● 
 Hepatitis B and C and HIV serologies 
 ● 
 Cystoscopy and random biopsies 
 ● 
 Tumor assessment (CT scan) 
 ● 
 Fresh  tumor  biopsies  collection  are  optional.  This  is  only  for  those  patients  who 
 signed the substudy informed consent. 
 ● 
 Urine  samples  collection  (optional;  only  for  a  patients  included  in  ICO 
 L’Hospitalet).  The  first  urine  in  the  morning  would  be  collected  using  a  standard  testing 
 tube of 50 ml. 
 8.1.2.  Treatment phase 
 Procedures  to  be  conducted  during  the  treatment  phase  of  the  study  are  presented  in  the 
 Schedule  of  Assessments.  Screening  procedures  performed  within  72  hours  of  Cycle  1 
 Day 1 (C1D1) do not need to be repeated on C1D1. 
 The following procedures will be performed during the treatment phase: 
 ● 
 Complete physical exam 
 ● 
 ECOG Performance Status 
 ● 
 Vitals signs, weight and height 
 ● 
 ECG 
 ● 
 Review of concomitant medications 
 ● 
 Clinical laboratory tests for: 
 o  Clinical chemistry (see Table 4); 
 o  Hematology (see Table 5); 
 o  Urinalysis (see Table 6). 
 o  Thyroid function tests (TSH and T3 and T4) 
 ● 
 Adverse event/serious adverse event assessment 
 ● 
 Peripheral blood collection 
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 8.1.3.  End of treatment and follow-up visits 
 The following procedures will be performed during the end of treatment visit (w12): 
 ● 
 Complete physical exam 
 ● 
 ECOG Performance Status 
 ● 
 Vitals signs, weight and height 
 ● 
 AE/SAE collection 
 ● 
 Concomitant medications 
 ● 
 Clinical laboratory tests for: 
 o 
 Clinical chemistry (see Table 4) 
 o 
 Hematology (see Table 5) 
 o 
 Urinalysis (see Table 6) 
 o 
 Coagulation (PT, PTT, INR) 
 o 
 Thyroid function tests (TSH and T3 and T4) 
 ● 
 Serum pregnancy test (for women of childbearing potential only) 
 ● 
 Tumor assessment by CT scan 
 ● 
 Peripheral blood collection 
 ● 
 Urine samples collection (optional; only for a group of patients). 
 8.1.4.  Safety 
 Safety  follow-up  visits  will  be  scheduled  up  to  90  days  after  the  last  dose  of  study 
 treatment,  the  procedures  to  be  performed  are  the  same  that  for  EOT  visit  except  for 
 peripheral  blood  collection  and  CT  scan  that  should  not  been  performed  in  this  visit, 
 unless PI criteria as per normal practice 
 8.1.5. Follow-up Visits 
 All  patients  will  be  followed  for  survival  until  the  end  of  the  study  regardless  of  further 
 treatments,  or  until  the  sponsor  ends  the  study.  It  is  of  special  interest  the  long-term 
 follow-up  of  survival,  disease  free  survival  and  the  preservation  of  the  bladder  free  of 
 tumor. 
 Given  the  potential  risk  for  delayed  immune-related  toxicities,  safety  follow-up  must  be 
 performed  up  to  90  days  after  the  last  dose  of  durvalumab  and  tremelimumab 
 administration. 
 The  extended  safety  follow-up  beyond  30  days  after  last  study  drug  administration  may 
 be  performed  either  via  a  site  visit  or  via  a  telephone  call  with  subsequent  site  visit 
 requested in case any concerns noted during the telephone call. 
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 8.2. 
 Description of study procedures 
 8.2.1.  Medical history and physical examination, electrocardiogram, weight and 
 vital signs 
 Findings  from  medical  history  (obtained  at  screening)  and  physical  examination  shall  be 
 given  a  baseline  grade  according  to  the  procedure  for  AEs.  Increases  in  severity  of 
 pre-existing  conditions  during  the  study  will  be  considered  AEs,  with  resolution 
 occurring when the grade returns to the pre-study grade or below. 
 Physical  examinations  will  be  performed  on  study  days  noted  in  the  Schedule  of 
 Assessments. 
 8.2.2.  Physical examination 
 Physical  examinations  will  be  performed  according  to  the  assessment  schedule.  Full 
 physical  examinations  will  include  assessments  of  the  head,  eyes,  ears,  nose,  and  throat 
 and  the  respiratory,  cardiovascular,  GI,  urogenital,  musculoskeletal,  neurological, 
 dermatological,  hematologic/lymphatic,  and  endocrine  systems.  Height  will  be  measured 
 at  screening  only.  Targeted  physical  examinations  are  to  be  utilized  by  the  Investigator  on 
 the  basis  of  clinical  observations  and  symptomatology.  Situations  in  which  physical 
 examination results should be reported as AEs are described in Section 10. 
 8.2.3.  Electrocardiograms 
 Resting  12-lead  ECGs  will  be  recorded  at  screening,  baseline,  (cycle  1  Day  1  within  1  hr 
 prior  to  the  start  of  the  first  study  treatment),  and  as  clinically  indicated  throughout  the 
 study.  ECGs  should  be  obtained  after  the  patient  has  been  in  a  supine  position  for 
 5 minutes  and  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 the finding. 
 Situations in which ECG results should be reported as AEs are described in Section  10.3.1 
 8.2.4.  Vital signs 
 Vital  signs  (blood  pressure  [BP],  pulse,  temperature,  and  respiration  rate)  will  be 
 evaluated  according  to  the  assessment  schedules  Body  weight  is  also  recorded  at  each 
 visit along with vital signs. 
 8.2.4.1.  First infusion 
 On  the  first  infusion  day,  patients  in  the  durvalumab  +  tremelimumab  combination 
 therapy  group  will  be  monitored  and  vital  signs  collected/recorded  in  eCRF  prior  to, 
 during and after infusion of IP as presented in the bulleted list below. 
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 BP  and  pulse  will  be  collected  before,  during,  and  after  each  infusion  at  the  following 
 times (based on a 60-minute infusion): 
 ●  Prior  to  the  beginning  of  the  infusion  (measured  once  from  approximately  30 minutes 
 before up to 0 minutes [i.e., the beginning of the infusion]) 
 ●  Approximately 30 minutes during the infusion ( halfway  through infusion) 
 ●  At the end of the infusion (approximately 60 minutes ±5 minutes) 
 If  the  infusion  takes  longer  than  60  minutes,  then  BP  and  pulse  measurements  should 
 follow  the  principles  as  described  above  or  be  taken  more  frequently  if  clinically 
 indicated.  A  1-hour  observation  period  is  recommended  after  the  first  infusion  of 
 durvalumab and tremelimumab. 
 8.2.4.2.  Subsequent infusions 
 BP,  pulse  and  other  vital  signs  should  be  measured,  collected/recorded  in  eCRF  prior  to 
 the  start  of  the  infusion.  Patients  should  be  carefully  monitored  and  BP  and  other  vital 
 signs  should  be  measured  during  and  post  infusion  as  per  institution  standard  and  as 
 clinically  indicated.  Any  clinically  significant  changes  in  vital  signs  should  be  entered 
 onto an unscheduled vital signs CRF page. 
 8.2.5.  Clinical laboratory tests 
 Blood  and  urine  samples  for  determination  of  clinical  chemistry,  hematology,  and 
 urinalysis  will  be  taken  at  the  times  indicated  in  the  assessment  schedules  and  as 
 clinically indicated (see Table 4 through Table 6). 
 Clinical  laboratory  safety  tests,  including  serum  pregnancy  tests,  will  be  performed  in  a 
 licensed  clinical  laboratory  according  to  local  standard  procedures.  Sample  tubes  and 
 sample  sizes  may  vary  depending  on  the  laboratory  method  used  and  routine  practice  at 
 the  site.  Urine  pregnancy  tests  may  be  performed  at  the  site  using  a  licensed  test  (urine  or 
 serum  pregnancy  test).  Abnormal  clinically  significant  laboratory  results  should  be 
 repeated as soon as possible (preferably within 24 to 48 hours). 
 Additional  safety  samples  may  be  collected  if  clinically  indicated  at  the  discretion  of  the 
 Investigator.  The  date,  time  of  collection,  and  results  (values,  units,  and  reference  ranges) 
 will be recorded on the appropriate eCRF. 
 The  laboratory  variables  to  be  measured  are  presented  in  Table  4  (clinical  chemistry), 
 Table 5 (hematology), and Table 6 (urinalysis). 
 Other  safety  tests  to  be  performed  at  screening  include  assessment  for  hepatitis  B  surface 
 antigen, hepatitis C antibodies and HIV antibodies. 
 The following laboratory variables will be measured: 
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 Table 4 .  Clinical chemistry 
 Albumin 
 Lipase  b 
 Alkaline phosphatase 
 Magnesium  c 
 ALT  a 
 Potassium 
 Amylase  b 
 Sodium 
 AST  a 
 Total bilirubin 
 Bicarbonate  c 
 Total protein 
 Calcium 
 TSH 
 Chloride  c 
 T3 free  d  (reflex) 
 Creatinine clearance  c 
 T4 free  d  (reflex) 
 Creatinine 
 Urea or blood urea nitrogen, depending on local practice 
 Gamma glutamyltransferase  c 
 Glucose 
 Lactate dehydrogenase 
 a 
 Tests  for  ALT,  AST,  alkaline  phosphatase,  and  total  bilirubin  must  be  conducted  and  assessed 
 concurrently.  If  total  bilirubin  is  ≥2×  ULN  (and  no  evidence  of  Gilbert’s  syndrome),  then  fractionate  into 
 direct and indirect bilirubin. 
 b 
 It  is  preferable  that  both  amylase  and  lipase  parameters  are  assessed.  For  sites  where  only  1  of 
 these parameters is routinely measured then either lipase or amylase is acceptable. 
 c 
 Bicarbonate  (where  available),  chloride,  creatinine  clearance,  gamma  glutamyltransferase,  and 
 magnesium  testing  are  to  be  performed  at  screening,  on  Day 0  (unless  screening  laboratory  assessments  are 
 performed within 3 days prior to Day 0), and if clinically indicated. 
 d  Free  T3  or  free  T4  will  only  be  measured  if  TSH  is  abnormal  or  if  there  is  a  clinical  suspicion  of  an  AE 
 related to the endocrine system 
 Table 5 .  Hematology 
 Absolute neutrophil count 
 Absolute lymphocyte count 
 Hemoglobin 
 Platelet count 
 Note:  For  coagulation  parameters,  activated  partial  thromboplastin  time  and  international  normalized  ratio  are  to  be 
 assessed at baseline and as clinically indicated. 
 Urinalysis should be done at baseline (screening) and then as clinically indicated 
 Table 6 .  Urianalysis 
 Bilirubin 
 Ketones 
 Blood 
 pH 
 Color and appearance 
 Protein 
 Glucose 
 Specific gravity 
 Note:  Microscopy  should  be  used  as  appropriate  to  investigate  white  blood  cells  and  use  the  high  power  field  for  red 
 blood cells. 
 If  a  patient  shows  an  AST  or  ALT  ≥3x  ULN  together  with  total  bilirubin  ≥2x  ULN,  refer 
 to  Appendix  1  for  further  instructions  on  cases  of  increases  in  liver  biochemistry  and 
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 evaluation  of  Hy’s  Law.  These  cases  should  be  reported  as  SAEs  if,  after  evaluation,  they 
 meet  the  criteria  for  a  Hy’s  law  case  or  if  any  of  the  individual  liver  test  parameters  fulfill 
 any of the SAE criteria. 
 All  patients  should  have  further  chemistry  profiles  performed  at  30 days  (±3 days),  2 
 months  (±1  week)  and  3  months  (±1  week)  after  permanent  discontinuation  of  IP  (see 
 Table 4). 
 Any  clinically  significant  abnormal  laboratory  values  should  be  repeated  as  clinically 
 indicated  and  recorded  on  the  eCRF.  Situations  in  which  laboratory  safety  results  should 
 be reported as AEs are described in Section 10.3.5. 
 All  patients  with  Grade  3  or  4  laboratory  values  at  the  time  of  completion  or 
 discontinuation  from  IP  must  have  further  tests  performed  until  the  laboratory  values 
 have  returned  to  Grade  1  or  2,  unless  these  values  are  not  likely  to  improve  because  of  the 
 underlying disease. 
 8.3. 
 Biological sampling procedures 
 8.3.1.  Biomarker/pharmacodynamic sampling and evaluation methods 
 8.3.1.1.  Peripheral blood 
 Information  about  peripheral  blood  studies  will  be  included  in  the  informed  consent  form 
 (ICF).  Blood  samples  for  biomarker  analysis  will  be  acquired  at  baseline  (Week  1  prior  to 
 the  administration  of  durvalumab  and  tremelimumab,  W2  before  initiation  of  RT,  W8  at 
 the end of RT, and W12 at the time of tumor response). 
 Extraction and Manipulation Procedure: 
 Every  peripheral  blood  sample  extraction  for  translational  studies  will  consist  in  2  whole 
 blood  tubes  for  peripheral  blood  mononuclear  cells  (PBMCs)  isolation,  2  plasma  tubes 
 and  1  serum  tube.  A  manual  with  the  detailed  procedures  of  extraction  and  manipulation 
 of  samples  will  be  sent  to  each  site.  Plasma  and  serum  tubes  will  be  kept  at  -80ºC  and 
 shipped  to  the  Translational  Research  Laboratory  1  at  the  Institut  Català  d’Oncologia 
 (ICO)  periodically.  Whole  blood  for  cytometry  will  be  processed  using  Ficoll  Hypaque  © 
 and  PBMCs  will  be  frozen  using  FBS  and  DMSO,  if  this  procedure  is  not  available  at  the 
 site, samples will be sent to the central laboratory in less than 24 hours. 
 The following translational studies are going to be performed: 
 ● 
 Correlation  between  changes  in  peripheral  blood  cell  populations  and  clinical 
 benefit.  Combination  of  anti-CTLA4  and  anti-PD1  leads  to  striking  change  in 
 characteristics  of  circulating  leukocytes  in  vivo  (Rituparna  et  al.  2015).  PBMCs  will  be 
 analyzed  using  flow  cytometry  to  determine  the  presence  of  activation  and  exhaustion 
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 markers such as but not limited to PD1, CD137, and TIM3. 
 ● 
 Correlation  between  patient  HLA  type  and  clinical  benefit  and  toxicity.  Whole 
 exome  sequence  (WES)  from  peripheral  blood  lymphocytes  is  going  to  be  performed  to 
 use  a  comparator  to  WES  from  tumor  metastasis.  We  are  going  to  use  this  information  to 
 check the HLA types from different patient with outcome and toxicity. 
 ● 
 Correlation  between  blood  circulating  cytokines  and  clinical  benefit.  Changes  in 
 circulating  cytokines  have  been  associated  to  tumor  response  (Sanmamed  et  al.  2014). 
 Blood  samples  will  be  evaluated  to  determine  variation  in  cytokines  such  as  but  not 
 limited to IL-1a, IL-2, IL-6, IL-8, IFNy, and TGFb. 
 ● 
 Identification  of  exosome  profile  in  peripheral  blood.  Exosomes  are  cell-derived 
 vesicles  that  are  present  in  many  and  perhaps  all  biological  fluids,  including  blood,  urine, 
 and  cultured  medium  of  cell  cultures.  The  reported  diameter  of  exosomes  is  between  30 
 and  100  nm.  It  is  becoming  increasingly  clear  that  exosomes  have  specialized  functions 
 and  play  key  role  in  intercellular  functions,  and  metastatic  niche  preparation.  On  the  other 
 hand,  immune  cells  can  secrete  exosomes  that  can  act  as  activators  of  immune  response. 
 The  delivery  and  expose  of  molecules  such  as  certain  heat  shock  proteins  (HSP)  that  can 
 act  as  damage-associated  molecular  pattern  molecules  (DAMPS)  and  interact  to  several 
 toll-like  receptors  (TLRs)  can  activate  immune  response.  Additionally,  dendritic 
 cell-derived  exosomes  express  MHC  I,  MHC  II,  and  costimulatory  molecules  and  have 
 been  proven  to  be  able  to  induce  and  enhance  antigen-specific  T  cell  responses  in  vivo. 
 (Benito-Martin  et  al.  2015).  We  are  going  to  explore  tumor  exosomes  (basal  samples), 
 and  treatment-induced  immune  exosomes  (induced  by  treatment)  and  correlate  with 
 treatment efficacy and toxicity. 
 8.3.1.2.  Urine  samples 
 Urine  samples  samples  will  be  optionally  required  from  patients  recruited  in  ICO 
 L'Hospitalet  at  the  time  of  screening  period  and  end  of  treatment  visit.  The  first  urine  in 
 the morning would be collected using a standard testing tube of 50 ml. 
 The  urine  will  follow  the  standard  procedures  and  should  be  delivered  to  the  central 
 laboratory  at  the  Institut  Català  d’Oncologia  (ICO)  L’Hospitalet.  If  for  any  reason  the 
 urine  can  not  be  delivered  to  the  central  laboratory  immediately  it  can  be  kept  at  room 
 temperature. 
 The  samples  will  be  collected  at  the  time  of  screening  period  and  the  end  of  treatment 
 visit  to  detect  and  to  quantify  CD8  and  CD4  lymphocytes  and  assess  their  immune  profile 
 (PD-1,  TIM-3,  CTLA-4,  ICOS,  and  4-1BB  expression  and  TCR  sequence.),  in  order  to 
 evaluate  possible  correlations  between  a  high  number  of  CD8-PDL1  with  worse 
 prognosis  (as  previously  reported  by  Dr.  Quezada,  J.  Exp.  Med.  2018).  Further  analysis 
 on could be implemented and will be detailed in the final Clinical Study Report. 
 8.3.2.  Estimate of volume of blood to be collected 
 The total volume of blood that will be drawn from each patient in this study is as follows: 
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 Table 7 .  Volume of blood to be drawn from each patient 
 Assessment 
 Sample volume 
 (mL) 
 No. of samples 
 Total volume 
 (mL) 
 Safety 
 Clinical chemistry 
 Local practice 
 Local practice 
 Local practice 
 Hematology 
 Local practice 
 Local practice 
 Local practice 
 Biomarker analysis 
 45 mL 
 4 
 180 
 8.3.3  Fresh tumor biopsies 
 If  the  patient  agrees  to  participate  in  the  substudy  a  fresh  tumor  biopsy  sample  will  be 
 required  at  the  time  of  initial  TUR.  A  fragment  of  tumor  tissue  will  be  processed 
 following  standard  procedures  for  formalin-fixing  at  the  pathology  unit,  a  suitable  tumor 
 block  or  15  unstained  slides  4  micrometer  thick  will  be  sent  to  the  central  laboratory. 
 Another  fragment  of  tumor  tissue  of  at  least  1  g  of  weight  will  be  frozen  immediately 
 using  an  optimal  cutting  temperature  (OCT)  compound,  tubes  will  be  kept  at  -80ºC  and 
 shipped  to  the  central  laboratory  at  the  Institut  Català  d’Oncologia  (ICO)  periodically. 
 Details  for  the  processing,  labelling  and  shipping  of  the  samples  will  be  given  to  each  site 
 in a manual. 
 Tumor assessment: 
 For  every  patients  who  have  not  achieved  complete  response  will  undergo  a  TUR  and 
 fresh  biopsy  will  be  obtained.  One  sample  will  be  fixed  in  formalin  and  two  additional 
 ones will be frozen and kept at -80ºC. 
 It  will  be  required  to  send  fresh  and  formalin  fixed  samples  of  the  pathological  surgical 
 specimen  from  patients  who  are  candidate  to  salvage  cystectomy.  For  sample  processing 
 and sending please follow the same procedures explained above for the TUR. 
 Deep-frozen  tissue  will  be  processed  according  to  standard  laboratory  procedures  to 
 isolate DNA and RNA. 
 The following translational studies are planned: 
 ●  Paraffin  embedded  tissue  will  be  used  for  immunohistochemistry  to  study  tumor 
 inflammatory  stroma  (such  as,  but  not  limited  to  CD3;  CD4;  CD8;  CD45RO;  FoxP3, 
 CD20,  CD11b;  CD68;  among  others),  and  lymphocyte  exhaustion  markers  (PD-1; 
 PD-L1;  CD137;  Granzyme  B;  Perforin;  among  others).  Ventana  SP263  (please  see 
 algorithm  in  appendix  II)  tumor  infiltration  and  PD-L1  expression  in  tumor  and 
 stroma  cells  has  been  related  to  tumor  response  among  different  tumors  and  also  in 
 bladder cancer treated with PDL1 (Herbst et al. 2014). 
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 ●  Correlation  of  neoantigen  presentation  and  clinical  benefit.  Tumor  mutational  load  is 
 relevant  to  response  to  immunotherapy  and  has  shown  predictive  value  in  bladder 
 cancer  treated  with  anti  PDL1  (Rosenberg  et  al.  2016).  We  will  perform  whole 
 exome-seq  (WES),  and  RNA-seq  to  get  information  on  tumor  somatic  mutations, 
 included  the  amino-acid  change  in  missense  mutations,  and  its  position  into  the 
 protein.  Additionally,  we  will  predict  the  immune-peptides  repertoire  for  each  patient, 
 combining  information  about  missense  mutations  and  inferred  HLA  alleles.  DNA 
 from  tumor  will  be  used  to  analyze  TCR-β  chain  clonality  analysis  to  achieve 
 information about T-cell diversity and clonality and associate to treatment benefit. 
 ●  Correlation  of  gene  signatures  and  clinical  response.  Sequencing  data  will  be  used  to 
 classify 
 the 
 tumors 
 according 
 to 
 the 
 bladder 
 cancer 
 TCGA 
 (https://portal.gdc.cancer.gov/).  Previous  data  show  correlation  between  subgroups 
 and  response  (Rosenberg  et  al.  2016).  DNA  and  RNA  data  will  be  used  to  explore 
 gene signatures related to Interferon signaling and T cell activation. 
 ●  Explore  changes  in  immune  infiltrate,  T-cell  clonality  and  gene  expression  between 
 pre-  and  post-treatment  samples  in  non-responding  patients  using  the  techniques 
 previously  explained.  This  will  allow  us  to  determine  the  changes  in  immune  cells 
 and tumor and make hypothesis about resistance mechanisms. 
 PD-L1 Testing 
 To  ensure  comparability  of  data  across  all  studies  of  durvalumab  and/or  tremelimumab 
 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. 
 Sample collection for PD-L1 testing 
 ●  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 
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 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 PD-L1 analysis. 
 Sample data collection for PD-L1 testing 
 The  following  fields  of  data  should  be  collected  from  the  site/institution  collecting  and  if, 
 indicated shipping of the samples: 
 ▪ 
 Patient identifier (e-code or 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 
 The following fields of data should be collected from PD-L1 testing laboratory: 
 ▪ 
 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 
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 ▪ 
 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. 
 Sample processing and if indicated submission process for PD-L1 testing 
 Preparing Stored samples for testing 
 ●  Where  samples  already  exist,  they  should  be  retrieved  from  the  Biobank  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. 
 Preparing newly acquired samples for PD-L1 testing 
 ●  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. 
 Fixation of biopsy samples for PD-L1 testing 
 ●  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. 
 Embedding in paraffin for PD-L1 testing 
 ●  An overnight processing schedule into paraffin wax is recommended 
 Storage of tumor blocks for PD-L1 testing 
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 ●  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. 
 If indicated, shipping samples to a PD-L1 testing laboratory 
 ●  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 microns thick) to be used for PD-L1 testing. 
 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 patient samples. 
 ●  Slides are stable under these conditions for 6 months. 
 ●  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 
 8.3.4.  Future biomarker studies and sample disposal 
 An  additional  ICF  will  be  issued  to  obtain  consent  for  future  biomarker  research.  All 
 research  performed  with  these  samples  will  be  subject  to  Ethical  Committee  evaluation 
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 and approval. 
 If future biomarker research is not consented samples will be kept at the central 
 laboratory and then disposed of in five years. 
 8.3.5.  Withdrawal of informed consent for donated biological samples 
 If  a  patient  withdraws  consent  to  the  use  of  donated  samples,  the  samples  will  be 
 disposed  of/destroyed,  and  the  action  documented.  As  collection  of  the  biological 
 samples  is  an  integral  part  of  the  study,  then  the  patient  is  withdrawn  from  further  study 
 participation. 
 The Principal Investigator: 
 ●  Ensures  that  biological  samples  from  that  patient,  if  stored  at  the  study  site,  are 
 immediately identified, disposed of /destroyed, and the action documented 
 ●  Ensures  the  laboratory(ies)  holding  the  samples  is/are  informed  about  the  withdrawn 
 consent  immediately  and  that  samples  are  disposed/destroyed,  the  action  documented 
 and the signed document returned to the study site 
 ●  Ensures that the patient and the sponsor are informed about the sample disposal. 
 9. 
 DISEASE EVALUATION AND METHODS 
 The  response  to  immunotherapy  may  differ  from  the  typical  responses  observed  with 
 cytotoxic  chemotherapy  including  the  following  (Wolchok  et  al  2009,  Nishino  et  al 
 2013): 
 ●  Response to immunotherapy may be delayed 
 ●  Response to immunotherapy may occur after PD by conventional criteria 
 ●  The appearance of new lesions may not represent PD with immunotherapy 
 ●  SD while on immunotherapy may be durable and represent clinical benefit. 
 Based  on  the  above-described  unique  response  to  immunotherapy  and  based  on 
 guidelines  from  regulatory  agencies,  e.g.,  European  Medicines  Agency  “Guideline  on  the 
 evaluation  of  anticancer  medicinal  products  in  man”  (EMA/CHMP/205/95/Rev.4)  for 
 immune  modulating  anticancer  compounds,  the  study  may  wish  to  implement  the 
 following in addition to standard RECIST 1.1 criteria: 
 ●  RECIST  will  be  modified  so  that  PD  must  be  confirmed  at  the  next  scheduled  visit, 
 preferably,  and  no  earlier  than  4  weeks  after  the  initial  assessment  of  PD  in  the 
 absence  of  clinically  significant  deterioration.  Treatment  with  durvalumab  + 
 tremelimumab  would  continue  between  the  initial  assessment  of  progression  and 
 confirmation for progression. 
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 ●  In  addition,  patients  may  continue  to  receive  durvalumab  +  tremelimumab  beyond 
 confirmed  PD  in  the  absence  of  clinically  significant  deterioration  and  if  investigators 
 consider that patients continue to receive benefit from treatment. 
 Modification  of  RECIST  as  described  may  discourage  the  early  discontinuation  of 
 durvalumab  +  tremelimumab  and  provide  a  more  complete  evaluation  of  its  antitumor 
 activity  than  would  be  seen  with  conventional  response  criteria.  Nonetheless,  the  efficacy 
 analysis  will  be  conducted  by  programmatically  deriving  each  efficacy  endpoint  based  on 
 RECIST 1.1 criteria. 
 Of  note,  clinically  significant  deterioration  is  considered  to  be  a  rapid  tumor  progression 
 that  necessitates  treatment  with  anticancer  therapy  other  than  durvalumab  + 
 tremelimumab  or  with  symptomatic  progression  that  requires  urgent  medical  intervention 
 (e.g.,  central  nervous  system  metastasis,  respiratory  failure  due  to  tumor  compression, 
 spinal cord compression). 
 9.1. 
 Efficacy variable 
 The  main  efficacy  variable  of  the  study  treatment  is  pathological  response  evaluated  by 
 biopsy  performed  via  cystoscopy  at  the  end  of  the  treatment.  Pathological  response  is 
 defined  as  the  absence  of  muscle-invasive  bladder  cancer  at  post-treatment  biopsy 
 (≤cT1).  Post-treatment  biopsy  will  be  performed  by  cystoscopy  performed  6  weeks  after 
 the  end  of  radiotherapy.  Persistence  of  invasive  cancer  in  the  bladder  is  considered  no 
 response  to  therapy,  and  radical  cystectomy,  if  feasible,  would  be  indicated.  Apparition  of 
 new lesions outside of the bladder is considered a first RECIST progression. 
 Confirmation of progression guidelines are set for the following reasons: 
 ●  for patient management and treatment decisions, 
 ●  in  the  absence  of  significant  clinical  deterioration,  to  promote  the  collection  of 
 additional  scans  after  the  first  radiologic  RECIST  1.1  assessment  of  progressive 
 disease  (PD)  in  order  to  distinguish  pseudoprogression  from  true  radiologic 
 progression, also known as RECIST 1.1 modified for confirmation of progression, 
 ●  when  scans  are  evaluated  by  Investigator  and  by  BICR,  to  reduce  informative 
 censoring  by  Investigator  assessments  (Investigator  assesses  PD  at  a  time-point 
 earlier than does BICR). 
 Confirmed  objective  disease  progression  refers  to  either  of  the  following  scenarios:  1. 
 clinical  progression/deterioration  followed  by  a  radiologic  verification  scan  (PD  by 
 RECIST  1.1);  or  2.  in  the  absence  of  significant  clinical  deterioration,  radiologic  PD  by 
 RECIST  1.1  followed  by  a  second  radiologic  confirmation  scan  with  PD  assessed 
 according  to  the  specific  confirmation  of  progression  criteria  listed  below.  RECIST  1.1 
 modified  for  confirmation  of  progression  refers  to  the  second  scenario  above.  The 
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 confirmatory  scan  should  occur  preferably  at  the  next  scheduled  imaging  visit  and  no 
 earlier  than  4  weeks  following  the  date  of  the  immediate  prior  assessment  of  RECIST  1.1 
 PD. 
 Immediate  prior  radiologic  progression  would  be  considered  confirmed  if  any  the 
 following criteria are met in the confirmatory scan: 
 ●  ≥20%  increase  in  the  sum  diameters  of  target  lesions  (TLs)  compared  with  the  nadir 
 at  2  consecutive  visits,  with  an  absolute  increase  of  at  least  5  mm  in  sum  of  diameters 
 compared to nadir, 
 ●  and/or  significant  progression  (worsening)  of  non-target  lesions  (NTLs)  and/or  of 
 pre-existing  new  lesions  at  the  confirmatory  scan  time-point  compared  with  the 
 immediate  prior  time-point  (Note:  Pre-existing  new  lesions  are  evaluated  as  NTLs  at 
 the confirmatory scan time-point), 
 ●  and/or additional new unequivocal lesions at the confirmatory scan time-point. 
 NOTE:  In  order  to  have  confirmed  objective  disease  progression,  there  should  be  two 
 consecutive  PD’s,  the  first  PD  by  RECIST  1.1  and  the  second  PD  using  the  confirmation 
 of  progression  criteria  (above).  If  the  first  PD  by  RECIST  1.1  is  not  confirmed,  continue 
 with  assessments  until  the  next  PD  by  RECIST  1.1,  which  in  turn  will  need  its  own 
 immediate subsequent confirmation scan. 
 In  the  absence  of  significant  clinical  deterioration,  treatment  with  study  drug  may 
 continue  between  the  initial  assessment  of  progression  and  the  scan  to  confirm 
 progression. 
 If  the  confirmation  scan  confirms  progression,  then  the  date  of  the  prior  scan  with  PD 
 should be declared as the date of progression. 
 If  progression  is  not  confirmed,  in  the  absence  of  significant  clinical  deterioration,  then 
 the  patient  should  continue  study  drug  and  on-treatment  assessments  until  the  next  PD 
 which  will  also  require  a  follow-up  confirmation  scan.  If  the  first  PD  is  not  confirmed 
 by  the  immediate  next  scan,  then  the  Investigator  should  not  change  the  PD 
 assessment of the first scan. 
 If  a  patient  discontinues  treatment  (and/or  receives  a  subsequent  anticancer  therapy)  prior 
 to  radiologic  progression,  then  the  patient  should  still  continue  to  be  followed  until 
 confirmed objective disease progression. 
 10.  ASSESSMENT OF SAFETY 
 The  Principal  Investigator  is  responsible  for  ensuring  that  all  staff  involved  in  the  study  is 
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 familiar with the content of this section. 
 10.1.  Safety parameters 
 10.1.1.  Definition of adverse events 
 An  adverse  event  is  the  development  of  an  undesirable  medical  condition  (other  than 
 progression  of  the  malignancy  under  evaluation)  or  the  deterioration  of  a  pre-existing 
 medical  condition  following  or  during  exposure  to  a  pharmaceutical  product,  whether  or 
 not  considered  causally  related  to  the  product.  An  undesirable  medical  condition  can  be 
 symptoms  (e.g.,  nausea,  chest  pain),  signs  (e.g.,  tachycardia,  enlarged  liver)  or  the 
 abnormal  results  of  an  investigation  (e.g.,  laboratory  findings,  electrocardiogram).  In 
 clinical  studies,  an  AE  can  include  an  undesirable  medical  condition  occurring  at  any 
 time,  including  run-in  or  washout  periods,  even  if  no  study  treatment  has  been 
 administered. 
 The term AE is used to include both serious and non-serious AEs. 
 10.1.2.  Definition of serious adverse events 
 A  serious  adverse  event  is  an  AE  occurring  during  any  study  phase  (i.e.,  screening, 
 run-in,  treatment,  wash-out,  follow-up),  at  any  dose  of  the  study  drugs  that  fulfils  one  or 
 more of the following criteria: 
 ●  Results in death 
 ●  Is immediately life-threatening 
 ●  Requires in-patient hospitalization or prolongation of existing hospitalization 
 ●  Results in persistent or significant disability or incapacity 
 ●  Is a congenital abnormality or birth defect in offspring of the patient 
 ●  Is  an  important  medical  event  that  may  jeopardize  the  patient  or  may  require  medical 
 intervention to prevent one of the outcomes listed above. 
 The  causality  of  SAEs  (their  relationship  to  all  study  treatment/procedures)  will  be 
 assessed by the investigator(s) and communicated to the sponsor. 
 10.1.3.  Durvalumab + tremelimumab adverse events of special interest 
 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  ±  tremelimumab  include  but  are  not  limited  to  events  with  a 
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 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. 
 If  the  Investigator  has  any  questions  in  regards  to  an  event  being  an  imAE,  the 
 Investigator should promptly contact the Study Physician. 
 AESIs observed with durvalumab ±tremelimumab include: 
 ●  Diarrhea / Colitis 
 ●  Intestinal perforation 
 ●  Pneumonitis / ILD 
 ●  ALT/AST increases / hepatitis / hepatotoxicity 
 ●  Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
 ●  Myositis/polymyositis 
 ●  Endocrinopathies  (i.e.  events  of  hypophysitis,  hypopituitarism,  adrenal  insufficiency, 
 diabetes insipidus, hyper- and hypothyroidism and type I diabetes mellitus) 
 ●  Rash / Dermatitis 
 ●  Nephritis / Blood creatinine increases 
 ●  Pancreatitis  (or  labs  suggestive  of  pancreatitis  -  increased  serum  lipase  ,  increased 
 serum amylase) . 
 ●  Myocarditis 
 ●  Other  inflammatory  responses  that  are  rare  with  a  potential  immune-mediated 
 aetiology  are  also  considered  as  AESIs  and  include,  but  are  not  limited  to, 
 pericarditis,  sarcoidosis,  uveitis  and  other  events  involving  the  eye,  skin, 
 haematological,  rheumatological  events,  vasculitis,  non-infectious  meningitis  and 
 non-infectious  encephalitis.  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 etiology are also considered AESIs. 
 Further  information  on  these  risks  (e.g.  presenting  symptoms)  can  be  found  in  the  current 
 version  of  the  durvalumab  and  tremelimumab  Investigator’s  Brochures.  More  specific 
 guidelines  for  their  evaluation  and  treatment  are  described  in  detail  in  the  Dosing 
 Modification  and  Toxicity  Management  Guidelines  (see  Appendix  1).  These  guidelines 
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 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. 
 If  new  or  worsening  pulmonary  symptoms  (e.g.  dyspnea)  or  radiological  abnormality 
 suggestive  of  pneumonitis/interstitial  lung  disease  is  observed,  toxicity  management  as 
 described  in  detail  in  the  Dosing  Modification  and  Toxicity  Management  Guidelines  (see 
 Appendix  1)  will  be  applied.  The  results  of  the  full  diagnostic  workup  (including 
 high-resolution  computed  tomography  (HRCT),  blood  and  sputum  culture,  hematological 
 parameters  etc)  will  be  captured  in  the  eCRF.  It  is  strongly  recommended  to  perform  a 
 full  diagnostic  workup,  to  exclude  alternative  causes  such  as  lymphangitic 
 carcinomatosis,  infection,  allergy,  cardiogenic  edema,  or  pulmonary  hemorrhage.  In  the 
 presence  of  confirmatory  HRCT  scans  where  other  causes  of  respiratory  symptoms  have 
 been  excluded,  a  diagnosis  of  pneumonitis  (ILD)  should  be  considered  and  the  Dosing 
 Modification and Toxicity Management Guidelines should be followed. 
 Pneumonitis (ILD) investigation 
 The  following  assessments,  and  additional  assessments  if  required,  will  be  performed  to 
 enhance  the  investigation  and  diagnosis  of  potential  cases  of  pneumonitis.  The  results  of 
 the assessment will be collected. 
 ●  Physical examination 
 ●  Signs  and  symptoms  (cough,  shortness  of  breath  and  pyrexia,  etc.)  including 
 auscultation for lung field will be assessed. 
 ●  Saturation of peripheral oxygen (SpO2) 
 ●  Other items 
 ●  When  pneumonitis  (ILD)  is  suspected  during  study  treatment,  the  following  markers 
 should be measured where possible: 
 1.  ILD Markers (KL-6, SP-D) and β-D-glucan 
 2.  Tumour  markers:  Particular  tumour  markers  which  are  related  to  disease 
 progression. 
 3.  Additional Clinical chemistry: CRP, LDH 
 10.2.  Assessment of safety parameters 
 10.2.1.  Assessment of severity 
 Assessment  of  severity  is  one  of  the  responsibilities  of  the  investigator  in  the  evaluation 
 of AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
 The  determination  of  severity  for  all  other  events  not  listed  in  the  CTCAE  should  be 
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 made  by  the  investigator  based  upon  medical  judgment  and  the  severity  categories  of 
 Grade 1 to 5 as defined below. 
 ●  Grade  1  (mild)  An  event  that  is  usually  transient  and  may  require  only  minimal 
 treatment  or  therapeutic  intervention.  The  event  does  not  generally  interfere  with 
 usual activities of daily living. 
 ●  Grade  2  (moderate)  An  event  that  is  usually  alleviated  with  additional  specific 
 therapeutic  intervention.  The  event  interferes  with  usual  activities  of  daily  living, 
 causing  discomfort  but  poses  no  significant  or  permanent  risk  of  harm  to  the 
 patient. 
 ●  Grade  3  (severe)  An  event  that  requires  intensive  therapeutic  intervention.  The 
 event  interrupts  usual  activities  of  daily  living,  or  significantly  affects  the  clinical 
 status of the patient. 
 ●  Grade  4  (life  threatening)  An  event,  and/or  its  immediate  sequelae,  that  is 
 associated  with  an  imminent  risk  of  death  or  with  physical  or  mental  disabilities 
 that  affect  or  limit  the  ability  of  the  patient  to  perform  activities  of  daily  living 
 (eating, ambulation, toileting, etc). 
 ●  Grade 5 (fatal) Death (loss of life) as a result of an event. 
 It  is  important  to  distinguish  between  serious  criteria  and  severity  of  an  AE.  Severity  is  a 
 measure  of  intensity  whereas  seriousness  is  defined  by  the  criteria  in  Section  10.2.1.  A 
 Grade  3  AE  need  not  necessarily  be  considered  an  SAE.  For  example,  a  Grade  3 
 headache  that  persists  for  several  hours  may  not  meet  the  regulatory  definition  of  an  SAE 
 and  would  be  considered  a  non  serious  event,  whereas  a  Grade  2  seizure  resulting  in  a 
 hospital admission would be considered an SAE. 
 10.2.2.  Assessment of relationship 
 The  Investigator’s  assessment  of  causality  must  be  provided  for  all  AEs  (serious  and 
 non-serious);  the  Investigator  must  record  the  causal  relationship  in  the  eCRF,  as 
 appropriate,  and  report  such  an  assessment  in  accordance  with  the  serious  adverse 
 reporting  requirements  if  applicable.  An  Investigator’s  causality  assessment  is  the 
 determination  of  whether  there  exists  a  reasonable  possibility  that  the  study  treatment 
 caused  or  contributed  to  an  AE;  generally,  the  facts  (evidence)  or  arguments  to  suggest  a 
 causal relationship should be provided. 
 If  the  Investigator  does  not  know  whether  or  not  the  study  treatment  caused  the  event, 
 then the event will be handled as “related to study treatment” for reporting purposes. 
 If  the  Investigator's  causality  assessment  is  “unknown  but  not  related  to  study  treatment”, 
 this should be clearly documented on study records. 
 In  addition,  if  the  Investigator  determines  an  SAE  is  associated  with  study  procedures, 
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 the  Investigator  must  record  this  causal  relationship  in  the  source  documents  and  eCRF, 
 as  appropriate,  and  report  such  an  assessment  in  accordance  with  the  SAE  reporting 
 requirements, if applicable. 
 10.3.  Recording of adverse events and serious adverse events 
 Adverse  events  will  be  recorded  eCRF  using  a  recognized  medical  term  or  diagnosis  that 
 accurately  reflects  the  event.  Adverse  events  will  be  assessed  by  the  investigator  for 
 severity,  relationship  to  the  investigational  product,  possible  etiologies,  and  whether  the 
 event  meets  criteria  of  an  SAE  and  therefore  requires  immediate  notification  to  the 
 sponsor. 
 The following variables will be collected for each AE: 
 In addition, the following variables will be collected for SAEs as applicable: 
 ●  AE (verbatim) 
 ●  The date when the AE started and stopped 
 ●  The maximum CTCAE grade reported 
 ●  Changes in CTCAE grade 
 ●  Whether the AE is serious or not 
 ●  Investigator causality rating against the IPs (yes or no) 
 ●  Action taken with regard to IPs 
 ●  Administration of treatment for the AE 
 ●  Outcome 
 In addition, the following variables will be collected for SAEs: 
 ●  Date the AE met criteria for SAE 
 ●  Date the Investigator became aware of the SAE 
 ●  Seriousness criteria fulfilled 
 ●  Date of hospitalization 
 ●  Date of discharge 
 ●  Probable cause of death 
 ●  Date of death 
 ●  Whether an autopsy was performed 
 ●  Causality assessment in relation to study procedure(s) 
 ●  Causality  assessment  in  relation  to  other  medication,  as  explained  in 
 Section 10.2.2 
 ●  Description of the SAE 
 The  grading  scales  found  in  the  revised  NCI  CTCAE  version  4.03  will  be  utilized  for  all 
 events  with  an  assigned  CTCAE  grading.  For  those  events  without  assigned  CTCAE 
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 grades,  the  recommendation  in  the  CTCAE  criteria  that  converts  mild,  moderate,  and 
 severe  events  into  CTCAE  grades  should  be  used.  A  copy  of  the  CTCAE  version  4.03 
 can  be  downloaded  from  the  Cancer  Therapy  Evaluation  Program  website 
 ( http://ctep.cancer.gov ). 
 Events,  which  are  unequivocally  due  to  disease  progression,  should  not  be  reported  as  an 
 AE during the study. 
 10.3.1.  Study recording period and follow-up for adverse events and serious adverse 
 events 
 Adverse  events  and  serious  adverse  events  will  be  recorded  from  time  of  signature  of 
 informed  consent,  throughout  the  treatment  period  and  including  the  follow-up  period  (90 
 days after the last dose of durvalumab + tremelimumab). 
 During  the  study,  all  AEs  and  SAEs  should  be  proactively  followed  up  for  each  patient. 
 Every  effort  should  be  made  to  obtain  a  resolution  for  all  events,  even  if  the  events 
 continue after discontinuation/study completion. 
 If  a  patient  discontinues  from  treatment  for  reasons  other  than  disease  progression,  and 
 therefore  continues  to  have  tumor  assessments,  drug  or  procedure-related  SAEs  must  be 
 captured  until  the  patient  is  considered  to  have  confirmed  PD  and  will  have  no  further 
 tumor assessments. 
 The  investigator  is  responsible  for  following  all  SAEs  until  resolution,  until  the  patient 
 returns  to  baseline  status,  or  until  the  condition  has  stabilized  with  the  expectation  that  it 
 will remain chronic, even if this extends beyond study participation. 
 10.3.2.  Causality collection 
 The  Investigator  will  assess  causal  relationship  between  the  IPs  and  each  AE  and  answer 
 “yes”  or  “no”  to  the  question  “Do  you  consider  that  there  is  a  reasonable  possibility  that 
 the event may have been caused by the investigational product?” 
 For  SAEs  causal  relationship  will  also  be  assessed  for  other  medication  and  study 
 procedures.  Note  that  for  SAEs  that  could  be  associated  with  any  study  procedure,  the 
 causal relationship is implied as “yes.” 
 10.3.3.  A  guide  to  the  interpretation  of  the  causality  question  is  found  in  next 
 section. Relationship to protocol procedures 
 The  Investigator  is  also  required  to  provide  an  assessment  of  the  relationship  of  SAEs  to 
 protocol  procedures  on  the  SAE  report  form.  This  includes  both  non-treatment–emergent 
 (i.e.,  SAEs  that  occur  prior  to  the  administration  of  IP)  and  treatment-emergent  SAEs.  A 
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 protocol-related  SAE  may  occur  as  a  result  of  a  procedure  or  intervention  required  during 
 the  study  (e.g.,  blood  collection).  The  following  guidelines  should  be  used  by 
 Investigators to assess the relationship of SAEs to the protocol: 
 ● 
 Protocol  related:  The  event  occurred  due  to  a  procedure  or  intervention  that  was 
 described  in  the  protocol  for  which  there  is  no  alternative  etiology  present  in  the 
 patient’s medical record. 
 ● 
 Not  protocol  related:  The  event  is  related  to  an  etiology  other  than  the  procedure  or 
 intervention  that  was  described  in  the  protocol.  The  alternative  etiology  must  be 
 documented in the study patient’s medical record. 
 10.3.4.  Adverse events based on signs and symptoms 
 All  AEs  spontaneously  reported  by  the  patient  or  reported  in  response  to  the  open 
 question  from  the  study  personnel:  “Have  you  had  any  health  problems  since  the  previous 
 visit/you  were  last  asked?”  or  revealed  by  observation  will  be  collected  and  recorded  in 
 the  eCRF.  When  collecting  AEs,  the  recording  of  diagnoses  is  preferred,  when  possible, 
 to  recording  a  list  of  signs  and  symptoms.  However,  if  a  diagnosis  is  known  and  there  are 
 other  signs  or  symptoms  that  are  not  generally  part  of  the  diagnosis,  the  diagnosis  and 
 each sign or symptom will be recorded separately. 
 10.3.5.  Adverse events based on examinations and tests 
 The  results  from  protocol-mandated  laboratory  tests  and  vital  signs  measurements  will  be 
 summarized  in  the  CSR.  Deterioration  as  compared  to  baseline  in  protocol-mandated 
 laboratory  values  and  vital  signs  should  therefore  only  be  reported  as  AEs  if  they  fulfill 
 any of the SAE criteria or are the reason for discontinuation of treatment with the IPs. 
 If  deterioration  in  a  laboratory  value  or  vital  sign  is  associated  with  clinical  signs  and 
 symptoms,  the  sign  or  symptom  will  be  reported  as  an  AE  and  the  associated  laboratory 
 result  or  vital  sign  will  be  considered  as  additional  information.  Whenever  possible,  the 
 reporting  Investigator  should  use  the  clinical  rather  than  the  laboratory  term  (e.g.,  anemia 
 versus  low  hemoglobin  value).  In  the  absence  of  clinical  signs  or  symptoms,  clinically 
 relevant deteriorations in nonmandated parameters should be reported as AEs. 
 Deterioration  of  a  laboratory  value  that  is  unequivocally  due  to  disease  progression 
 should not be reported as an AE/SAE. 
 Any  new  or  aggravated  clinically  relevant  abnormal  medical  finding  at  a  physical 
 examination as compared with the baseline assessment will be reported as an AE. 
 10.3.6.  Hy’s Law 
 Cases  where  a  patient  shows  elevations  in  liver  biochemistry  may  require  further 
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 evaluation  and  occurrences  of  AST  or  ALT  ≥3  × ULN  together  with  total  bilirubin  ≥2 
 × ULN  may  need  to  be  reported  as  SAEs.  Please  refer  to  Appendix  1  for  further 
 instruction on cases of increases in liver biochemistry and evaluation of Hy’s law. 
 10.3.7.  Disease progression 
 Disease  progression  can  be  considered  as  a  worsening  of  a  patient’s  condition  attributable 
 to  the  disease  for  which  the  IP  is  being  studied.  It  may  be  an  increase  in  the  severity  of 
 the  disease  under  study  and/or  increases  in  the  symptoms  of  the  disease.  The 
 development  of  new  or  progression  of  existing  metastasis  to  the  primary  cancer  under 
 study  should  be  considered  as  disease  progression  and  not  an  AE.  Events  that  are 
 unequivocally  due  to  disease  progression  should  not  be  reported  as  an  AE  during  the 
 study. 
 10.3.8.  New cancers 
 The  development  of  a  new  cancer  should  be  regarded  as  an  SAE.  New  primary  cancers 
 are  those  that  are  not  the  primary  reason  for  the  administration  of  the  IP  and  have  been 
 identified after the patient’s inclusion in this study. 
 10.3.9.  Reporting of serious adverse events 
 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  Regulatory 
 Authority of the SAE as per local requirements. 
 Each  AE  is  to  be  assessed  to  determine  if  it  meets  the  criteria  for  SAEs.  If  an  SAE  occurs, 
 expedited reporting will follow local and international regulations, as appropriate. 
 The  sponsor  must  inform  the  AEMPS  of  any  Suspected  serious  or  unexpected  serious 
 adverse  events  (SUSAR)  that  occur  in  accordance  with  the  reporting  obligations,  and  will 
 concurrently  forward  all  such  reports  to  AstraZeneca.  A  copy  of  the  report  must  be  sent 
 by e-mail to AstraZeneca at the time the event is reported to the AEMPS by the sponsor. 
 * A cover page should accompany the SAE form indicating the following: 
 • 
 External Scientific Research (ESR) 
 • 
 The investigator’s name and address 
 • 
 The trial name/title and AstraZeneca ESR reference number 
 *  Send  SAE  report  and  accompanying  cover  page  by  way  of  Email  to 
 AEMailboxClinicalTrialTCS@astrazeneca.com 
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 If a non-serious AE becomes serious, the same process described before will be followed. 
 Serious  adverse  events  that  do  not  require  expedited  reporting  to  the  AEMPS  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. 
 The  following  reportable  events  must  be  submitted  to  the  sponsor  within  24  hours  (or 
 immediately for death or life-threatening events). 
 Serious Adverse Events 
 • 
 Exposure  during  Pregnancy  or  Breastfeeding  (even  if  not  associated  with  an 
 adverse event). 
 • 
 Occupational exposure (even if not associated with an adverse event) 
 • 
 Potential  drug-induced  liver  injury  (Hy’s  Law  cases): 
 These  events  are 
 considered important medical events and should be reported as SAEs. 
 Site  staff  should  send  SAE  report  and  accompanying  cover  page  by  fax  or  email  to 
 sponsor/CRO’s designated mailbox: 
 DEPARTAMENTO DE INVESTIGACIÓN, MFAR Clinical Research. 
 Fax: +34 93 253 11 68 
 Email: i nvestigacion@mfar.net 
 10.3.9.1. Reporting of deaths to 
 All  deaths  that  occur  during  the  study,  or  within  the  protocol  defined  90  day  post  last 
 dose  of  durvalumab  +  tremelimumab  safety  follow  up  period  must  be  reported  to  the 
 sponsor as follows: 
 ●  Death  that  is  clearly  the  result  of  disease  progression  should  be  documented  but 
 should not be reported as an SAE. 
 ●  Where  death  is  not  due  (or  not  clearly  due)  to  progression  of  the  disease  under 
 study,  the  AE  causing  the  death  must  be  reported  to  the  sponsor  as  a  SAE  within 
 24 hours  (see  Section  10.3.2  for  further  details).  The  report  should  contain  a 
 comment  regarding  the  co-involvement  of  progression  of  disease,  if  appropriate, 
 and should assign main and contributory causes of death. 
 ●  Deaths with an unknown cause should always be reported as a SAE. 
 Deaths  occurring  after  the  protocol  defined  safety  follow  up  period  after  the 
 administration  of  the  last  dose  of  study  drug  should  be  documented  in  the  Statement  of 
 Death  page.  If  the  death  occurred  as  a  result  of  an  event  that  started  after  the  defined 
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 safety  follow  up  period  and  the  event  is  considered  to  be  due  to  a  late  onset  toxicity  to 
 study drug, then it should also be reported as an SAE. 
 10.3.10. Other events requiring reporting 
 10.3.10.1. Overdose 
 Use  of  durvalumab  or  tremelimumab  in  doses  in  excess  of  that  specified  in  the  protocol  is 
 considered  to  be  an  overdose.  There  is  currently  no  specific  treatment  in  the  event  of 
 overdose  of  durvalumab  or  tremelimumab,  and  possible  symptoms  of  overdose  are  not 
 established. 
 ●  An  overdose  with  associated  AEs  will  be  recorded  as  the  AE  diagnosis  or 
 symptoms  in  the  relevant  AE  modules  of  the  eCRF  and  in  the  Overdose  eCRF 
 module. 
 ●  An  overdose  without  associated  symptoms  will  only  be  reported  in  the  Overdose 
 eCRF module. 
 If  an  overdose  of  an  AstraZeneca  IP  occurs  in  the  course  of  the  study,  then  the 
 Investigator  or  other  site  personnel  will  inform  appropriate  sponsor  representatives 
 immediately, or  no later than 24 hours  of when he  or she becomes aware of it. 
 The  designated  sponsor  representative  will  work  with  the  Investigator  to  ensure  that  all 
 relevant information is provided. 
 For  overdoses  associated  with  an  SAE,  the  standard  reporting  timelines  apply,  see  Section 
 10.3.10.1. For other overdoses, reporting must occur within 30 days. 
 10.3.10.2. Pregnancy 
 All pregnancies and outcomes of pregnancy should be reported to the sponsor except for: 
 ●  Pregnancy discovered before the study patient has received any study drugs. 
 ●  Pregnancy  of  a  female  partner  of  male  patient,  providing  there  is  no  restriction  of 
 male patient fathering a child. 
 10.3.11. Maternal exposure 
 If  a  patient  becomes  pregnant  during  the  course  of  the  study,  the  IPs  should  be 
 discontinued immediately. 
 Pregnancy  itself  is  not  regarded  as  an  AE  unless  there  is  a  suspicion  that  the  IP  under 
 study  may  have  interfered  with  the  effectiveness  of  a  contraceptive  medication. 
 Congenital  abnormalities  or  birth  defects  and  spontaneous  miscarriages  should  be 
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 reported  and  handled  as  SAEs.  Elective  abortions  without  complications  should  not  be 
 handled  as  AEs.  The  outcome  of  all  pregnancies  (spontaneous  miscarriage,  elective 
 termination,  ectopic  pregnancy,  normal  birth,  or  congenital  abnormality)  should  be 
 followed up and documented even if the patient was discontinued from the study. 
 If  any  pregnancy  occurs  in  the  course  of  the  study,  then  the  Investigator  or  other  site 
 personnel  should  inform  the  appropriate  sponsor  representatives  within  1  day,  i.e., 
 immediately, but  no later than 24 hours  of when he  or she becomes aware of it. 
 The  designated  sponsor  representative  will  work  with  the  Investigator  to  ensure  that  all 
 relevant  information  is  provided  within  1  to  5 calendar  days  for  SAEs  and  within  30  days 
 for all other pregnancies. 
 The same timelines apply when outcome information is available. 
 10.3.12. Paternal exposure 
 Male  patients  should  refrain  from  fathering  a  child  or  donating  sperm  during  the  study 
 and  for  180 days  after  the  last  dose  of  durvalumab  +  tremelimumab  combination  therapy 
 or  90 days  after  the  last  dose  of  durvalumab  monotherapy,  whichever  is  the  longer  time 
 period. 
 Pregnancy  of  the  patient’s  partner  is  not  considered  to  be  an  AE.  However,  the  outcome 
 of  all  pregnancies  (spontaneous  miscarriage,  elective  termination,  ectopic  pregnancy, 
 normal  birth,  or  congenital  abnormality)  occurring  from  the  date  of  the  first  dose  until 
 180 days  after  the  last  dose  of  durvalumab  +  tremelimumab  combination  therapy  or 
 90 days  after  the  last  dose  of  durvalumab  monotherapy,  whichever  is  the  longer  time 
 period should, if possible, be followed up and documented. 
 Where  a  report  of  pregnancy  is  received,  prior  to  obtaining  information  about  the 
 pregnancy,  the  Investigator  must  obtain  the  consent  of  the  patient’s  partner.  Therefore,  the 
 local  study  team  should  adopt  the  generic  ICF  template  in  line  with  local  procedures  and 
 submit it to the relevant Ethics Committees (ECs) prior to use. 
 10.4. Medication error 
 For  the  purposes  of  this  clinical  study  a  medication  error  is  an  unintended  failure  or 
 mistake  in  the  treatment  process  for  an  AstraZeneca  study  drug  that  either  causes  harm  to 
 the patient or has the potential to cause harm to the patient. 
 A  medication  error  is  not  lack  of  efficacy  of  the  drug,  but  rather  a  human  or  process 
 related failure while the drug is in control of the study site staff or patient. 
 Medication error includes situations where an error. 
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 ●  occurred 
 ●  was identified and intercepted before the patient received the drug 
 ●  did not occur, but circumstances were recognized that could have led to an error 
 Examples of events to be reported in clinical studies as medication errors: 
 ●  Drug name confusion 
 ●  Dispensing  error  e.g.  medication  prepared  incorrectly,  even  if  it  was  not  actually 
 given to the patient 
 ●  Drug  not  administered  as  indicated,  for  example,  wrong  route  or  wrong  site  of 
 administration 
 ●  Drug  not  taken  as  indicated  e.g.  tablet  dissolved  in  water  when  it  should  be  taken 
 as a solid tablet 
 ●  Drug  not  stored  as  instructed  e.g.  kept  in  the  fridge  when  it  should  be  at  room 
 temperature 
 ●  Wrong patient received the medication (excluding IVRS/IWRS errors) 
 ●  Wrong drug administered to patient (excluding IVRS/IWRS errors) 
 ●  Examples  of  events  that  do  not  require  reporting  as  medication  errors  in  clinical 
 studies: 
 • 
 Errors  related  to  or  resulting  from  IVRS/IWRS  -  including  those 
 which  lead  to  one  of  the  above  listed  events  that  would  otherwise 
 have been a medication error 
 • 
 Patient  accidentally  missed  drug  dose  (s)  e.g.  forgot  to  take 
 medication 
 • 
 Accidental overdose (will be captured as an overdose) 
 • 
 Patient failed to return unused medication or empty packaging 
 • 
 Errors  related  to  background  and  rescue  medication,  or  standard  of 
 care medication in open label studies, even if an AZ product 
 Medication  errors  are  not  regarded  as  AEs  but  AEs  may  occur  as  a  consequence  of  the 
 medication error. 
 If  a  medication  error  occurs  in  the  course  of  the  study,  then  the  Investigator  or  other  site 
 personnel  informs  the  appropriate  sponsor  representatives  within  1  day  i.e.,  immediately 
 but  no later than 24 hours  of when he or she becomes  aware of it. 
 The  designated  sponsor  representative  works  with  the  Investigator  to  ensure  that  all 
 relevant  information  is  completed  within  1  or  5  calendar  days  if  there  is  an  SAE 
 associated  with  the  medication  error  (see  Section  10.3.10)  and  within  30  days  for  all  other 
 medication errors. 
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 11. 
 STATISTICAL 
 METHODS 
 AND 
 SAMPLE 
 SIZE 
 DETERMINATION 
 11.1. Description of analysis sets 
 11.1.1. Safety analysis set 
 The  safety  analysis  set  will  include  all  patients  who  receive  at  least  1  dose  of  study 
 treatment.  The  safety  analysis  set  will  be  the  primary  population  for  evaluating  treatment 
 administration/compliance and safety. 
 11.1.2. Efficacy analysis set 
 The  efficacy  analysis  will  be  a  per  protocol  analysis .  The  efficacy  analysis  set  will 
 include  all  patients  who  receive  at  least  2  cycles  of  durvalumab  and  3  weeks  of 
 radiotherapy.  The  efficacy  analysis  set  will  be  the  primary  population  for  evaluating 
 treatment efficacy. 
 Additionally, intention to treat analysis will be performed for efficacy data. 
 11.2. Methods of statistical analyses 
 11.2.1. Safety analyses 
 Safety  analysis  will  be  performed  weekly  during  the  length  of  the  treatment  and  every 
 three  months  later  (late  toxicity  associated  with  radiotherapy).  Toxicities  will  be  graded 
 according to NCI CTCAE, Version 4.03 and RTOG/EORTC grading system. 
 11.2.2. Efficacy analyses and exploratory analyses 
 Table 8 .  Efficacy analyses and exploratory analyses 
 Objectives 
 Variable 
 Analysis 
 Clinical factors 
 Analysis 
 population 
 Primary: efficacy of 
 durvalumab plus 
 tremelimumab with 
 concurrent radiotherapy 
 in terms of pathological 
 response rate 
 Pathological response rate 
 1.  Proportion estimation with a 
 95% confidence interval 
 2.  Simon two stage decision rule 
 3.  Logistic regression with clinical 
 factors 
 Tumour size 
 Tumour localization 
 Histology 
 Biomarkers 
 Per 
 protocol 
 Secondary 1a: bladder 
 preservation. 
 Rate of bladder preserved 
 1.  Proportion estimation with a 
 95% confidence interval 
 2.  Logistic regression with clinical 
 factors 
 Tumour size 
 Tumour localization 
 Histology 
 Biomarkers 
 Per 
 protocol 
 Secondary 1b: bladder 
 preservation. 
 Rate of immediate and late 
 salvage cystectomies. 
 1.  Proportion estimation with a 
 95% confidence interval 
 2.  Logistic regression with clinical 
 factors 
 Tumour size 
 Tumour localization 
 Histology 
 Biomarkers 
 Per 
 protocol 
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 Secondary 1c: bladder 
 preservation. 
 Time from start of 
 immunotherapy to the date 
 of recurrence of muscle 
 invasive bladder carcinoma 
 or metastases. 
 Kaplan Meier estimation of 
 survival with a 95 % confidence 
 interval 
 Not applicable 
 Per 
 protocol 
 Secondary 1d: 
 Overall survival 
 Time from treatment start 
 to exitus. 
 Kaplan Meier estimation of 
 survival with a 95 % confidence 
 interval 
 Per 
 protocol 
 Secondary 1.3: 
 Progression free survival 
 Time from treatment start 
 to tumour relapse or distant 
 progression. 
 Kaplan Meier estimation of 
 survival with a 95 % confidence 
 interval 
 Per 
 protocol 
 Secondary 2: Safety 
 profile and tolerability of 
 combination 
 CTCAE V4.03 
 1. Frequency  table with adverse 
 events, grades and relationship to 
 study drugs and to radiotherapy 
 treatment 
 2. Frequency table with severe 
 toxicity. 
 Durvalumab cumulative 
 dose, tremelimumab 
 cumulative dose, 
 radiotherapy treatment 
 constraints (dose in risk 
 organs). 
 Safety 
 population 
 Secondary 3: To 
 evaluate the long term 
 functionalism and late 
 sequel of the treatment 
 in the preserved 
 bladders. 
 Bladder control scale 
 Repeated measures analysis 
 Per 
 protocol 
 Exploratory 1: 
 Biomarkers and 
 pathological response 
 rate 
 Biomarkers and pathological 
 response rate 
 Logistic regression in which respons
 or not Is the response and baseline
 biomarkers are factors to be studied
 Biomarkers 
 Per 
 protocol 
 Exploratory 2: 
 Biomarkers evolution 
 between baseline and 
 surgery time 
 Biomarkers evaluated at 
 baseline vs surgery 
 evaluation 
 Paired t-test or Wilcoxon Signed 
 Rank Test (depending on the natur
 of variables) 
 Per 
 protocol 
 11.2.3. Interim analyses 
 ●  Safety:  To  monitor  accurately  the  potential  toxicity  of  radiotherapy  associated  with 
 durvalumab  and  tremelimumab,  an  initial  cohort  of  5  patients  will  be  treated.  If  no 
 dose  limiting  toxicity  is  observed  in  ≥2  of  these  patients  at  the  end  of  the  treatment, 
 the  rest  of  patients  will  be  treated  at  full  doses.  In  contrast,  if  severe  toxicity  is 
 observed  in  ≥2  of  these  patients,  3  additional  patients  will  be  treated.  If  dose  limiting 
 toxicity  is  seen  in  one  of  these  additional  patients,  the  therapeutic  regimen  will  be 
 modified  in  the  subsequent  ones,  administering  full  doses  of  durvalumab  but 
 discontinuing tremelimumab after the first dose. 
 ●  Efficacy:  The  study  will  be  conducted  using  a  Simon  “Optimal  design”  two-stage 
 sequential  design.  An  interim  analysis  of  response  will  be  performed  at  the  end  of  the 
 first  stage,  after  the  treatment  of  the  first  twelve  patients  treated.  Six  or  more 
 responses in the first stage were required for continuation to second stage accrual. 
 11.3. Determination of sample size 
 The  study  will  be  conducted  using  a  two-stage  sequential  design.  Using  the  assumption 
 that  the  treatment  would  be  considered  ineffective  if  it  had  a  response  proportion  similar 
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 to  radiotherapy  alone  (P0:  0.5)  but  would  be  of  considerable  interest  if  it  had  a  response 
 proportion  of  70%  of  more  (P1:  0.7),  the  sample  size  requirement  is  12  patients  for  the 
 first  stage  and  20  additional  patients  for  the  second  stage.  Six  or  more  responses  in  the 
 first  stage  were  required  for  continuation  to  second  stage  accrual,  and  19  of  a  total  of  32 
 patients  treated  to  consider  the  study  positive.  The  study  was  planned  to  have  a  type  I 
 error of 0.10 and a power of 80%. 
 12.  ETHICAL AND REGULATORY REQUIREMENTS 
 12.1. Ethics Committee 
 It  is  the  responsibility  of  the  sponsor  to  have  prospective  approval  of  the  study  protocol, 
 protocol  amendments,  informed  consent  documents,  and  other  relevant  documents,  e.g., 
 recruitment  advertisements,  if  applicable,  from  the  EC  and  Regulatory  Authorities 
 according  to  applicable  legislation.  All  correspondence  with  the  EC  should  be  retained  in 
 the investigator and sponsor Trial Master File, when applicable according GCPs. 
 The  only  circumstance  in  which  an  amendment  may  be  initiated  prior  to  EC  approval  is 
 where  the  change  is  necessary  to  eliminate  apparent  immediate  hazards  to  the  patients.  In 
 that  event,  the  sponsor  must  notify  the  EC  in  writing  immediately  after  the 
 implementation. 
 12.2. Ethical Conduct of the Study 
 The  study  will  be  conducted  in  accordance  with  legal  and  regulatory  requirements,  as 
 well  as  the  general  principles  set  forth  in  the  International  Ethical  Guidelines  for 
 Biomedical  Research  Involving  Human  Patients  (Council  for  International  Organizations 
 of  Medical  Sciences  2002),  Guidelines  for  GCP  (Adopted  by  CHMP,  15  December  2016, 
 issued  as  EMA/CHMP/ICH/135/1995),  and  the  Declaration  of  Helsinki  (64th  WMA 
 General Assembly, Fortaleza, Brazil, October 2013). 
 In  addition,  the  study  will  be  conducted  in  accordance  with  the  protocol,  and  applicable 
 local regulatory requirements and laws. 
 12.3. Patient Information and Consent 
 All  parties  will  ensure  protection  of  patient  personal  data  and  will  not  include  patient 
 names  on  any  sponsor  forms,  reports,  publications,  or  in  any  other  disclosures,  except 
 where required by laws. 
 When  study  data  are  compiled  for  transfer  to  the  sponsor  and  other  authorized  parties, 
 patient  names,  addresses,  and  other  identifiable  data  will  be  replaced  by  a  numerical  code 
 based  on  a  numbering  system  provided  by  the  sponsor  in  order  to  de-identify  study 
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 patients.  The  study  site  will  maintain  a  confidential  list  of  patients  who  participated  in  the 
 study,  linking  each  patient’s  numerical  code  to  his  or  her  actual  identity.  In  case  of  data 
 transfer,  the  sponsor  will  maintain  high  standards  of  confidentiality  and  protection  of 
 patient’s personal data consistent with applicable privacy laws. 
 The  informed  consent  document  must  be  in  compliance  with  ICH  GCP,  local  regulatory 
 requirements, and legal requirements, including applicable privacy laws. 
 The  informed  consent  document(s)  used  during  the  informed  consent  process  must  be 
 reviewed by the sponsor, approved by the IEC before use, and available for inspection. 
 The  Investigator  must  ensure  that  each  study  patient,  or  her  legally  acceptable 
 representative,  is  fully  informed  about  the  nature  and  objectives  of  the  study  and  possible 
 risks  associated  with  participation.  The  patient,  or  her  legally  acceptable  representative, 
 will  provide  her  consent,  by  personally  signing,  dating  and  naming  the  appropriate 
 informed consent document. 
 Whenever  consent  is  obtained  from  a  patient’s  legally  acceptable  representative,  the 
 patient’s  assent  (affirmative  agreement)  must  subsequently  be  obtained  when  the  patient 
 has  the  capacity  to  provide  assent,  as  determined  by  the  EC.  If  the  investigator  determines 
 that  a  patient’s  decisional  capacity  is  so  limited  she  cannot  reasonably  be  consulted,  then, 
 as  permitted  by  the  EC  and  consistent  with  local  regulatory  and  legal  requirements,  the 
 patient’s  assent  may  be  waived  with  source  documentation  of  the  reason  assent  was  not 
 obtained.  If  the  study  patient  does  not  provide  her  own  consent,  the  source  documents 
 must  record  why  the  patient  did  not  provide  consent  (e.g.,  ,  decisional  impaired  adult), 
 how  the  investigator  determined  that  the  person  signing  the  consent  was  the  patient’s 
 legally  acceptable  representative,  the  consent  signer’s  relationship  to  the  study  patient 
 (e.g.,  parent,  spouse),  and  that  the  patient’s  assent  was  obtained,  or  waived.  If  assent  is 
 obtained verbally it must be documented in the source documents. 
 The  Investigator,  or  a  person  designated  by  the  Investigator,  will  obtain  written  informed 
 consent  from  each  patient  or  the  patient’s  legal  representative  before  any  study-specific 
 activity  is  performed.  The  Investigator  will  retain  the  original  of  each  patient’s  signed 
 consent document and a copy will be provided to the patient. 
 13. STUDY MANAGEMENT 
 13.1. Training of study site personnel 
 ●  The  study  will  be  performed  in  centers  with  multidisciplinary  teams  (oncologists, 
 radiotherapists,  urologists)  with  wide  experience  in  multimodal  bladder 
 preservation therapy  trained in GCP’s. 
 ●  The  principal  investigator  will  maintain  a  record  of  all  center  staff  involved  in  the 
 clinical  trial  (doctors,  nurses  and  other  staff  involved)  ensuring  that  they  receive 
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 appropriate  training  to  perform  the  study,  and  that  any  new  information  of 
 relevance to the study will be transmitted to them. 
 ●  Researchers  will  be  instructed  about  the  documents  (Protocol,  ICF,  IB,  etc.) 
 procedures  of  the  trial  (selection,  inclusion,  treatment,  safety,  notifications,  eCRF, 
 among  others)  during  the  initiation  visits  made  by  monitors  to  each  participating 
 center prior to the study start. 
 13.2. Monitoring of the study 
 The CRO in charge of monitoring this trial is: 
 MFAR Clinical Research 
 C/ Sinfonía, 28, 2ª planta Nº1. 28054 Madrid 
 Email: investigacion@mfar.net 
 Phone: (34) 91 061 62 28 / 93 434 44 12; Fax: (34) 93 253 11 68 
 The  sponsor’s  or  representative  (e.g.,  CRO’s  CRA)  will  maintain  contact  with  the 
 investigator  and  designated  staff  by  telephone,  and/or  letter,  and/or  email  between  study 
 visits.  Monitoring  visits  to  each  investigational  site  will  be  conducted  by  the  assigned 
 CRA  as  described  in  the  monitoring  plan.  The  investigator  (if  regionally  required,  the 
 heads  of  the  medical  institutions)  will  allow  the  CRA  to  inspect  the  clinical,  laboratory, 
 and  pharmacy  facilities  to  assure  compliance  with  Good  Clinical  Practices,  MFAR 
 Clinical Research  SOPs and local regulatory requirements. 
 The  eCRFs  and  subject’s  corresponding  original  medical  records  (source  documents)  are 
 to  be  fully  available  for  review  by  the  sponsor’s  representatives  at  regular  intervals. 
 These  reviews  verify  adherence  to  the  study  protocol  and  data  accuracy  in  accordance 
 with  federal  regulations.  All  records  at  the  investigational  site,  including  source 
 documents,  are  subject  to  inspection  by  the  regulatory  authorities  and  to  review  by  the 
 Ethical Committee. 
 13.3. Source data 
 Source  data  are  defined  as  all  data  in  original  records  and  certified  copies  of  original 
 records  of  clinical  findings,  observations,  or  other  activities  in  a  clinical  trial  that  are 
 necessary for the reconstruction and evaluation of the trial. 
 The  Investigator  must  keep  a  file  (medical  file,  original  medical  records)  on  paper  or 
 electronically  for  every  subject  in  the  trial.  It  must  be  possible  to  identify  each  subject  by 
 using  this  subject  file.  This  file  will  contain  the  demographic  and  medical  information  for 
 the subject listed below and should be as complete as possible. 
 ●  Subject’s full name, date of birth, sex, height, weight 
 ●  Medical history and concomitant diseases 
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 ●  Prior and concomitant therapies (including changes during the trial) 
 ●  Trial  identification,  that  is,  the  Sponsor  trial  number  for  this  clinical  trial,  and 
 subject number 
 ●  Dates for entry into the trial (informed consent) and visits to the site 
 ●  Any  medical  examinations  and  clinical  findings  predefined  in  this  clinical  trial 
 protocol 
 ●  All AEs 
 ●  Date  that  the  subject  left  the  trial  including  any  reason  for  early  withdrawal  from 
 the trial or IMP (if applicable). 
 All  documents  containing  source  data  must  be  filed,  including,  but  not  limited  to  CT  or 
 MRI  scan  images,  ECG  recordings,  and  laboratory  results.  Such  documents  must  bear  the 
 subject  number  and  the  date  of  the  procedure.  If  possible,  this  information  should  be 
 printed  by  the  instrument  used  to  perform  the  assessment  or  measurement.  As  necessary, 
 medical  evaluation  of  such  records  should  be  performed;  all  evaluations  should  be 
 documented, signed, and dated by the Investigator. 
 Electronic  subject  files  will  be  printed  whenever  the  Monitor  performs  source  data 
 verification.  Printouts  must  be  signed  and  dated  by  the  Investigator,  countersigned  by  the 
 Monitor and kept in a safe place at the site. 
 13.4.  Study timetable and end of study 
 Study duration 
 Authorities submission                                                                   2Q 2018 (May 31, 2018) 
 Trial start date                                                                                 4Q 2018 (Nov. 14, 2018) 
 First patient                                                                                     1Q 2019 (Jan. 24, 2019) 
 Estimated last patient in                                                                                           3Q 2020 
 Estimated last patient last treatment                                                                         3Q 2022 
 Estimated trial completion date                                                                                2Q 2023 
 14. DATA MANAGEMENT 
 14.1. Data Management Plan 
 The  Data  Management  Plan  (DMP)  defines  and  documents  the  procedures  necessary  to 
 ensure  data  quality.  These  activities  must  be  followed  to  ensure  data  are  properly  entered, 
 validated, coded, integrated, reconciled and reviewed. 
 SAP will include: 
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 ●  Data source strategy 
 ●  Analysis of objectives 
 ●  Analysis of sets/ populations/subgroups 
 ●  Endpoints and covariates management 
 ●  Handling of missing values and other data conventions 
 ●  Statistical methodology 
 Database elaboration and validation plan will include: 
 ●  Data management plan 
 ●  DB and sintaxis elaboration and validation procedure 
 ●  Clinical coding (medication, AE, LNR) with client-specific dictionaries 
 ●  Reviewing procedure and consolidation management 
 ●  Project management of data, data validation and query resolution 
 ●  SAE Reconciliation 
 ●  Quality Assurance Audit and Quality Control Procedures 
 Statistical report 
 ●  Elaboration according SAP and client-specific requirements 
 ●  Reviewing process 
 ●  Final validation process 
 All  software  applications  used  in  the  collection  and  validation  of  data  must  be  properly 
 validated  following  standard  computer  system  validation  and  must  be  compliant  to  all 
 regulatory requirements. 
 14.2. Data Handling and Report Keeping 
 14.2.1. Electronic Data Capture 
 Data  required  by  the  protocol  are  collected  on  an  electronic  Case  Report  Form  (eCRF) 
 and  entered  into  a  validated  data  management  system  which  is  compliant  to  all  regulatory 
 requirements.  As  defined  by  ICH  Guidelines,  the  Case  Report  Form  (CRF)  is  an 
 electronic  document  designed  to  record  all  of  the  protocol  required  information  to  be 
 reported  to  the  sponsor  on  each  trial  subject’.  In  this  study,  CRF  should  refer  to  electronic 
 data  collection  form.  Data  collected  on  the  CRF  must  follow  the  instructions  described  in 
 the CRF Completion Guidelines. 
 Any  corrections  to  entries  made  on  the  CRF  will  be  documented  in  a  valid  audit  trail 
 where  the  corrections  will  be  fully  tracked  (by  means  of  non-transferable  user-name  and 
 secret  password).  Only  data  required  by  the  protocol  for  the  purposes  of  the  study  should 
 be collected. 
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 The  compliance  with  the  21  CFR11  and  EU  and  local  guidelines  of  the  computerized 
 systems  used  are  guaranteed.  The  e-CRF  is  a  solution  from  Medical  R&C,  and  the 
 hardware  infrastructure  is  hosted  by  Claranet  Inc.  that  ensures  high  availability  and  also 
 implement all the security controls regarding access to the hardware hosting the eCRF. 
 The  e-CRF  software  implements  all  the  internal  security  protocols  and  data  entry 
 recommendations, such as: 
 ●  Access limited to authorized individuals 
 ●  Audit trail 
 ●  Data encryption 
 ●  Data consistency 
 ●  Range checks and alerts. 
 ●  Backup system (systems necessary to avoid data loss and ensure data integrity) 
 A  CRF  is  required  and  should  be  completed  for  each  included  patient.  The  Investigator 
 has  ultimate  responsibility  for  the  collection  and  reporting  of  all  clinical,  safety  and 
 laboratory  data  entered  on  the  CRFs  and  any  other  data  collection  forms  (source 
 documents)  and  ensuring  that  they  are  accurate,  authentic/original,  attributable,  complete, 
 consistent, legible, timely (contemporaneous), enduring and available when required. 
 The  source  documents  are  the  hospital's  or  the  physician's  patient  chart.  In  these  cases, 
 data collected on the CRFs must match the data in those charts. 
 14.2.2. Record Retention 
 To  enable  evaluations  and/or  audits  from  regulatory  authorities  or  the  sponsor,  the 
 Investigator  agrees  to  keep  all  essential  documents  according  to  the  GCPs,  including  the 
 identity  of  all  participating  patients  (sufficient  information  to  link  records,  e.g.,  CRFs  and 
 hospital  records),  all  original  signed  informed  consent  documents,  copies  of  all  CRFs, 
 safety  reporting  forms,  source  documents,  and  detailed  records  of  treatment  disposition, 
 and  adequate  documentation  of  relevant  correspondence  (e.g.,  letters,  meeting  minutes, 
 telephone calls reports). 
 The  records  should  be  retained  by  the  Investigator  according  to  International  Conference 
 on  Harmonization  (ICH)  guidelines,  according  to  local  regulations,  or  as  specified  in  the 
 Clinical Study Agreement (CSA), whichever is longer. 
 If  the  Investigator  becomes  unable  for  any  reason  to  continue  to  retain  study  records  for 
 the  required  period  (e.g.,  retirement,  relocation),  the  sponsor  should  be  prospectively 
 notified.  The  study  records  must  be  transferred  to  a  designee  acceptable  to  the  sponsor, 
 such  as  another  Investigator,  another  institution,  or  to  an  independent  third  party  arranged 
 by the sponsor. 
 Investigator  records  must  be  kept  for  a  minimum  of  25  years  after  completion  or 
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 discontinuation of the study or for longer if required by applicable local regulations. 
 14.3. Sponsor Discontinuation Criteria 
 Premature  termination  of  this  study  may  occur  because  of  a  regulatory  authority  decision, 
 change  in  opinion  of  the  IRB/IEC,  study  treatment  safety  problems,  or  at  the  discretion  of 
 the sponsor. 
 If  a  study  is  prematurely  terminated  or  discontinued,  the  sponsor  will  promptly  notify  the 
 Investigator.  After  notification,  the  Investigator  must  contact  all  participating  patients  and 
 the  hospital  pharmacy  (if  applicable)  within  1  month.  As  directed  by  the  sponsor,  all 
 study materials must be collected and all eCRFs completed to the greatest extent possible. 
 14.4. Study governance and oversight 
 The  safety  of  this  Study  will  be  closely  monitored  on  an  ongoing  basis  by  Sponsor.  Issues 
 identified  will  be  addressed;  for  instance,  this  could  involve  amendments  to  the  study 
 protocol and letters to Investigators. 
 14.4.1. Trial Insurance Policy 
 The  sponsor  has  contracted  an  insurance  policy  to  cover  the  responsibilities  of  the 
 investigator  and  other  parties  participating  in  the  study,  according  to  the  applicable 
 Spanish legislation. 
 14.4.2. Publication Policy 
 The  sponsor  commits  to  responsible  publication  of  both  the  positive  and  negative  results 
 from  its  clinical  trials  as  required  by  all  governing  regulatory  and  health  authorities, 
 according what is stated in article 42 of RD 1090/2015 of clinical trial. 
 Investigators  will  not  publish  the  global  study  results  (all  sites)  unless  the  sponsor  has  not 
 done  so  in  a  suitable  time  period  after  the  clinical  study  report  (CSR)  has  been  available. 
 Should  the  Investigator(s)  independently  seek  to  publish  results  of  this  study  which  occur 
 at  their  site(s),  they  must  inform  the  study  sponsor  of  any/all  drafts  (including,  but  not 
 limited  to  papers,  manuscripts  or  abstracts)  at  least  60  days  before  submission  to  the 
 congress,  meeting  or  journal.  The  sponsor  and  Investigator(s)  will  agree  with  all  aspects 
 related  to  any  proposed  publications  with  regards  to  the  following:  1)  any  proposed 
 publications  will  be  drafted  in  agreement  with  international  recommendations,  such  as 
 those  from  the  International  Committee  of  Medical  Journal  Editors  (ICMJE)  and  all 
 elements  of  the  Consort  Statement  (2010),  to  maintain  integrity  of  the  trial  results  in  all 
 communications;  2)  any  proposed  publications  will  state  the  Clinical  Research  Ethics 
 Committees  which  approved  the  trial  and  the  funding  sources  of  the  trial;  3)  any  proposed 
 publications  will  occur  before  disclosure  of  results  to  lay  people;  4)  any  proposed 
 publications  will  not  report  premature  or  partial  data  prior  to  completion  of  the  analysis 
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 of the overall results of the trial. 
 14.4.3. Authorship 
 The  order  of  the  authors  will  follow  the  SOGUG  standard  and  will  take  into  in  account 
 the researchers' contribution to the study. 
 15. INVESTIGATIONAL PRODUCT AND TREATMENTS 
 15.1. Identity of investigational product(s) 
 Table 9 .  List of investigational products for this  study 
 Investigational product 
 Dosage form and strength 
 Manufacturer 
 Durvalumab 
 50 mg/mL solution for infusion after dilution 
 MedImmune 
 Tremelimumab 
 20 mg/mL solution for infusion after dilution 
 MedImmune 
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 APPENDICES 
 APPENDIX 
 1. 
 DOSING 
 MODIFICATION 
 AND 
 TOXICITY 
 MANAGEMENT 
 GUIDELINES 
 FOR 
 IMMUNE-MEDIATED, 
 INFUSION-RELATED,  AND  NON-IMMUNE-MEDIATED  REACTIONS 
 (MEDI4736  MONOTHERAPY  OR  COMBINATION  THERAPY  WITH 
 TREMELIMUMAB OR TREMELIMUMAB MONOTHERAPY) 
 Toxicity Management Guidelines (TMGs)
 Drug Substance
 Durvalumab and tremelimumab
 TMG Version
 17 Oct 2019, CTCAE v4.03
 ANNEX TO PROTOCOL 
 Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
 Infusion-Related, and Non-Immune-Mediated Reactions (MEDI4736 Monotherapy or 
 Combination Therapy with Tremelimumab or Tremelimumab Monotherapy) 
 Note: Annex is to be used in any clinical trial protocol within which patients are treated with 
 MEDI4736 Monotherapy, MEDI4736 + Tremelimumab Combination Therapy, and/or 
 Tremelimumab Monotherapy 
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 Page  101 / 135 


 VERSION HISTORY 
 17 October 2019, CTCAE version 4.03 
 The  Toxicity  Management  Guidelines  (TMGs)  have  been  developed  to  assist  investigators  with 
 the  recognition  and  management  of  toxicities  associated  with  use  of  the  immune-checkpoint 
 inhibitors  durvalumab  [MEDI4736]  (PD-L1  inhibitor)  and  tremelimumab  (CTLA-4  inhibitor). 
 Given  the  similar  underlying  mechanism  of  toxicities  observed  with  these  two  compounds,  these 
 TMGs  are  applicable  to  the  management  of  patients  receiving  either  drug  as  monotherapy  or  both 
 drugs  in  combination.  Additionally,  these  guidelines  are  applicable  when  either  drug  is  used  alone 
 or  both  drugs  are  used  in  combination  and,  also,  other  anti-cancer  drugs  (i.e.,  antineoplastic 
 chemotherapy,  targeted  agents)  are  administered  concurrently  or  sequentially  as  part  of  a 
 protocol-specific  treatment  regimen.  The  TMGs  provide  information  for  the  management  of 
 immune-mediated  reactions,  infusion-related  reactions,  and  non-immune-mediated  reactions  that 
 may  be  observed  with  monotherapy  or  combination  checkpoint  inhibitor  regimens,  with  specific 
 instructions  for  checkpoint  inhibitor-specific  dose  modifications  (including  discontinuation)  and 
 treatment  interventions.  Investigators  are  advised  however  to  use  local  practice  guidelines  and 
 consult  local  references  for  the  management  of  toxicities  observed  with  other  anti-cancer 
 treatment. 
 Dosing  modification  and  toxicity  management  for  immune-mediated,  infusion-related,  and 
 non-immune–mediated  reactions  associated  with  the  use  of  a  checkpoint  inhibitor  or  checkpoint 
 inhibitors  in  this  protocol  –  whether  that  is  MEDI4736  alone,  tremelimumab  alone,  or  MEDI4736 
 +  tremelimumab  in  combination,  or  MEDI4736  +/-  tremelimumab  in  combination  with  other 
 anti-cancer  drugs  (i.e.,  antineoplastic  chemotherapy,  targeted  agents)  administered  concurrently  or 
 sequentially  –  should  therefore  be  performed  in  accordance  with  this  Annex  to  Protocol,  which 
 for  the  purposes  of  submission  and  approval  of  substantial  updates  is  maintained  as  a  standalone 
 document. 
 TMG  updates  are  iterated  by  date,  and  issued  in  CTCAE  version  as  specified  in  the  clinical  study 
 protocol.  This  Annex  to  Protocol  presents  the  dated  version  of  the  TMGs  issued  in  CTCAE 
 version 4.03. 
 Although  the  TMG  versioning  is  independent  of  the  protocol,  the  TMG  Annex  to  Protocol  should 
 be  read  in  conjunction  with  the  Clinical  Study  Protocol,  where  if  applicable  additional  references 
 for  the  management  of  toxicities  observed  with  other  anti-cancer  treatment  are  included  in  the 
 specific section of the Clinical Study Protocol. 
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 Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, 
 and 
 Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With 
 Tremelimumab or Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03) 
 General Considerations regarding Immune-Mediated Reactions 
 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 v4.03 (unless indicated 
 otherwise). 
 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 of the start of the 
 immune-mediated adverse event (imAE) 
 ● 
 Grade 3 recurrence of a previously experienced 
 treatment-related imAE 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. 
 Patients 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 patient is clinically stable as per 
 Investigator or treating physician’s 
 clinical judgement. 
 3. 
 Doses of prednisone are at ≤10 mg/day 
 or equivalent. 
 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, patients should 
 be thoroughly evaluated to rule out any 
 alternative etiology (e.g., 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 – e.g., 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 [e.g., 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). 
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 Grade 3 
 Depending on the individual 
 toxicity, study drug/study regimen may be 
 permanently discontinued. Please refer to 
 guidelines below. 
 Grade 4 
 Permanently discontinue study drug/study 
 regimen. 
 Note: For asymptomatic amylase or lipase levels of 
 >2.0×ULN, 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 – e.g., 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 
 – e.g., 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 (i.e., 
 hyperthyroidism, hypothyroidism, Type 1 diabetes 
 mellitus). 
 − 
 More potent immunosuppressives such as TNF 
 inhibitors (e.g., infliximab; also refer to the 
 individual sections of the imAEs for specific type 
 of 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 – e.g., 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 
 (e.g., 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 patient. 
 AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for 
 Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI National Cancer 
 Institute; PO By mouth. 
 Pediatric Considerations regarding Immune-Mediated Reactions 
 Dose Modifications 
 Toxicity Management 
 The criteria for permanent discontinuation of study 
 drug/study regimen based on CTC grade/severity is the 
 same for pediatric patients as it is for adult patients, as well 
 as to permanently discontinue study drug/study regimen if 
 unable to reduce corticosteroid ≤ a dose equivalent to that 
 required for corticosteroid replacement therapy within 
 12 weeks of the start of the immune-mediated event 
 − 
 All recommendations for specialist consultation 
 should occur with a pediatric specialist in the 
 specialty recommended. 
 − 
 The recommendations for dosing of steroids (i.e., 
 mg/kg/day) and for IV IG and plasmapheresis that 
 are provided for adult patients should also be used 
 for pediatric patients. 
 − 
 The infliximab 5 mg/kg IV dose recommended 
 for adults is the same as recommended for 
 pediatric patients ≥ 6 years old.  For dosing in 
 children younger than 6 years old, consult with a 
 pediatric specialist. 
 − 
 For pediatric dosing of mycophenolate mofetil, 
 consult with a pediatric specialist. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  104 / 135 


 − 
 With long-term steroid and other 
 immunosuppressive use, consider need for PJP 
 prophylaxis, gastrointestinal protection, and 
 glucose monitoring. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  105 / 135 


 Specific Immune-Mediated Reactions 
 Adverse Events  Severity Grade of 
 the Event (NCI 
 CTCAE 
 version 4.03) 
 Dose Modifications 
 Toxicity Management 
 Pneumonitis/ 
 Interstitial Lung 
 Disease (ILD) 
 Any Grade 
 General Guidance 
 For Any Grade: 
 − 
 Monitor patients for signs and 
 symptoms of pneumonitis or ILD 
 (new onset or worsening 
 shortness of breath or cough). 
 Patients should be evaluated with 
 imaging and pulmonary function 
 tests, including other diagnostic 
 procedures as described below. 
 − 
 Initial work-up may include 
 clinical evaluation, monitoring of 
 oxygenation via pulse oximetry 
 (resting and exertion), laboratory 
 work-up, and high- resolution 
 CT scan. 
 Grade 1 
 (asymptomatic, 
 clinical or diagnostic 
 observations only; 
 intervention not 
 indicated) 
 No dose modifications 
 required. However, consider 
 holding study drug/study 
 regimen dose as clinically 
 appropriate and during 
 diagnostic work-up for other 
 etiologies. 
 For Grade 1 (radiographic changes 
 only): 
 − 
 Monitor and closely follow up in 
 2 to 4 days for clinical 
 symptoms, pulse oximetry 
 (resting and exertion), and 
 laboratory work-up and then as 
 clinically indicated. 
 − 
 Consider Pulmonary and 
 Infectious Disease consults. 
 Grade 2 
 (symptomatic; 
 medical intervention 
 indicated; limiting 
 instrumental ADL) 
 Hold study drug/study regimen 
 dose until Grade 2 resolution to 
 Grade ≤1. 
 ● 
 If toxicity worsens, then 
 treat as Grade 3 or Grade 
 4. 
 ● 
 If toxicity improves to 
 Grade ≤1, then the decision 
 to reinitiate study 
 drug/study regimen will be 
 based upon treating 
 physician’s clinical 
 judgment and after 
 completion of steroid taper. 
 For Grade 2 (mild to moderate new 
 symptoms): 
 − 
 Monitor symptoms daily and 
 consider hospitalization. 
 − 
 Promptly start systemic steroids 
 (e.g., prednisone 1 to 
 2 mg/kg/day PO or IV 
 equivalent). 
 − 
 Reimage as clinically indicated. 
 − 
 If no improvement within 3 to 5 
 days, additional workup should 
 be considered and prompt 
 treatment with IV 
 methylprednisolone 2 to 
 4 mg/kg/day started 
 − 
 If still no improvement within 3 
 to 5 days despite IV 
 methylprednisolone at 2 to 
 4 mg/kg/day, promptly start 
 immunosuppressive therapy such 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  106 / 135 


 as TNF inhibitors 
 (e.g., infliximab at 5 mg/kg 
 every 2 weeks). Caution: It is 
 important to rule out sepsis and 
 refer to infliximab label for 
 general guidance before using 
 infliximab. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, or 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections)a 
 − 
 Consider Pulmonary and 
 Infectious Disease consults. 
 − 
 Consider, as necessary, 
 discussing with study physician. 
 Grade 3 or 4 
 (Grade 3: severe 
 symptoms; limiting 
 self-care ADL; 
 oxygen indicated) 
 (Grade 4: 
 life-threatening 
 respiratory 
 compromise; urgent 
 intervention 
 indicated [e.g., 
 tracheostomy or 
 intubation]) 
 Permanently discontinue study 
 drug/study regimen. 
 For Grade 3 or 4 (severe or new 
 symptoms, new/worsening hypoxia, 
 life-threatening): 
 − 
 Promptly initiate empiric IV 
 methylprednisolone 1 to 
 4 mg/kg/day or equivalent. 
 − 
 Obtain Pulmonary and Infectious 
 Disease consults; consider, as 
 necessary, discussing with study 
 physician. 
 − 
 Hospitalize the patient. 
 − 
 Supportive care (e.g., oxygen). 
 − 
 If no improvement within 3 to 5 
 days, additional workup should 
 be considered and prompt 
 treatment with additional 
 immunosuppressive therapy such 
 as TNF inhibitors 
 (e.g., infliximab at 5 mg/kg 
 every 2 weeks’ dose) started. 
 Caution: rule out sepsis and refer 
 to infliximab label for general 
 guidance before using 
 infliximab. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and, in 
 particular, anti-PJP treatment 
 (refer to current NCCN 
 guidelines for treatment of 
 cancer-related infections).  a 
 Diarrhea/Colitis 
 Any Grade 
 General Guidance 
 For Any Grade: 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  107 / 135 


 Large intestine 
 perforation/ 
 Intestine 
 perforation 
 − 
 Monitor for symptoms that may 
 be related to 
 diarrhea/enterocolitis (abdominal 
 pain, cramping, or changes in 
 bowel habits such as increased 
 frequency over baseline or blood 
 in stool) or related to bowel 
 perforation (such as sepsis, 
 peritoneal signs, and ileus). 
 − 
 When symptoms or evaluation 
 indicate a perforation is 
 suspected, consult a surgeon 
 experienced in abdominal 
 surgery immediately without any 
 delay. 
 − 
 Patients should be thoroughly 
 evaluated to rule out any 
 alternative etiology (e.g., disease 
 progression, other medications, 
 or infections), including testing 
 for clostridium difficile toxin, 
 etc. 
 − 
 Steroids should be considered in 
 the absence of clear alternative 
 etiology, even for low-grade 
 events, in order to prevent 
 potential progression to higher 
 grade event, including 
 perforation. 
 − 
 Use analgesics carefully; they 
 can mask symptoms of 
 perforation and peritonitis. 
 Grade 1 
 (Diarrhea: stool 
 frequency of <4 over 
 baseline per day) 
 (Colitis: 
 asymptomatic; 
 clinical or diagnostic 
 observations only) 
 No dose modifications. 
 For Grade 1: 
 − 
 Monitor closely for worsening 
 symptoms. 
 − 
 Consider symptomatic treatment, 
 including hydration, electrolyte 
 replacement, dietary changes 
 (e.g., American Dietetic 
 Association colitis diet), and 
 loperamide. Use probiotics as per 
 treating physician’s clinical 
 judgment. 
 Grade 2 
 (Diarrhea: stool 
 frequency of 4 to 6 
 over baseline per 
 day) (Colitis: 
 abdominal pain; 
 mucus or blood in 
 stool) 
 Hold study drug/study regimen 
 until resolution to Grade ≤1 
 ● 
 If toxicity worsens, then 
 treat as Grade 3 or Grade 
 4. 
 ● 
 If toxicity improves to 
 Grade ≤1, then study 
 drug/study regimen can be 
 For Grade 2: 
 − 
 Consider symptomatic treatment, 
 including hydration, electrolyte 
 replacement, dietary changes 
 (e.g., American Dietetic 
 Association colitis diet), and 
 loperamide and/or budesonide. 
 − 
 Promptly start prednisone 1 to 2 
 mg/kg/day PO or IV equivalent. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  108 / 135 


 (Perforation: 
 symptomatic; 
 medical intervention 
 indicated*) 
 * “medical 
 intervention” is not 
 invasive 
 resumed after completion 
 of steroid taper. 
 − 
 If event is not responsive within 
 3 to 5 days or worsens despite 
 prednisone at 1 to 2 mg/kg/day 
 PO or IV equivalent, GI consult 
 should be obtained for 
 consideration of further workup, 
 such as imaging and/or 
 colonoscopy, to confirm colitis 
 and rule out perforation, and 
 prompt treatment with IV 
 methylprednisolone 2 to 4 
 mg/kg/day started. 
 − 
 If still no improvement within 3 
 to 5 days despite 2 to 4 mg/kg IV 
 methylprednisolone, promptly 
 start immunosuppressives such 
 as infliximab at 5 mg/kg once 
 every 2 weeks  a  . Caution: it is 
 important to rule out bowel 
 perforation and refer to 
 infliximab label for general 
 guidance before using 
 infliximab. 
 − 
 Consider, as necessary, 
 discussing with study physician 
 if no resolution to Grade ≤1 in 3 
 to 4 days. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 Grade 3 or 4 
 (Grade 3 Diarrhea: 
 stool frequency of 
 ≥7 over baseline per 
 day; 
 Grade 4 Diarrhea: 
 life threatening 
 consequences) 
 (Grade 3 Colitis: 
 severe abdominal 
 pain, change in 
 bowel habits, 
 medi-cal 
 intervention 
 indicated, peritoneal 
 signs; 
 Grade 4 Colitis: 
 life-threatening 
 consequences, 
 Grade 3 
 Permanently discontinue study 
 drug/study regimen for Grade 3 
 if toxicity does not improve to 
 Grade ≤1 within 14 days; study 
 drug/study regimen can be 
 resumed after completion of 
 steroid taper. 
 Grade 4 
 Permanently discontinue 
 study drug/study regimen. 
 For Grade 3 or 4: 
 − 
 Promptly initiate empiric IV 
 methylprednisolone 2 to 
 4 mg/kg/day or equivalent. 
 − 
 Monitor stool frequency and 
 volume and maintain hydration. 
 − 
 Urgent GI consult and imaging 
 and/or colonoscopy as 
 appropriate. 
 − 
 If still no improvement within 3 
 to 5 days of IV 
 methylprednisolone 2 to 4 
 mg/kg/day or equivalent, 
 promptly start further 
 immunosuppressives (e.g., 
 infliximab at 5 mg/kg once every 
 2 weeks). Caution: Ensure GI 
 consult to rule out bowel 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  109 / 135 


 urgent intervention 
 indicated) 
 (Grade 3 
 Perforation: severe 
 symptoms, elective* 
 operative 
 intervention 
 indicated; Grade 4 
 Perforation: 
 life-threatening 
 consequences, 
 urgent intervention 
 indicated) 
 *This guidance 
 anticipates that 
 Grade 3 operative 
 interventions  of 
 perforations are 
 usually not elective 
 perforation and refer to 
 infliximab label for general 
 guidance before using 
 infliximab. If perforation is 
 suspected, consult a surgeon 
 experienced in abdominal 
 surgery immediately without any 
 delay. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 Hepatitis 
 (elevated LFTs) 
 Infliximab should 
 not be used for 
 management of 
 immune-related 
 hepatitis. 
 PLEASE SEE 
 shaded area 
 immediately below 
 this section to find 
 guidance for 
 management of 
 “Hepatitis (elevated 
 LFTS) in HCC 
 patients. 
 Any Elevations in 
 AST, ALT or TB 
 as Described Below 
 General Guidance 
 For Any Elevations Described: 
 − 
 Monitor and evaluate liver 
 function test: AST, ALT, ALP, 
 and TB. 
 − 
 Evaluate for alternative 
 etiologies (e.g., viral hepatitis, 
 disease progression, concomitant 
 medications). 
 AST or ALT 
 >ULN and 
 ≤3.0×ULN if 
 baseline normal, 
 1.5-3.0×baseline if 
 baseline abnormal; 
 and/or TB > ULN 
 and  ≤1.5×ULN  if 
 baseline normal, 
 >1.0-1.5×baseline if 
 baseline abnormal 
 ● 
 No dose modifications. 
 ● 
 If it worsens, then treat as 
 described for elevations in 
 the row below. 
 − 
 Continue LFT monitoring per 
 protocol. 
 AST or 
 ALT >3.0×ULN 
 and ≤5.0×ULN if 
 baseline normal, 
 >3-5×baseline if 
 baseline abnormal; 
 and/or 
 TB >1.5×ULN and 
 ≤3.0×ULN if 
 baseline normal, 
 >1.5- 3.0×baseline 
 ● 
 Hold study drug/study 
 regimen dose until 
 resolution to AST or ALT 
 ≤3.0×ULN and/or TB 
 ≤1.5×ULN if baseline 
 normal, or to AST or ALT 
 ≤3.0×baseline and/or TB 
 ≤1.5×baseline if baseline 
 abnormal. 
 ● 
 If toxicity worsens, then 
 treat as  described for 
 elevation in the row below. 
 − 
 Regular and frequent checking of 
 LFTs (e.g., every 1 to 2 days) 
 until elevations of these are 
 improving or resolved. 
 − 
 If no resolution to AST or ALT 
 ≤3.0×ULN and/or TB ≤1.5×ULN 
 if baseline normal, or to AST or 
 ALT ≤3.0×baseline and/or TB 
 ≤1.5×baseline if baseline 
 abnormal, in 1 to 2 days, 
 consider, as necessary, discussing 
 with study physician. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  110 / 135 


 if baseline 
 abnormal 
● 
 If toxicity improves to AST 
 or ALT ≤3.0×ULN and/or 
 TB ≤1.5×ULN if baseline 
 normal, or to AST or ALT 
 ≤3.0×baseline and/or TB 
 ≤1.5×baseline if baseline 
 abnormal, resume study 
 drug/study regimen after 
 completion of steroid taper. 
 − 
 If event is persistent (>3 to 5 
 days) or worsens, promptly start 
 prednisone 1 to 2 mg/kg/day PO 
 or IV equivalent. 
 − 
 If still no improvement within 3 
 to 5 days despite 1 to 
 2 mg/kg/day of prednisone PO or 
 IV equivalent, consider 
 additional work up and start 
 prompt treatment with IV 
 methylprednisolone 2 to 
 4 mg/kg/day. 
 − 
 If still no improvement within 3 
 to 5 days despite 2 to 
 4 mg/kg/day of IV 
 methylprednisolone, promptly 
 start immunosuppressives (i.e., 
 mycophenolate mofetil).a 
 Discuss with study physician if 
 mycophenolate mofetil is not 
 available. 
 Infliximab should NOT be 
 used. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).a 
 AST or 
 ALT >5.0×ULN if 
 baseline normal, 
 >5×baseline if 
 baseline abnormal; 
 and/or 
 TB >3.0×ULN if 
 baseline normal; 
 >3.0×baseline if 
 baseline abnormal 
 For elevations in transaminases 
 ≤8×ULN and/or in TB 
 ≤5×ULN if baseline normal, or 
 for elevations in transaminases 
 ≤8×baseline and/or TB 
 ≤5×baseline if baseline 
 abnormal: 
 ●  Hold study drug/study 
 regimen dose until 
 resolution to AST or ALT 
 ≤3.0×ULN and/or TB 
 ≤1.5×ULN  if baseline 
 normal, or to AST or ALT 
 ≤3.0×baseline and/or TB 
 ≤1.5×baseline if baseline 
 abnormal 
 ●  Resume study drug/study 
 regimen if elevations 
 downgrade to AST or ALT 
 ≤3.0×ULN and/or TB 
 ≤1.5×ULN  if baseline 
 normal, or to AST or ALT 
 − 
 Promptly initiate empiric IV 
 methylprednisolone at 1 to 
 4 mg/kg/day or equivalent. 
 − 
 If still no improvement within 3 
 to 5 days despite 1 to 
 4 mg/kg/day methylprednisolone 
 IV or equivalent, promptly start 
 treatment with 
 immunosuppressive therapy (i.e., 
 mycophenolate mofetil). Discuss 
 with study physician if 
 mycophenolate is not available. 
 Infliximab should NOT be used. 
 − 
 Request Hepatology consult, and 
 perform abdominal workup and 
 imaging as appropriate. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  111 / 135 


 ≤3.0×baseline and/or TB 
 ≤1.5×baseline if baseline 
 abnormal, within 14 days 
 and after completion of 
 steroid taper. 
 ●  Permanently discontinue 
 study drug/study regimen if 
 the elevations do not 
 downgrade as described in 
 bullet above within 14 days 
 For elevations in transaminases 
 >8×ULN or elevations in TB 
 >5×ULN if baseline normal, or 
 for elevations in transaminases 
 >8×baseline and/or TB 
 >5×baseline if baseline 
 abnormal, permanently 
 discontinue study drug/study 
 regimen. 
 Permanently discontinue study 
 drug/study regimen for any 
 case meeting Hy’s law criteria 
 (AST and/or ALT >3 × ULN + 
 bilirubin >2 × ULN without 
 initial findings of cholestasis 
 (i.e., elevated alkaline P04) and 
 in the absence of any 
 alternative cause.  b 
 treatment of cancer-related 
 infections).  a 
 Hepatitis 
 (elevated LFTs) 
 Infliximab should 
 not be used for 
 management of 
 immune-related 
 hepatitis. 
 THIS shaded area 
 is guidance only for 
 management of 
 “Hepatitis (elevated 
 LFTs)” in HCC 
 patients 
 See instructions at 
 bottom of shaded 
 area 
 if transaminase rise 
 is 
 not isolated but (at 
 any time) occurs in 
 setting 
 of either  increasing 
 bilirubin or signs of 
 DILI/liver 
 decompensation 
 Any Elevations in 
 AST, ALT or TB as 
 Described Below 
 General Guidance 
 For Any Elevations Described: 
 − 
 Monitor and evaluate liver 
 function test: AST, ALT, ALP, 
 and TB. 
 − 
 Evaluate for alternative 
 etiologies (e.g., viral hepatitis, 
 disease progression, concomitant 
 medications, worsening of liver 
 cirrhosis [e.g., portal vein 
 thrombosis]). 
 − 
 For HBV+ patients: evaluate 
 quantitative HBV viral load, 
 quantitative HBsAg, or HBeAg 
 − 
 For HCV+ patients: evaluate 
 quantitative HCV viral load 
 − 
 Consider consulting 
 hepatologist/Infectious Disease 
 specialist regarding 
 change/implementation in/of 
 antiviral medications for any 
 patient with an elevated HBV 
 viral load >2000 IU/ml 
 − 
 Consider consulting 
 hepatologist/Infectious Disease 
 specialist regarding 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  112 / 135 


 change/implementation in/of 
 antiviral HCV medications if 
 HCV viral load increased by 
 ≥2-fold 
 − 
 For HCV+ with HBcAB+: 
 Evaluate for both HBV and HCV 
 as above 
 Isolated AST or 
 ALT >ULN and 
 ≤5.0×ULN, 
 whether normal or 
 elevated at baseline 
 ● 
 No dose modifications. 
 ● 
 If ALT/AST elevations 
 represents significant 
 worsening based on 
 investigator assessment, 
 then treat as  described for 
 elevations in the row below. 
 For all transaminase elevations, 
 see instructions at bottom of 
 shaded area if transaminase rise 
 is not isolated but (at any time) 
 occurs in setting of either 
 increasing bilirubin or signs of 
 DILI/liver decompensation. 
 Isolated AST or 
 ALT >5.0×ULN 
 and ≤8.0×ULN, if 
 normal at baseline 
 Isolated AST or 
 ALT >2.0×baseline 
 and ≤12.5×ULN, if 
 elevated >ULN at 
 baseline 
 ● 
 Hold study drug/study 
 regimen dose until 
 resolution to AST or ALT 
 ≤5.0×ULN. 
 ● 
 If toxicity worsens, then 
 treat as  described for 
 elevations in the rows 
 below. 
 If toxicity improves to AST or 
 ALT ≤5.0×ULN, resume study 
 drug/study regimen after 
 completion of steroid taper. 
 − 
 Regular and frequent checking of 
 LFTs (e.g., every 1 to 3 days) 
 until elevations of these are 
 improving or resolved. 
 − 
 Recommend consult 
 hepatologist; consider abdominal 
 ultrasound, including Doppler 
 assessment of liver perfusion. 
 − 
 Consider, as necessary, 
 discussing with study physician. 
 − 
 If event is persistent (>3 to 5 
 days) or worsens, and 
 investigator suspects toxicity to 
 be immune-mediated AE, 
 recommend to start prednisone 1 
 to 2 mg/kg/day PO or IV 
 equivalent. 
 − 
 If still no improvement within 3 
 to 5 days despite 1 to 
 2 mg/kg/day of prednisone PO or 
 IV equivalent, consider 
 additional workup and treatment 
 with IV methylprednisolone 2 to 
 4 mg/kg/day. 
 − 
 If still no improvement within 3 
 to 5 days despite 2 to 
 4 mg/kg/day of IV 
 methylprednisolone, consider 
 additional abdominal workup 
 (including liver biopsy) and 
 imaging (i.e., liver ultrasound), 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  113 / 135 


 and consider starting 
 immunosuppressives (i.e., 
 mycophenolate mofetil).a 
 Discuss with study physician if 
 mycophenolate mofetil is not 
 available. 
 Infliximab should NOT be 
 used. 
 Isolated AST or 
 ALT >8.0×ULN 
 and ≤20.0×ULN, if 
 normal at baseline 
 Isolated AST or 
 ALT >12.5×ULN 
 and ≤20.0×ULN, if 
 elevated >ULN at 
 baseline 
 ●  Hold study drug/study 
 regimen dose until 
 resolution to  AST or ALT 
 ≤5.0×ULN 
 ●  Resume study drug/study 
 regimen if elevations 
 downgrade to AST or ALT 
 ≤5.0×ULN within 14 days 
 and after completion of 
 steroid taper. 
 ●  Permanently discontinue 
 study drug/study regimen if 
 the elevations do not 
 downgrade to AST or ALT 
 ≤5.0×ULN within 14 days 
 Permanently discontinue study 
 drug/study regimen for any 
 case meeting Hy’s law criteria, 
 in the absence of any 
 alternative cause.  b 
 − 
 Regular and frequent checking of 
 LFTs (e.g., every 1-2 days) until 
 elevations of these are improving 
 or resolved. 
 − 
 Consult hepatologist (unless 
 investigator is hepatologist); 
 obtain abdominal ultrasound, 
 including Doppler assessment of 
 liver perfusion; and consider 
 liver biopsy. 
 − 
 Consider, as necessary, 
 discussing with study physician. 
 − 
 If investigator suspects toxicity 
 to be immune-mediated, 
 promptly initiate empiric IV 
 methylprednisolone at 1 to 
 4 mg/kg/day or equivalent. 
 − 
 If no improvement within 3 to 5 
 days despite 1 to 4 mg/kg/day 
 methylprednisolone IV or 
 equivalent, obtain liver biopsy (if 
 it has not been done already) and 
 promptly start treatment with 
 immunosuppressive therapy 
 (mycophenolate mofetil). 
 Discuss with study physician if 
 mycophenolate is not available. 
 Infliximab should NOT be 
 used. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PCP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 Isolated AST or 
 ALT >20×ULN, 
 whether normal or 
 elevated at baseline 
 Permanently discontinue study 
 drug/study regimen. 
 Same as above 
 (except would recommend obtaining 
 liver biopsy early) 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  114 / 135 


 If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin 
 (≥1.5×ULN, if normal at baseline; or 2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation 
 (e.g., fever, elevated INR): 
 - 
 Manage dosing for  each level of transaminase rise as instructed for the next highest level of 
 transaminase rise. For example, manage dosing for second level of transaminase rise (i.e.,  AST or 
 ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, 
 if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT 
 >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if 
 elevated >ULN at baseline). 
 - 
 For the third and fourth levels of transaminase rises, permanently discontinue study drug/study 
 regimen 
 Nephritis or renal 
 dysfunction 
 (elevated serum 
 creatinine) 
 Any Grade 
 General Guidance 
 For Any Grade: 
 − 
 Consult with nephrologist. 
 − 
 Monitor for signs and symptoms 
 that may be related to changes in 
 renal function (e.g., routine 
 urinalysis, elevated serum BUN 
 and creatinine, decreased 
 creatinine clearance, electrolyte 
 imbalance, decrease in urine 
 output, or proteinuria). 
 − 
 Patients should be thoroughly 
 evaluated to rule out any 
 alternative etiology (e.g., disease 
 progression or infections). 
 − 
 Steroids should be considered in 
 the absence of clear alternative 
 etiology even for low-grade 
 events (Grade 2), in order to 
 prevent potential progression to 
 higher grade event. 
 Grade 1 
 (Serum creatinine 
 > 1 to 1.5×baseline; 
 > ULN to 1.5×ULN) 
 No dose modifications. 
 For Grade 1: 
 − 
 Monitor serum creatinine weekly 
 and any accompanying 
 symptoms. 
 ●  If creatinine returns to baseline, 
 resume its regular monitoring per 
 study protocol. 
 ●  If creatinine worsens, depending 
 on the severity, treat as Grade 2, 
 3, or 4. 
 − 
 Consider symptomatic treatment, 
 including hydration, electrolyte 
 replacement, and diuretics. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  115 / 135 


 Grade 2 
 (serum creatinine 
 >1.5 to 3.0×baseline; 
 >1.5 to 3.0×ULN) 
 Hold study drug/study regimen 
 until resolution to Grade ≤1 or 
 baseline. 
 ● 
 If toxicity worsens, then 
 treat as Grade 3 or 4. 
 ● 
 If toxicity improves to 
 Grade ≤1 or baseline, then 
 resume study drug/study 
 regimen after completion 
 of steroid taper. 
 For Grade 2: 
 − 
 Consider symptomatic treatment, 
 including hydration, electrolyte 
 replacement, and diuretics. 
 − 
 Carefully monitor serum 
 creatinine every 2 to 3 days and 
 as clinically warranted. 
 − 
 Consult nephrologist and 
 consider renal biopsy if clinically 
 indicated. 
 − 
 If event is persistent (>3 to 5 
 days) or worsens, promptly start 
 prednisone 1 to 2 mg/kg/day PO 
 or IV equivalent. 
 − 
 If event is not responsive within 
 3 to 5 days or worsens despite 
 prednisone at 1 to 2 mg/kg/day 
 PO or IV equivalent, additional 
 workup should be considered 
 and prompt treatment with IV 
 methylprednisolone at 2 to 
 4 mg/kg/day started. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).a 
 − 
 When event returns to baseline, 
 resume study drug/study regimen 
 and routine serum creatinine 
 monitoring per study protocol. 
 Grade 3 or 4 
 (Grade 3: serum 
 creatinine 
 >3.0×baseline; >3.0 
 to 6.0×ULN) 
 (Grade 4: serum 
 creatinine 
 >6.0×ULN) 
 Permanently discontinue study 
 drug/study regimen. 
 For Grade 3 or 4: 
 − 
 Carefully monitor serum 
 creatinine on daily basis. 
 − 
 Consult nephrologist and 
 consider renal biopsy if clinically 
 indicated. 
 − 
 Promptly start prednisone 1 to 2 
 mg/kg/day PO or IV equivalent. 
 − 
 If event is not responsive within 
 3 to 5 days or worsens despite 
 prednisone at 1 to 2 mg/kg/day 
 PO or IV equivalent, additional 
 workup should be considered 
 and prompt treatment with IV 
 methylprednisolone 2 to 
 4 mg/kg/day started. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  116 / 135 


 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 Rash or Dermatitis 
 (including 
 Pemphigoid) 
 Any Grade 
 (refer to NCI 
 CTCAE v 4.03 for 
 definition of 
 severity/grade 
 depending on type of 
 skin rash) 
 General Guidance 
 For Any Grade: 
 − 
 Monitor for signs and symptoms 
 of dermatitis (rash and pruritus). 
 − 
 IF THERE IS ANY BULLOUS 
 FORMATION, THE STUDY 
 PHYSICIAN SHOULD BE 
 CONTACTED  AND STUDY 
 DRUG DISCONTINUED IF 
 SUSPECT 
 STEVENS-JOHNSON 
 SYNDROME OR TOXIC 
 EPIDERMAL NECROLYSIS. 
 Grade 1 
 No dose modifications. 
 For Grade 1: 
 − 
 Consider symptomatic treatment, 
 including oral antipruritics (e.g., 
 diphenhydramine or 
 hydroxyzine) and topical therapy 
 (e.g., urea cream). 
 Grade 2 
 For persistent (>1 to 2 weeks) 
 Grade 2 events, hold scheduled 
 study drug/study regimen until 
 resolution to Grade ≤1 or 
 baseline. 
 ● 
 If toxicity worsens, then 
 treat as Grade 3. 
 ● 
 If toxicity improves to 
 Grade ≤1 or baseline, then 
 resume drug/study 
 regimen after completion 
 of steroid taper. 
 For Grade 2: 
 − 
 Obtain Dermatology consult. 
 − 
 Consider symptomatic treatment, 
 including oral antipruritics (e.g., 
 diphenhydramine or 
 hydroxyzine) and topical therapy 
 (e.g., urea cream). 
 − 
 Consider moderate-strength 
 topical steroid. 
 − 
 If no improvement of rash/skin 
 lesions occurs within 3 to 5 days 
 or is worsening despite 
 symptomatic treatment and/or 
 use of moderate strength topical 
 steroid, consider, as necessary, 
 discussing with study physician 
 and promptly start systemic 
 steroids such as prednisone 1 to 
 2 mg/kg/day PO or IV 
 equivalent. 
 − 
 Consider skin biopsy if the event 
 is persistent for >1 to 2 weeks or 
 recurs. 
 Grade 3 or 4 
 For Grade 3: 
 For Grade 3 or 4: 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 Hold study drug/study regimen 
 until resolution to Grade ≤1 or 
 baseline. 
 If temporarily holding the 
 study drug/study regimen does 
 not provide improvement of the 
 Grade 3 skin rash to Grade ≤1 
 or baseline within 30 days, then 
 permanently discontinue study 
 drug/study regimen. 
 For Grade 4: 
 Permanently discontinue study 
 drug/study regimen. 
 − 
 Consult Dermatology. 
 − 
 Promptly initiate empiric IV 
 methylprednisolone 1 to 
 4 mg/kg/day or equivalent. 
 − 
 Consider hospitalization. 
 − 
 Monitor extent of rash [Rule of 
 Nines]. 
 − 
 Consider skin biopsy (preferably 
 more than 1) as clinically 
 feasible. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 − 
 Consider, as necessary, 
 discussing with study physician. 
 Endocrinopathy 
 (e.g.,  
 hyperthyroidism, 
 thyroiditis, 
 hypothyroidism, 
 Type 1 diabetes 
 mellitus, 
 hypophysitis, 
 hypopituitarism, and 
 adrenal 
 insufficiency; 
 exocrine event of 
 amylase/lipase 
 increased also 
 included in this 
 section) 
 Any Grade 
 (depending on the 
 type of 
 endocrinopathy, 
 refer to NCI CTCAE 
 v4.03 for defining 
 the CTC 
 grade/severity) 
 General Guidance 
 For Any Grade: 
 − 
 Consider consulting an 
 endocrinologist for endocrine 
 events. 
 − 
 Consider, as necessary, 
 discussing with study physician. 
 − 
 Monitor patients for signs and 
 symptoms of endocrinopathies. 
 Non-specific symptoms include 
 headache, fatigue, behavior 
 changes, changed mental status, 
 vertigo, abdominal pain, unusual 
 bowel habits, polydipsia, 
 polyuria, hypotension, and 
 weakness. 
 − 
 Patients should be thoroughly 
 evaluated to rule out any 
 alternative etiology (e.g., disease 
 progression including brain 
 metastases, or infections). 
 − 
 Depending on the suspected 
 endocrinopathy, monitor and 
 evaluate thyroid function tests: 
 TSH, free T3 and free T4 and 
 other relevant endocrine and 
 related labs (e.g., blood glucose 
 and ketone levels, HgA1c). 
 − 
 For asymptomatic elevations in 
 serum amylase and lipase >ULN 
 and <3×ULN, corticosteroid 
 treatment is not indicated as long 
 as there are no other signs or 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  118 / 135 


 symptoms of pancreatic 
 inflammation. 
 − 
 If a patient experiences an AE 
 that is thought to be possibly of 
 autoimmune nature (e.g., 
 thyroiditis, pancreatitis, 
 hypophysitis, or diabetes 
 insipidus), the investigator 
 should send a blood sample for 
 appropriate autoimmune 
 antibody testing. 
 Grade 1 
 No dose modifications. 
 For Grade 1 (including those with 
 asymptomatic TSH elevation): 
 − 
 Monitor patient with appropriate 
 endocrine function tests. 
 − 
 For suspected 
 hypophysitis/hypopituitarism, 
 consider consultation of an 
 endocrinologist to guide 
 assessment of early-morning 
 ACTH, cortisol, TSH and free 
 T4; also consider gonadotropins, 
 sex hormones, and prolactin 
 levels, as well as cosyntropin 
 stimulation test (though it may 
 not be useful in diagnosing early 
 secondary adrenal insufficiency). 
 − 
 If TSH < 0.5 × LLN, or TSH >2 
 × ULN, or consistently out of 
 range in 2 subsequent 
 measurements, include free T4 at 
 subsequent cycles as clinically 
 indicated and consider 
 consultation of an 
 endocrinologist. 
 Grade 2 
 For Grade 2 endocrinopathy 
 other than hypothyroidism and 
 Type 1 diabetes mellitus, hold 
 study drug/study regimen dose 
 until patient is clinically stable. 
 ● 
 If toxicity worsens, then 
 treat as Grade 3 or Grade 
 4. 
 Study drug/study regimen can 
 be resumed once event 
 stabilizes and after completion 
 of steroid taper. 
 Patients with endocrinopathies 
 who may require prolonged or 
 continued steroid replacement 
 (e.g., adrenal insufficiency) can 
 be retreated with study 
 For Grade 2 (including those with 
 symptomatic endocrinopathy): 
 − 
 Consult endocrinologist to guide 
 evaluation of endocrine function 
 and, as indicated by suspected 
 endocrinopathy and as clinically 
 indicated, consider pituitary 
 scan. 
 − 
 For all patients with abnormal 
 endocrine work up, except those 
 with isolated hypothyroidism or 
 Type 1 DM, and as guided by an 
 endocrinologist, consider 
 short-term corticosteroids (e.g., 1 
 to 2 mg/kg/day 
 methylprednisolone or IV 
 equivalent) and prompt initiation 
 of treatment with relevant 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 drug/study regimen on the 
 following conditions: 
 1. 
 The event stabilizes and is 
 controlled. 
 2. 
 The patient is clinically 
 stable as per investigator 
 or treating physician’s 
 clinical judgement. 
 3. 
 Doses of prednisone are 
 ≤10 mg/day or equivalent. 
 hormone replacement (e.g., 
 hydrocortisone, sex hormones). 
 − 
 Isolated hypothyroidism may be 
 treated with replacement therapy, 
 without study drug/study 
 regimen interruption, and 
 without corticosteroids. 
 − 
 Isolated Type 1 diabetes mellitus 
 (DM) may be treated with 
 appropriate diabetic therapy, 
 without study drug/study 
 regimen interruption, and 
 without corticosteroids. 
 − 
 Once patients on steroids are 
 improving, gradually taper 
 immunosuppressive steroids (as 
 appropriate and with guidance of 
 endocrinologist) over ≥28 days 
 and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).a 
 − 
 For patients with normal 
 endocrine workup (laboratory 
 assessment or MRI scans), repeat 
 laboratory assessments/MRI as 
 clinically indicated. 
 Grade 3 or 4 
 For Grade 3 or 4 
 endocrinopathy other than 
 hypothyroidism and Type 1 
 diabetes mellitus, hold study 
 drug/study regimen dose until 
 endocrinopathy symptom(s) are 
 controlled. 
 Study drug/study regimen can 
 be resumed once event 
 stabilizes and after completion 
 of steroid taper. 
 Patients with endocrinopathies 
 who may require prolonged or 
 continued steroid replacement 
 (e.g., adrenal insufficiency) can 
 be retreated with study 
 drug/study regimen on the 
 following conditions: 
 1. 
 The event stabilizes and is 
 controlled. 
 2. 
 The patient is clinically 
 stable as per investigator 
 or treating physician’s 
 clinical judgement. 
 For Grade 3 or 4: 
 − 
 Consult endocrinologist to guide 
 evaluation of endocrine function 
 and, as indicated by suspected 
 endocrinopathy and as clinically 
 indicated, consider pituitary 
 scan. Hospitalization 
 recommended. 
 − 
 For all patients with abnormal 
 endocrine work up, except those 
 with isolated hypothyroidism or 
 Type 1 DM, and as guided by an 
 endocrinologist, promptly initiate 
 empiric IV methylprednisolone 1 
 to 2 mg/kg/day or equivalent, as 
 well as relevant hormone 
 replacement (e.g., 
 hydrocortisone, sex hormones). 
 − 
 For adrenal crisis, severe 
 dehydration, hypotension, or 
 shock, immediately initiate IV 
 corticosteroids with 
 mineralocorticoid activity. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 3. 
 Doses of prednisone are 
 ≤10 mg/day or equivalent. 
 − 
 Isolated hypothyroidism may be 
 treated with replacement therapy, 
 without study drug/study 
 regimen interruption, and 
 without corticosteroids. 
 − 
 Isolated Type 1 diabetes mellitus 
 may be treated with appropriate 
 diabetic therapy, without study 
 drug/study regimen interruption, 
 and without corticosteroids. 
 − 
 Once patients on steroids are 
 improving, gradually taper 
 immunosuppressive steroids (as 
 appropriate and with guidance of 
 endocrinologist) over ≥28 days 
 and consider prophylactic 
 antibiotics, antifungals, and 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 Neurotoxicity 
 (to include but not 
 be limited to limbic 
 encephalitis and 
 autonomic 
 neuropathy, 
 excluding 
 Myasthenia Gravis 
 and Guillain-Barre) 
 Any Grade 
 (depending on the 
 type of 
 neurotoxicity, refer 
 to NCI CTCAE 
 v4.03 for defining 
 the CTC grade/ 
 severity) 
 General Guidance 
 For Any Grade: 
 − 
 Patients should be evaluated to 
 rule out any alternative etiology 
 (e.g., disease progression, 
 infections, metabolic syndromes, 
 or medications). 
 − 
 Monitor patient for general 
 symptoms (headache, nausea, 
 vertigo, behavior change, or 
 weakness). 
 − 
 Consider appropriate diagnostic 
 testing (e.g., electromyogram 
 and nerve conduction 
 investigations). 
 − 
 Perform symptomatic treatment 
 with Neurology consult as 
 appropriate. 
 Grade 1 
 No dose modifications. 
 For Grade 1: 
 − 
 See “Any Grade” 
 recommendations above. 
 Grade 2 
 For acute motor neuropathies 
 or neurotoxicity, hold study 
 drug/study regimen dose until 
 resolution to Grade ≤1. 
 For sensory 
 neuropathy/neuropathic pain, 
 consider holding study 
 drug/study regimen dose until 
 resolution to Grade ≤1. 
 For Grade 2: 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 − 
 Obtain Neurology consult. 
 − 
 Sensory neuropathy/neuropathic 
 pain may be managed by 
 appropriate medications (e.g., 
 gabapentin or duloxetine). 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 If toxicity worsens, then 
 treat as Grade 3 or 4. 
 Study drug/study regimen can 
 be resumed once event 
 improves to Grade ≤1 and after 
 completion of steroid taper. 
 − 
 Promptly start systemic steroids 
 prednisone 1 to 2 mg/kg/day PO 
 or IV equivalent. 
 − 
 If no improvement within 3 to 5 
 days despite 1 to 2 mg/kg/day 
 prednisone PO or IV equivalent, 
 consider additional workup and 
 promptly treat with additional 
 immunosuppressive therapy 
 (e.g., IV IG). 
 Grade 3 or 4 
 For Grade 3: 
 Hold study drug/study regimen 
 dose until resolution to Grade 
 ≤1. 
 Permanently discontinue study 
 drug/study regimen if Grade 3 
 imAE does not resolve to 
 Grade ≤1 within 30 days. 
 For Grade 4: 
 Permanently discontinue study 
 drug/study regimen. 
 For Grade 3 or 4: 
 − 
 Consider, as necessary, 
 discussing with study physician. 
 − 
 Obtain Neurology consult. 
 − 
 Consider hospitalization. 
 − 
 Promptly initiate empiric IV 
 methylprednisolone 1 to 
 2 mg/kg/day or equivalent. 
 − 
 If no improvement within 3 to 5 
 days despite IV corticosteroids, 
 consider additional workup and 
 promptly treat with additional 
 immunosuppressants (e.g., IV 
 IG). 
 − 
 Once stable, gradually taper 
 steroids over ≥28 days. 
 Peripheral 
 neuromotor 
 syndromes 
 (such as Guillain- 
 Barre and 
 myasthenia gravis) 
 Any Grade 
 General Guidance 
 For Any Grade: 
 − The prompt diagnosis of 
 immune-mediated peripheral 
 neuromotor syndromes is important, since 
 certain patients may 
 unpredictably experience acute 
 decompensations that can result 
 in substantial morbidity or in the worst 
 case, death. Special 
 care should be taken for certain sentinel 
 symptoms that may 
 predict a more severe outcome, such as 
 prominent dysphagia, rapidly progressive 
 weakness, and signs of respiratory 
 insufficiency or autonomic instability. 
 − Patients should be evaluated to rule out 
 any alternative etiology 
 (e.g., disease progression, infections, 
 metabolic syndromes or 
 medications). It should be noted that the 
 diagnosis of immune- 
 mediated peripheral neuromotor 
 syndromes can be particularly 
 challenging in patients with underlying 
 cancer, due to the 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 multiple potential confounding effects of 
 cancer (and its 
 treatments) throughout the neuraxis. 
 Given the importance of 
 prompt and accurate diagnosis, it is 
 essential to have a low 
 threshold to obtain a Neurology consult. 
 − Neurophysiologic diagnostic testing 
 (e.g., electromyogram and 
 nerve conduction investigations, and 
 “repetitive stimulation” if 
 myasthenia is suspected) are routinely 
 indicated upon suspicion 
 of such conditions and may be best 
 facilitated by means of a 
 Neurology consultation. 
 Grade 1 
 No dose modifications. 
 For Grade 1: 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 − 
 Care should be taken to monitor 
 patients for sentinel symptoms of 
 a potential decompensation as 
 described above. 
 − 
 Obtain a Neurology consult. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 Grade 2 
 Hold study drug/study regimen 
 dose until 
 resolution to Grade ≤1. 
 Permanently discontinue study 
 drug/study 
 regimen if it does not resolve to 
 Grade ≤1 
 within 30 days or if there are 
 signs of 
 respiratory insufficiency or 
 autonomic instability. 
 For Grade 2: 
 − Consider, as necessary, discussing with 
 the study physician. 
 − Care should be taken to monitor 
 patients for sentinel symptoms 
 of a potential decompensation as 
 described above. 
 − Obtain a Neurology consult 
 − Sensory neuropathy/neuropathic pain 
 may be managed by 
 appropriate medications (e.g., gabapentin 
 or duloxetine). 
 MYASTHENIA GRAVIS: 
 o Steroids may be successfully used to 
 treat myasthenia gravis. It is important to 
 consider that steroid therapy (especially 
 with high doses) may result in transient 
 worsening of myasthenia and should 
 typically be administered in a monitored 
 setting under supervision of a consulting 
 neurologist. 
 o Patients unable to tolerate steroids may 
 be candidates for treatment with 
 plasmapheresis or IV IG. Such decisions 
 are best made in consultation with a 
 neurologist, taking into account the 
 unique needs of each patient. 
 o If myasthenia gravis-like neurotoxicity 
 is present, consider starting AChE 
 inhibitor therapy in addition to steroids. 
 Such therapy, if successful, can also serve 
 to reinforce the diagnosis. 
 GUILLAIN-BARRE: 
 o It is important to consider here that the 
 use of steroids as the primary treatment of 
 Guillain-Barre is not typically considered 
 effective. 
 o Patients requiring treatment should be 
 started with IV IG and followed by 
 plasmapheresis if not responsive to IV IG. 
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 Myocarditis 
 Any Grade 
 General Guidance 
 Discontinue drug permanently 
 if biopsy-proven 
 immune-mediated myocarditis. 
 For Any Grade: 
 − 
 The prompt diagnosis of 
 immune-mediated myocarditis is 
 important, particularly in patients 
 with baseline cardiopulmonary 
 disease and reduced cardiac 
 function. 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 − 
 Monitor patients for signs and 
 symptoms of myocarditis (new 
 onset or worsening chest pain, 
 arrhythmia, shortness of breath, 
 peripheral edema). As some 
 symptoms can overlap with lung 
 toxicities, simultaneously 
 evaluate for and rule out 
 pulmonary toxicity as well as 
 other causes (e.g., pulmonary 
 embolism, congestive heart 
 failure, malignant pericardial 
 effusion). A Cardiology 
 consultation should be obtained 
 early, with prompt assessment of 
 whether and when to complete a 
 cardiac biopsy, including any 
 other diagnostic procedures. 
 − 
 Initial work-up should include 
 clinical evaluation, BNP, cardiac 
 enzymes, ECG, echocardiogram 
 (ECHO), monitoring of 
 oxygenation via pulse oximetry 
 (resting and exertion), and 
 additional laboratory work-up as 
 indicated. Spiral CT or cardiac 
 MRI can complement ECHO to 
 assess wall motion abnormalities 
 when needed. 
 − 
 Patients should be thoroughly 
 evaluated to rule out any 
 alternative etiology (e.g., disease 
 progression, other medications, 
 or infections) 
 Grade 1 
 (asymptomatic with 
 laboratory [e.g., 
 BNP] or cardiac 
 imaging 
 abnormalities) 
 No dose modifications required 
 unless clinical suspicion is 
 high, in which case hold study 
 drug/study regimen dose during 
 diagnostic work-up for other 
 etiologies. If study drug/study 
 regimen is held, resume after 
 complete resolution to Grade 0. 
 For Grade 1 (no definitive findings): 
 - 
 Monitor  and  closely  follow  up  in 
 2 
 to 
 4 
 days 
 for 
 clinical 
 symptoms, 
 BNP, 
 cardiac 
 enzymes,  ECG,  ECHO,  pulse 
 oximetry  (resting  and  exertion), 
 and 
 laboratory 
 work-up 
 as 
 clinically indicated. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 - 
 Consider  using  steroids  if  clinical 
 suspicion is high. 
 Grade 2, 3 or 4 
 (Grade 2: Symptoms 
 with mild to 
 moderate activity or 
 exertion) 
 (Grade 3: Severe 
 with symptoms at 
 rest or with minimal 
 activity or exertion; 
 intervention 
 indicated) 
 (Grade 4: 
 Life-threatening 
 consequences; 
 urgent 
 intervention 
 indicated (e.g., 
 continuous IV 
 therapy or 
 mechanical 
 hemodynamic 
 support)) 
 -  If Grade 2 -- Hold study 
 drug/study regimen dose 
 until resolution to Grade 0. 
 If toxicity rapidly improves 
 to Grade 0, then the decision 
 to reinitiate study drug/study 
 regimen will be based upon 
 treating physician’s clinical 
 judgment and after 
 completion of steroid taper. 
 If toxicity does not rapidly 
 improve, permanently. 
 discontinue study drug/study 
 regimen. 
 If Grade 3-4, permanently 
 discontinue study drug/study 
 regimen. 
 For Grade 2-4: 
 − 
 Monitor symptoms daily, 
 hospitalize. 
 − 
 Promptly start IV 
 methylprednisolone 2 to 
 4 mg/kg/day or equivalent after 
 Cardiology consultation has 
 determined whether and when to 
 complete diagnostic procedures 
 including a cardiac biopsy. 
 − 
 Supportive care (e.g., oxygen). 
 − 
 If no improvement within 3 to 5 
 days despite IV 
 methylprednisolone at 2 to 
 4 mg/kg/day, promptly start 
 immunosuppressive therapy such 
 as TNF inhibitors 
 (e.g., infliximab at 5 mg/kg 
 every 2 weeks). Caution: It is 
 important to rule out sepsis and 
 refer to infliximab label for 
 general guidance before using 
 infliximab. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, or 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 Myositis/ 
 Polymyositis 
 (“Poly/myositis”) 
 Any Grade 
 General Guidance 
 For Any Grade: 
 − 
 Monitor patients for signs and 
 symptoms of poly/myositis. 
 Typically, muscle weakness/pain 
 occurs in proximal muscles 
 including upper arms, thighs, 
 shoulders, hips, neck and back, 
 but rarely affects the extremities 
 including hands and fingers; also 
 difficulty breathing and/or 
 trouble swallowing can occur 
 and progress rapidly. Increased 
 general feelings of tiredness and 
 fatigue may occur, and there can 
 be new-onset falling, difficulty 
 getting up from a fall, and 
 trouble climbing stairs, standing 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 up from a seated position, and/or 
 reaching up. 
 − 
 If poly/myositis is suspected, a 
 Neurology consultation should 
 be obtained early, with prompt 
 guidance on diagnostic 
 procedures. Myocarditis may 
 co-occur with poly/myositis; 
 refer to guidance under 
 Myocarditis. Given breathing 
 complications, refer to guidance 
 under Pneumonitis/ILD. 
 Given possibility of an existent 
 (but previously unknown) 
 autoimmune disorder, consider 
 Rheumatology consultation. 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 − 
 Initial work-up should include 
 clinical evaluation, creatine 
 kinase, aldolase, LDH, 
 BUN/creatinine, erythrocyte 
 sedimentation rate or C-reactive 
 protein level, urine myoglobin, 
 and additional laboratory 
 work-up as indicated, including a 
 number of possible 
 rheumatological/antibody tests 
 (i.e., consider whether a 
 rheumatologist consultation is 
 indicated and could guide need 
 for rheumatoid factor, 
 antinuclear antibody, anti-smooth 
 muscle, antisynthetase [such as 
 anti-Jo-1], and/or 
 signal-recognition particle 
 antibodies). Confirmatory testing 
 may include electromyography, 
 nerve conduction studies, MRI of 
 the muscles, and/or a muscle 
 biopsy. Consider Barium 
 swallow for evaluation of 
 dysphagia or dysphonia. 
 Patients should be thoroughly evaluated to 
 rule out any alternative etiology (e.g., 
 disease progression, other medications, or 
 infections). 
 Grade 1 
 (mild pain) 
 -  No dose modifications. 
 For Grade 1: 
 − 
 Monitor and closely follow up in 
 2 to 4 days for clinical symptoms 
 and initiate evaluation as 
 clinically indicated. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 − 
 Consider Neurology consult. 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 Grade 2 
 (moderate pain 
 associated with 
 weakness; pain 
 limiting instrumental 
 activities of daily 
 living [ADLs]) 
 Hold study drug/study regimen 
 dose until resolution to Grade 
 ≤1. 
 -  Permanently discontinue 
 study drug/study regimen if 
 it does not resolve to Grade 
 ≤1 within 30 days or if there 
 are signs of respiratory 
 insufficiency. 
 For Grade 2: 
 − 
 Monitor symptoms daily and 
 consider hospitalization. 
 − 
 Obtain Neurology consult, and 
 initiate evaluation. 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 − 
 If clinical course is rapidly 
 progressive (particularly if 
 difficulty breathing and/or 
 trouble swallowing), promptly 
 start IV methylprednisolone 2 to 
 4 mg/kg/day systemic steroids 
 along with receiving input from 
 Neurology consultant 
 − 
 If clinical course is not rapidly 
 progressive, start systemic 
 steroids (e.g., prednisone 1 to 
 2 mg/kg/day PO or IV 
 equivalent); if no improvement 
 within 3 to 5 days, continue 
 additional work up and start 
 treatment with IV 
 methylprednisolone 2 to 
 4 mg/kg/day 
 − 
 If after start of IV 
 methylprednisolone at 2 to 
 4 mg/kg/day there is no 
 improvement within 3 to 5 days, 
 consider start of 
 immunosuppressive therapy such 
 as TNF inhibitors 
 (e.g., infliximab at 5 mg/kg 
 every 2 weeks). Caution: It is 
 important to rule out sepsis and 
 refer to infliximab label for 
 general guidance before using 
 infliximab. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, or 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).a 
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 Grade 3 or 4 
 (pain associated with 
 severe weakness; 
 limiting self-care 
 ADLs) 
 For Grade 3: 
 Hold study drug/study regimen 
 dose until resolution to Grade 
 ≤1. 
 Permanently discontinue study 
 drug/study regimen if Grade 3 
 imAE does not resolve to 
 Grade ≤1 within 30 days or if 
 there are signs of respiratory 
 insufficiency. 
 For Grade 4: 
 -  Permanently discontinue 
 study drug/study regimen. 
 For Grade 3 or 4 (severe or 
 life-threatening events): 
 − 
 Monitor symptoms closely; 
 recommend hospitalization. 
 − 
 Obtain Neurology consult, and 
 complete full evaluation. 
 − 
 Consider, as necessary, 
 discussing with the study 
 physician. 
 − 
 Promptly start IV 
 methylprednisolone 2 to 
 4 mg/kg/day systemic steroids 
 along with receiving input from 
 Neurology consultant. 
 − 
 If after start of IV 
 methylprednisolone at 2 to 
 4 mg/kg/day there is no 
 improvement within 3 to 5 days, 
 consider start of 
 immunosuppressive therapy such 
 as TNF inhibitors 
 (e.g., infliximab at 5 mg/kg 
 every 2 weeks). Caution: It is 
 important to rule out sepsis and 
 refer to infliximab label for 
 general guidance before using 
 infliximab. 
 − 
 Consider whether patient may 
 require IV IG, plasmapheresis. 
 − 
 Once the patient is improving, 
 gradually taper steroids over ≥28 
 days and consider prophylactic 
 antibiotics, antifungals, or 
 anti-PJP treatment (refer to 
 current NCCN guidelines for 
 treatment of cancer-related 
 infections).  a 
 a  ASCO  Educational  Book  2015  “Managing  Immune  Checkpoint  Blocking  Antibody  Side  Effects”  by  Michael 
 Postow MD. 
 b  FDA  Liver  Guidance  Document  2009  Guidance  for  Industry:  Drug  Induced  Liver  Injury  –  Premarketing  Clinical 
 Evaluation. 
 AChE  Acetylcholine  esterase;  ADL  Activities  of  daily  living;  AE  Adverse  event;  ALP  Alkaline  phosphatase  test; 
 ALT  Alanine  aminotransferase;  AST  Aspartate  aminotransferase;  BUN  Blood  urea  nitrogen;  CT  Computed 
 tomography;  CTCAE  Common  Terminology  Criteria  for  Adverse  Events;  ILD  Interstitial  lung  disease;  imAE 
 immune-mediated  adverse  event;  IG  Immunoglobulin;  IV  Intravenous;  GI  Gastrointestinal;  LFT  Liver  function 
 tests;  LLN  Lower  limit  of  normal;  MRI  Magnetic  resonance  imaging;  NCI  National  Cancer  Institute;  NCCN 
 National  Comprehensive  Cancer  Network;  PJP Pneumocystis  jirovecii  pneumonia  (formerly  known  as 
 Pneumocystis  carinii  pneumonia);  PO  By  mouth;  T3   Triiodothyronine;  T4  Thyroxine;  TB  Total  bilirubin;  TNF 
 Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 Infusion-Related Reactions 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
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 Severity Grade of 
 the Event (NCI 
 CTCAE 
 version 4.03) 
 Dose Modifications 
 Toxicity Management 
 Any Grade 
 General Guidance 
 For Any Grade: 
 − 
 Manage per institutional standard at the 
 discretion of investigator. 
 − 
 Monitor patients for signs and symptoms of 
 infusion-related reactions (e.g., fever and/or 
 shaking chills, flushing and/or itching, alterations 
 in heart rate and blood pressure, dyspnea or chest 
 discomfort, or skin rashes) and anaphylaxis 
 (e.g., generalized urticaria, angioedema, 
 wheezing, hypotension, or tachycardia). 
 Grade 1 or 2 
 For Grade 1: 
 The infusion rate of study drug/study 
 regimen may be decreased by 50% or 
 temporarily interrupted until 
 resolution of the event. 
 For Grade 2: 
 The infusion rate of study drug/study 
 regimen may be decreased 50% or 
 temporarily interrupted until 
 resolution of the event. 
 Subsequent infusions may be given at 
 50% of the initial infusion rate. 
 For Grade 1 or 2: 
 − 
 Acetaminophen and/or antihistamines may be 
 administered per institutional standard at the 
 discretion of the investigator. 
 − 
 Consider premedication per institutional standard 
 prior to subsequent doses. 
 − 
 Steroids should not be used for routine 
 premedication of Grade ≤2 infusion reactions. 
 Grade 3 or 4 
 For Grade 3 or 4: 
 Permanently discontinue study 
 drug/study regimen. 
 For Grade 3 or 4: 
 − 
 Manage severe infusion-related reactions per 
 institutional standards (e.g., IM epinephrine, 
 followed by IV diphenhydramine and ranitidine, 
 and IV glucocorticoid). 
 CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer 
 Institute. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  130 / 135 


 Non–Immune-Mediated Reactions 
 Severity Grade of 
 the Event (NCI 
 CTCAE 
 version 4.03) 
 Dose Modifications 
 Toxicity Management 
 Any Grade 
 Note: Dose modifications are not 
 required for AEs not deemed to be 
 related to study treatment (i.e., events 
 due to underlying disease) or for 
 laboratory abnormalities not deemed 
 to be clinically significant. 
 Treat accordingly, as per institutional standard. 
 Grade 1 
 No dose modifications. 
 Treat accordingly, as per institutional standard. 
 Grade 2 
 Hold study drug/study regimen until 
 resolution to ≤Grade 1 or baseline. 
 Treat accordingly, as per institutional standard. 
 Grade 3 
 Hold study drug/study regimen until 
 resolution to ≤Grade 1 or baseline. 
 For AEs that downgrade to ≤Grade 2 
 within 7 days or resolve to ≤Grade 1 
 or baseline within 14 days, resume 
 study drug/study regimen 
 administration. Otherwise, discontinue 
 study drug/study regimen. 
 Treat accordingly, as per institutional standard. 
 Grade 4 
 Discontinue study drug/study regimen 
 (Note: For Grade 4 labs, decision to 
 discontinue should be based on 
 accompanying clinical 
 signs/symptoms, the Investigator’s 
 clinical judgment, and consultation 
 with the Sponsor). 
 Treat accordingly, as per institutional standard. 
 Note:  As  applicable,  for  early  phase  studies,  the  following  sentence  may  be  added:  “Any  event  greater  than  or  equal  to  Grade  2, 
 please discuss with Study Physician.” 
 AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  131 / 135 


 APPENDIX 2. 
 DURVALUMAB DOSE CALCULATIONS 
 For durvalumab dosing done depending on patient weight: 
 1. Cohort dose: X mg/kg 
 2. Patient weight: Y kg 
 3. Dose for patient: XY mg = X (mg/kg) × Y (kg) 
 4. Dose to be added into infusion bag: 
 Dose  (mL)  =  XY  mg/50  (mg/mL)  where  50  mg/mL  is  durvalumab  nominal 
 concentration. 
 The  corresponding  volume  of  durvalumab  should  be  rounded  to  the  nearest  tenth  mL 
 (0.1  mL).  Dose  adjustments  for  each  cycle  are  only  needed  for  greater  than  10% 
 change in weight. 
 5.  The  theoretical  number  of  vials  required  for  dose  preparation  is  the  next  greatest 
 whole number of vials from the following formula: 
 Number of vials = Dose (mL)/10.0 (mL/vial) 
 Example: 
 1. Cohort dose: 10 mg/kg 
 2. Patient weight: 30 kg 
 3. Dose for patient: 300 mg = 10 (mg/kg) × 30 (kg) 
 4. Dose to be added into infusion bag: 
 Dose (mL) = 300 mg/50 (mg/mL) = 6.0 mL 
 5. The theoretical number of vials required for dose preparation: 
 Number of vials = 6.0 (mL)/10.0 (mL/vial) = 1 vials 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  132 / 135 


 APPENDIX 3. DURVALUMAB DOSE VOLUME CALCULATIONS 
 For durvalumab flat dosing: 
 1. Cohort dose: X g 
 2. Dose to be added into infusion bag: 
 Dose  (mL)  =  X  g  ×  1000/50  (mg/mL)  where  50  mg/mL  is  durvalumab  nominal 
 concentration. 
 The  corresponding  volume  of  durvalumab  should  be  rounded  to  the  nearest  tenth  mL 
 (0.1 mL). 
 3.  The  theoretical  number  of  vials  required  for  dose  preparation  is  the  next  greatest 
 whole number of vials from the following formula: 
 Number of vials = Dose (mL)/10.0 (mL/vial) 
 Example: 
 1. Cohort dose: 1.5 g 
 2. Dose to be added into infusion bag: 
 Dose (mL) = 1.5 g ×1000/50 (mg/mL) = 30.0 mL 
 3. The theoretical number of vials required for dose preparation: 
 Number of vials = 30.0 (mL)/10.0 (mL/vial) = 3 vials 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  133 / 135 


 APPENDIX 4. 
 TREMELIMUMAB DOSE CALCULATIONS 
 (Not  needed  unless  tremelimumab  monotherapy  arm  is  10  mg/kg  or  fixed-dose 
 equivalent) 
 For tremelimumab dosing done depending on patient weight: 
 1. Cohort dose: X mg/kg 
 2. Patient weight: Y kg 
 3. Dose for patient: XY mg = X (mg/kg) × Y (kg) 
 4. Dose to be added into infusion bag: 
 Dose  (mL)  =  XY  mg/20  (mg/mL)  where  20  mg/mL  is  tremelimumab  nominal 
 concentration. 
 The  corresponding  volume  of  tremelimumab  should  be  rounded  to  the  nearest  tenth 
 mL  (0.1  mL).  Dose  adjustments  for  each  cycle  are  only  needed  for  greater  than  10% 
 change in weight. 
 5.  The  theoretical  number  of  vials  required  for  dose  preparation  is  the  next  greatest 
 whole number of vials from the following formula: 
 Number of vials = Dose (mL)/20.0 (mL/vial) 
 Example: 
 1. Cohort dose: 1 mg/kg 
 2. Patient weight: 30 kg 
 3. Dose for patient: 30 mg = 1 (mg/kg) × 30 (kg) 
 4. Dose to be added into infusion bag: 
 Dose (mL) = 30 mg/20 (mg/mL) = 1.5 mL 
 5. The theoretical number of vials required for dose preparation: 
 Number of vials = 1.5 (mL)/20.0 (mL/vial) = 1 vials 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  134 / 135 


 APPENDIX 5. TREMELIMUMAB DOSE VOLUME CALCULATIONS 
 For tremelimumab flat dosing: 
 1. Cohort dose: X mg 
 2. Dose to be added into infusion bag: 
 Dose (mL) = X mg/20 (mg/mL) 
 s tremelimumab nominal concentration 
 The  corresponding  volume  of  tremelimumab  should  be  rounded  to  the  nearest  tenth 
 mL (0.1 mL). 
 3.  The  theoretical  number  of  vials  required  for  dose  preparation  is  the  next  greatest 
 whole number of vials from the following formula: 
 Number of vials = Dose (mL)/20 (mL/vial) 
 Example: 
 1. Cohort dose: 75 mg 
 2. Dose to be added into infusion bag: 
 Dose (mL) = 75 mg/20 (mg/mL) = 3.8 mL 
 3. The theoretical number of vials required for dose preparation: 
 Number of vials = 3.8 (mL)/20 (mL/vial) = 1 vial 
 SOGUG-2017-A-IEC(VEJ)-1 Protocol Version - 3.0 12 NOV.2019 
 Page  135 / 135 


 Phase II trial of durvalumab 
 (Medi4736) plus tremelimumab with 
 concurrent radiotherapy in patients 
 with localized muscle invasive bladder 
 cancer treated with a selective bladder 
 preservation approach - 
 INMUNOPRESERVE STUDY - 
 MANUSCRIPT 2022 


 1.  T  ABLE  OF  C  ONTENTS 
 2. 
 INCLUSION CRITERIA 
 7 
 2.1. 
 SCREENING FAILURES 
 7 
 2.2. 
 PATIENT POPULATIONS 
 8 
 3. 
 RESULTS 
 9 
 3.1. 
 POPULATION AND RECRUITED PATIENTS 
 9 
 3.2. 
 BASELINE CHARACTERISTICS 
 10 
 3.2.1.  BASELINE - DEMOGRAPHIC DATA 
 10 
 3.2.2.  PREVIOUS RELEVANT ILLNESSES 
 12 
 3.2.3.  PREVIOUS RELEVANT TREATMENTS 
 14 
 3.2.4.  CANCER HISTORY 
 16 
 3.2.5.  BASELINE - HEMATOLOGY AND COAGULATION 
 18 
 3.2.6.  BASELINE - BIOCHEMISTRY AND SEROLOGY 
 19 
 3.2.7.  BASELINE - OTHER ANALYTICS 
 22 
 3.2.8.  PD-L1 
 23 
 3.3. 
 TREATMENT 
 24 
 3.3.1.  DURVALUMAB TREATMENT 
 24 
 3.3.2.  TREMELIMUMAB TREATMENT 
 26 
 3.3.3.  RADIOTHERAPY TREATMENT 
 28 
 3.4. 
 END OF TREATMENT 
 31 
 3.5. 
 Median Follow-up 
 32 
 3.6. 
 Median Follow-up (only alive patients) 
 32 
 3.7. 
 RESPONSE EVALUATION TO THERAPY 
 33 
 3.8. 
 Primary efficacy analysis 
 34 
 3.9. 
 Secondary Objective 1a: Bladder preservation  at 6 weeks after RT 
 36 
 3.10. 
 Secondary objective 1b: Bladder preservation  immediate and late 
 salvage cystectomies 
 38 
 3.11. 
 Secondary objective 1c: Bladder preservation  EFS 
 40 
 3.11.1. 
 EFS Bladder preservation estimated at 6, 12,  18 and 24 months 
 (Kaplan-Meier) 
 41 
 3.11.1.1.  Figure: EFS Bladder preservation 
 41 
 3.12. 
 Secondary objective 1d: Event free survival  (Specific) 
 43 
 3.12.1. 
 EFS specific estimated at 6, 12, 18 and 24  months (Kaplan-Meier) 44 
 3.12.1.1.  Figure: EFS Specific 
 44 
 3.13. 
 Secondary objective 1e: PFS (Tumour assessment) 
 46 


 3.13.1. 
 PFS Tumour assessment estimated at 6, 12, 18 and 24 months 
 (Kaplan-Meier) 
 46 
 3.13.1.1.  Figure: PFS Tumour assessment 
 47 
 3.14. 
 Secondary objective 1f: Overall Survival 
 48 
 3.14.1. 
 OS estimated at 6, 12, 18 and 24 months (Kaplan-Meier) 
 48 
 3.14.1.1.  Figure: Overall Survival 
 49 
 3.15. 
 Secondary objective: EFS MUSCLE INVASIVE 
 50 
 3.15.1. 
 EFS Muscle Invasive estimated at 6, 12, 18  and 24 months 
 (Kaplan-Meier) 
 50 
 3.15.1.1.  Figure: EFS Muscle Invasive 
 51 
 3.16. 
 Secondary objective: EFS NON MUSCLE INVASIVE 
 52 
 3.16.1. 
 EFS NON MUSCLE Invasive estimated at 6, 12,  18 and 24 months 
 (Kaplan-Meier) 
 52 
 3.16.1.1.  Figure: EFS NON MUSCLE Invasive 
 53 
 3.17. 
 Secondary objective: METASTASES 
 54 
 3.17.1. 
 EFS METASTASES estimated at 6, 12, 18 and  24 months 
 (Kaplan-Meier) 
 54 
 3.17.1.1.  Figure: EFS METASTASES 
 55 
 3.18. 
 ESTIMATION OF CUMULATIVE INCIDENCE (COMPETING  RISKS 
 ANALYSIS) 
 56 
 3.18.1. 
 CIF: MUSCLE INVASIVE BLADDER CANCER 
 56 
 3.18.1.1.  Figure: CIF Muscle Invasive Bladder Cancer  and competitive 
 events 
 57 
 3.18.2. 
 CIF: MUSCLE NON INVASIVE BLADDER CANCER 
 58 
 3.18.2.1.  Figure: CIF Muscle Non Invasive Bladder  Cancer and 
 competitive events 
 59 
 3.18.3. 
 CIF: RELAPSE BLADDER CANCER 
 60 
 3.18.3.1.  Figure: CIF Relapse Bladder Cancer and competitive  events 
 61 
 3.18.4. 
 CIF: METASTASES 
 62 
 3.18.4.1.  Figure: CIF Metastases and competitive events 
 63 
 4. 
 PROGNOSIS FACTORS FOR EFS BLADDER PRESERVATION,  EFS (specific), PFS 
 AND OS 
 64 
 4.1. 
 EFS bladder preservation 
 64 
 4.1.1.  Age 
 64 
 4.1.1.1.  Figure: EFS bladder preservation vs Age (abowe  or below 71)  65 
 4.1.2.  Gender 
 66 


 4.1.2.1.  Figure: EFS bladder preservation vs gender 
 67 
 4.1.3.  Stage: T2 vs. T3/T4 
 68 
 4.1.3.1.  Figure: EFS bladder preservation vs Stage:  T2 vs T3/T4 
 69 
 4.1.4.  ECOG: 0 vs. 1 
 70 
 4.1.4.1.  Figure: EFS bladder preservation vs ECOG:  0 vs. 1 
 71 
 4.1.5.  Non Invasive Cancer History: Yes vs. No 
 72 
 4.1.5.1.  Figure: EFS bladder preservation vs Non invasive  Cancer History: 
 Yes vs. No 
 73 
 4.1.6.  PD-L1: High vs. Low/Negative 
 74 
 4.1.6.1.  Figure: EFS bladder preservation vs PD-L1:  High 
 vs. Low/Negative 
 75 
 4.1.7.  Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 76 
 4.1.7.1.  Figure: EFS bladder preservation vs Creatinine  clearance: < 60 vs 
 ≥ 60 (mL/min) 
 77 
 4.1. 
 EFS bladder preservation univariate and multivariate  Cox model 
 78 
 4.1.1.1.  Figure: FOREST PLOT EFS bladder preservation  univariate COX 
 MODEL  79 
 4.2. 
 EFS (specific) 
 82 
 4.2.1.  Age 
 82 
 4.2.1.1.  Figure: EFS (specific) vs Age (abowe or below  71) 
 83 
 4.2.2.  Gender 
 84 
 4.2.2.1.  Figure: EFS (specific) vs gender 
 85 
 4.2.3.  Stage: T2 vs. T3/T4 
 86 
 4.2.3.1.  Figure: EFS (specific) vs Stage: T2 vs T3/T4 
 87 
 4.2.4.  ECOG: 0 vs. 1 
 88 
 4.2.4.1.  Figure: EFS (specific) vs ECOG: 0 vs. 1 
 89 
 4.2.5.  Non Invasive Cancer History: Yes vs. No 
 90 
 4.2.5.1.  Figure: EFS (specific) vs Non invasive Cancer  History: Yes vs. No 
 91 
 4.2.6.  PD-L1: High vs. Low/Negative 
 92 
 4.2.6.1.  Figure: EFS (specific) vs PD-L1: High vs. Low/Negative 
 93 
 4.2.7.  Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 94 
 4.2.7.1.  Figure: EFS (specific) vs Creatinine clearance:  < 60 vs ≥ 60 
 (mL/min)  95 
 4.3. 
 EFS (specific) univariate and multivariate Cox  model 
 96 


 4.3.1.1.  Figure: FOREST PLOT EFS (SPECIFIC) univariate  COX MODEL 
 97 
 4.4. 
 PFS 
 99 
 4.4.1.  Age 
 99 
 4.4.1.1.  Figure: PFS vs Age (abowe or below 71) 
 100 
 4.4.2.  Gender 
 101 
 4.4.2.1.  Figure: PFS vs gender 
 102 
 4.4.3.  Stage: T2 vs. T3/T4 
 103 
 4.4.3.1.  Figure: PFS vs Stage: T2 vs T3/T4 
 104 
 4.4.4.  ECOG: 0 vs. 1 
 105 
 4.4.4.1.  Figure: PFS vs ECOG: 0 vs. 1 
 106 
 4.4.5.  Non Invasive Cancer History: Yes vs. No 
 107 
 4.4.5.1.  Figure: PFS vs Non invasive Cancer History:  Yes vs. No 
 108 
 4.4.6.  PD-L1: High vs. Low/Negative 
 109 
 4.4.6.1.  Figure: PFS vs PD-L1: High vs. Low/Negative 
 110 
 4.4.7.  Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 111 
 4.4.7.1.  Figure: PFS vs Creatinine clearance: < 60  vs ≥ 60 (mL/min) 
 112 
 4.5. 
 PFS univariate and multivariate Cox model 
 113 
 4.5.1.1.  Figure: FOREST PLOT PFS univariate COX MODEL 
 114 
 4.6. 
 OS 
 116 
 4.6.1.  Age 
 116 
 4.6.1.1.  Figure: OS vs Age (abowe or below 71) 
 117 
 4.6.2.  Gender 
 118 
 4.6.2.1.  Figure: OS vs gender 
 119 
 4.6.3.  Stage: T2 vs. T3/T4 
 120 
 4.6.3.1.  Figure: OS vs Stage: T2 vs T3/T4 
 121 
 4.6.4.  ECOG: 0 vs. 1 
 122 
 4.6.4.1.  Figure: OS vs ECOG: 0 vs. 1 
 123 
 4.6.5.  Non Invasive Cancer History: Yes vs. No 
 124 
 4.6.5.1.  Figure: OS vs Non invasive Cancer History:  Yes vs. No 
 125 
 4.6.6.  PD-L1: High vs. Low/Negative 
 126 
 4.6.6.1.  Figure: OS vs PD-L1: High vs. Low/Negative 
 127 
 4.6.7.  Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 128 
 4.6.7.1.  Figure: OS vs Creatinine clearance: < 60  vs ≥ 60 (mL/min) 
 129 


 4.7. 
 OS univariate and multivariate Cox model 
 130 
 4.7.1.1.  Figure: FOREST PLOT OS univariate COX MODEL 
 131 
 5. 
 SAFETY ANALYSIS 
 132 
 5.1. 
 SAFETY SUMMARY: ALL EVENTS IN OVERALL (SAFETY 
 POPULATION) 
 132 
 5.2. 
 SAES 
 133 
 5.3. 
 TOXICITIES 
 135 
 5.3.1.  Most frequent toxicities (related to any treat.) 
 135 
 5.3.2.  Toxicities grade ≥ 3 
 137 
 5.3.1.  AES 
 139 
 5.3.1.1.  Most frequent AES 
 139 
 5.3.2.  AES grade ≥ 3 
 143 


 The  information  of  this  analysis  was  done  with  a  database  downloaded  on 
 XX/XX/20XX. 
 2.  INCLUSION CRITERIA 
 2.1.  SCREENING FAILURES 
 Table 1: Screening Failure 
 Screening failure 
 N 
 % 
 No 
 Yes 
 Total 
 Table 2: Screening failures details 
 Patient number 
 Screening failure 
 Reason 
 Safety analysis set 


 2.2.  PATIENT POPULATIONS 
 Safety analysis set 
 The  safety  analysis  set  will  include  all  patients  who  receive  at  least  1  dose  of  study 
 treatment.  The  safety  analysis  set  will  be  the  primary  population  for  evaluating 
 treatment administration/compliance and safety. 
 Efficacy analysis set 
 The  efficacy  analysis  will  be  a  per  protocol  analysis.  The  efficacy  analysis  set  will 
 include  all  patients  who  receive  at  least  2  cycles  of  durvalumab  and  3  weeks  of 
 radiotherapy.  The  efficacy  analysis  set  will  be  the  primary  population  for  evaluating 
 treatment efficacy. 
 Table 3: Population details 
 Patient 
 number 
 Screening 
 failure 
 Safety set 
 ITT 
 Dosis 
 Durvaluma 
 b Week 1 
 Dosis 
 Durvaluma 
 b Week 5 
 2 dosis 
 Durvaluma 
 b 
 Radiotherapy 
 duration 
 (weeks) 
 Radiothera 
 py >3 
 weeks 
 PP 
 3.  RESULTS 
 3.1.  POPULATION AND RECRUITED PATIENTS 
 Analysis Population Definitions 
 All  efficacy  and  safety  analyses  will  be  performed  using  the  Safety  population 
 because  all  the  patients  (n  =  32)  fullfil  the  conditions  to  be  included  in  the  safety 
 and  efficacy  (PP)  populations,  which  include  all  patients  who  received  at  least  2 
 doses of Durvalumab and at least 3 weeks of radiotherapy. 
 Table 4: Populations and Hospital 
 (N=) 
 Safety analysis set 
    Yes 
 Intention to treat population 
    Yes 
 Per protocol population 
    Yes 
 Hospital 


 3.2.  BASELINE CHARACTERISTICS 
 3.2.1. BASELINE - DEMOGRAPHIC DATA 
 Table 5: Baseline - Demographic Data 
 (N=) 
 Sex 
    Female 
    Male 
 Age at treatment (year) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Age at screening (year) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Weight (kg) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Race 
    Caucasian 
 Systolic Blood Pressure 
 (mmHg) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Diastolic Blood Pressure 
 (mmHg) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Temperature (ºC) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Height (cm) 
    N 
    Mean (95%CI) 


 (N=) 
    SD 
    Median (95%CI) 
    Range 
 Pulse Rate (bpm) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 ECOG 
    0 
    1 
 Table 6: Tobacco smoking history 
 (N=) 
 Tobacco Smoking History 
    Never smoker (<= 100 cigarrettes/life time) 
    Former smoker (>= 1 year) 
    Smoker 
 Tobacco Cigarrettes Day History 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Tobacco Pack Year History 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Table 7: Alcohol use and others current status 
 (N=) 
 Alcoholic drinks per 
 day 
    < 1/Day 
    1-2/Day 
    UK 
 History Drug Abuse 
    No 
    Yes 
 ND 
 Current Drug Abuse 
    No 
 Yes 
    ND 


 3.2.2. PREVIOUS RELEVANT ILLNESSES 
 Table 8: Relevant illnesses 
 Variables 
 N (%) 
 Comorbidities 
 Yes 
 No 
 Total 
 Table 9: All comorbidities 
 Variables 
 N (%) 
 Comorbidities 


 3.2.3. PREVIOUS RELEVANT TREATMENTS 
 Table 10: Concomitant Medications 
 Variables 
 N (%) 
 Concomitant medications 
 No 
 Yes 
 Total 
 Table 11: All Concomitant Medication 
 Variables 
 N (%) 
 ConcomitantMedication 
 Table 12: Other Concomitant Medication 
 Variables 
 N (%) 
 Other concomitant medications 


 3.2.4. CANCER HISTORY 
 Table 13: Baseline - Cancer History 
 (N=) 
 Non Invasive Cancer History 
    Yes 
    No 
 Time since Non-Invasive urothelial carcinoma diagnosis until treatment started 
 (months) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Non Invasive Carcinoma Grade 
    High 
    Low 
    UK 
 BCG Treatment 
    Yes 
    No 
 Duration BCG treatment (months) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Note:  Patient  01-001  doesn’t have information about  the duration of BCG treatment. 
 Table 14: Non-Invasive Other Treatments 
 Variables 
 N (%) 
 Non-invasive other treatments 
 Table 15: Baseline - Cancer History - Infiltrating carcinoma diagnose 
 (N=) 
 Time since Infiltrating carcinoma diagnosis until treatment started (months) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Time since Transurethral resection date until treatment started (months) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 


 (N=) 
    Range 
 Histological Diagnosis 
    Urothelial carcinoma 
    Mixed urothelial carcinoma 
 Initial T Stage 
    T2 
    T2a 
    T2b 
    T3 
    T4 
 Initial N Stage 
    N0 
 Initial M Stage 
    M0 
 Carcinoma Grade 
 Low 
    High 
 Previous Treatments 
    Yes 
    No 
 Partial Cystectomy 
    No 
 Cancer Other Treatments 
    Yes 
    No 
 List of Cancer Other Treatments 
     


 3.2.5. BASELINE - HEMATOLOGY AND COAGULATION 
 Table 16: Hematology 
 (N=) 
 Hemoglobin (g/dl) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Neutrophils 
 (x10e9/l) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Limphocytes 
 (x10e9/l) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Platelets (x10e9/l) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Table 17: Coagulation 
 (N=) 
 INR 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 PTT (sec) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 PTT (ratio) 
     


 3.2.6. BASELINE - BIOCHEMISTRY AND SEROLOGY 
 Table 18: Biochemistry (I) 
 (N=) 
 Creatinine (mg/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Albumin (g/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 CreatinineClearingValue.BasAnaBi 
 o 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Total Bilirrubin (mg/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 AST (U/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 ALT (U/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Phosphatase (U/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 GGT (U/L) 
    N 
    Mean (95%CI) 
    SD 


 (N=) 
    Median (95%CI) 
    Range 
 Urea (mg/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 LDH (U/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 BUN (mg/dL) 
    N 
    Mean (SD) 
    Median (Range) 
 Table 19: Patients with creatinine clearance < 40 ml/min 
 Patient Number 
 Hospital 
 Creatinine clearance 
 Table 20: Biochemistry (II) 
 (N=) 
 Calcium (mg/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Magnesium (mg/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Sodium (mEq/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Potassium (mEq/L) 
    N 
    Mean (95%CI) 


 (N=) 
    SD 
    Median (95%CI) 
    Range 
 Chloride (mEq/L)) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Glucose (mg/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Amylase (U/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Bicarbonate (mEq/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Lipase (U/L) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Total Protein (g/dL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Table 21: Serology 
 (N=) 
 HCV 
    Negative 
 HbsAg 
    Negative 
 HIV 
    Negative 


 3.2.7. BASELINE - OTHER ANALYTICS 
 Table 22: Thyroid Function 
 (N=) 
 THS Value 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Free T3 (pg/mL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Free T4 (ng/mL) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Table 23: Urinalysis 
 (N=) 
 Urinalysis 
 result 
    Missing data 
    Negative 
    Traces 
    +1 
    +2 
 Bilirubin 
    Positive 
    Negative 
    ND 
 Blood 
    Positive 
    Negative 
    ND 
 Color/appearen 
 ce 
    Normal 
    ND 
 Glucose 
    Normal 
    Abnormal 
    ND 
 pH 
    N 
    Mean (95%CI) 
    SD 
    Median 
 (95%CI) 


 (N=) 
    Range 
 Ketones 
    Positive 
    Negative 
    ND 
 Specific Gravity 
    N 
    Mean (95%CI) 
    SD 
    Median 
 (95%CI) 
    Range 
 TSH (mIU/L) 
    Positive 
    Negative 
    ND 
 Table 24: Electrocardiogram 
 (N=) 
 ECG result 
    Normal 
    Abnormal 
    ND 
 ECG QTc 
 (msec) 
    N 
    Mean (95%CI) 
    SD 
    Median 
 (95%CI) 
    Range 
 Table 25: Pregnancy Test 
 Pregnancy Test (females 
 only) 
    NA 
    ND 
 3.2.8. PD-L1 
 Table 26: PD-L1 High status 
 (N=) 
 PD-L1 High 
 status 
    Missing data 
    Low/Negative 
    High 


 3.3.  TREATMENT 
 3.3.1. DURVALUMAB TREATMENT 
 Table 27: Durvalumab compliance 
 (N=) 
 1 dosis of Durvalumab 
    No 
    Yes 
 2 dosis of Durvalumab 
    No 
    Yes 
 3 dosis of Durvalumab 
    No 
    Yes 
 Number of Durvalumab 
 dosis 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Number of Durvalumab 
 dosis 
    1 dosis 
    2 dosis 
    3 dosis 
 Table 28: Durvalumab dosage 
 (N=) 
 Dosis of Durvalumab week 
 1 
    1500 
 Dosis of Durvalumab week 
 5 
    1500 
 Dosis of Durvalumab week 
 9 
    1500 
    None 
 Table 29: Durvalumab Not administered reasons 
 (N=) 
 Not administered reasons week 1 
     


 (N=) 
 Not administered reasons week 5 
    
 Not administered reasons week 9 
 Table 30: Durvalumab delay 
 (N=) 
 Patients with at least one delay of Durvalumab 
    No 
    Yes 
 Number of dosis of Durvalumab delayed 
    None 
    1 delay 
    2 delays 
    3 delays 
 Dosis of Durvalumab delayed 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Durvalumab dosis delay week 1 
    Yes 
    No 
 Durvalumab dosis delay week 5 
    Yes 
    No 
 Durvalumab dosis delay week 9 
    Yes 
    No 
 Reason Durvalumab dosis delay week 1 
 Reason Durvalumab dosis delay week 5 
     
 Reason Durvalumab dosis delay week 9 
   


 3.3.2. TREMELIMUMAB TREATMENT 
 Table 31: Tremelimumab compliance 
 (N=) 
 1 dosis of Tremelimumab 
    Yes 
 2 dosis of Tremelimumab 
    Yes 
 3 dosis of Tremelimumab 
    No 
    Yes 
 Number of Tremelimumab 
 dosis 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Number of Tremelimumab 
 dosis 
    1 dosis 
    2 dosis 
    3 dosis 
 Table 32: Tremelimumab dosage 
 (N=) 
 Dosis of Tremelimumab week 
 1 
    75 
 Dosis of Tremelimumab week 
 5 
    75 
 Dosis of Tremelimumab week 
 9 
    75 
 Table 33: Tremelimumab Not administered reasons 
 (N=) 
 Not administered reasons week 1 
 Not administered reasons week 5 
   
 Not administered reasons week 9 


 Table 34: Tremelimumab delay 
 (N=) 
 Patients with at least one delay of Tremelimumab 
    No 
    Yes 
 Number of dosis of Tremelimumab delayed 
    None 
    1 delay 
    2 delays 
    3 delays 
 Dosis of Tremelimumab delayed 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Tremelimumab dosis delay week 1 
    Yes 
    No 
 Tremelimumab dosis delay week 5 
    Yes 
    No 
 Tremelimumab dosis delay week 9 
    Yes 
    No 
 Reason Tremelimumab dosis delay week 1 
 Reason Tremelimumab dosis delay week 5 
     
 Reason Tremelimumab dosis delay week 9 
 Table 35: List of patients with Durvalumab or Tremelimumab delay 
 Patient ID 
 Reason Durvalumab delay in week 5 
 Reason Tremelimumab delay in week 5 


 3.3.3. RADIOTHERAPY TREATMENT 
 Table 36: Radiotherapy treatment details 
 (N=) 
 Radiotherapy Sessions (total number) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Radiotherapy Sessions (total number) 
    10 
    25 
    27 
    28 
    30 
    31 
    32 
    33 
    35 
    66 
 Radiotherapy Fractions (per week) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Radiotherapy Fractions (per week) 
    Missing data 
    4 
    5 
    10 
    23 
 Radiotherapy Dose per Fraction (Gy) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Radiotherapy Dose per Fraction (Gy) 
    Missing data 
    2 
    4 
 Radiotherapy Doses Minor Pelvis (Gy) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Radiotherapy Doses Minor Pelvis (Gy) 
    Missing data 


 (N=) 
    46 
    51 
    52 
 Radiotherapy Total Dose administered in bladder (Gy) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Radiotherapy Total Dose administered in bladder (Gy) 
    50 
    54 
    60 
    61 
    64 
    65 
    66 
 Radiotherapy treatment duration (weeks) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Radiotherapy interruptions 
 Table 37: Radiotherapy interruptions 
 (N=) 
 Radiotherapy Interruption 
    Yes 
    No 
 Number of radiotherapy interruptions 
    N 
    Mean (SD) 
    Median (Range) 
 Number of radiotherapy interruptions 
    1 interruption 
    2 interruptions 
    3 interruptions 
    None 
 Radiotherapy ReStart 
    Yes 
    No 
    NA 
 Total duration of radiotherapy interruptions (days) 
    N 
    Mean (SD) 
    Median (Range) 
 Radiotherapy Interruption Reason 


 (N=) 
     
 List of patients with their radiotherapy interruptions details 
 Table 38: List of patients with their radiotherapy interruptions details 
 Patient 
 ID 
 Hospital 
 Number of 
 radiotherapy 
 interruptions 
 Radiotherpay 
 restarted 
 Radiotherapy 
 interruption 
 total duration 
 (days) 
 Reason for radiotherapy interruption 


 3.4.  END OF TREATMENT 
 Table 39: End of treatment details 
 (N=) 
 Treatment duration (weeks) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 End Treatment Reason 
    Unnacceptable toxicity 
    AE not related to treatment 
    Complete the protocol 
 treatment 
 List of patients with their end of treatment reason and treatment duration: 
 Table 40: End of treatment reason and treatment duration by patient 
 Patient ID 
 Hospital 
 Treatment 
 duration (weeks) 
 End of treatment reason 
 3.5.  M  EDIAN  F  OLLOW -  UP 
 Table 41: Median follow-up (overall) 
 (N=) 
 Follow-up in 
 months 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 3.6.  M  EDIAN  F  OLLOW -  UP  (  ONLY  ALIVE  PATIENTS ) 
 Table 42: Median follow-up (only alive patients) 
 (N=) 
 Follow-up in 
 months 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 


 Table 43: List of patients: follow-up (months) 
 Patient ID 
 Hospital 
 Status 
 Overall Survival Time 
 (months) 
 3.7.  RESPONSE EVALUATION TO THERAPY 
 Table 44: Response evaluation: Cystoscopy details 
 (N=) 
 Time since end of treatment until Cystoscopy (weeks) 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 Cytoscopy done 
    Yes 
    No 
 Reason response evaluation not done 
 List of patients without Cystoscopy 
 Table 45: List of patients without Cystoscopy 
 Patient 
 ID 
 Hospital 
 Cystoscopy 
 done 
 Reason Cystoscopy 
 not done 
 Death Reason 


 3.8.  P  RIMARY  EFFICACY  ANALYSIS 
 Efficacy  of  durvalumab  plus  tremelimumab  with  concurrent  radiotherapy  in  terms  of 
 pathological  response  rate  (Response  evaluation  by  cystoscopy  6  weeks  after  end 
 of RT). 
 Muscle Invasive Bladder Cancer 
 Table 46: Response Evaluation: Muscle-invasive bladder cancer 
 Muscle-invasive bladder cancer 
 N 
 % 
 95%CI 
 Cytoscopy not done 
 Yes 
 No 
 Total 
 Non Invasive Bladder Cancer 
 Table 47: Response Evaluation: Non Invasive Bladder Cancer 
 Non Invasive Bladder Cancer 
 N 
 % 
 95%CI 
 Cytoscopy not done 
 Yes 
 No 
 Total 
 Non-Invasive bladder cancer (including Muscle invasive) 
 Table  48:  Response  Evaluation:  Non  Invasive  Bladder  Cancer  (including  Muscle 
 Invasive 
 Non Invasive Bladder Cancer 
 N 
 % 
 95%CI 
 Cytoscopy not done 
 Yes (Non Invasive Bladder Cancer) 
 Yes (Muscle Invasive Bladder Cancer) 
 No 
 Total 
 Table 49: Response Evaluation: TNM 
 (N=) 
 T Stage 
    T0 
    T1 
    T2 
    T4 
 T Stage (including Not 
 evaluated) 


 (N=) 
    Cytoscopy not done 
    T0 
    T1 
    T2 
    T4 
 N Stage 
    N0 
 N Stage (including Not 
 evaluated) 
    Cytoscopy not done 
    N0 
 M Stage 
    M0 
 M Stage (including Not 
 evaluated) 
    Cytoscopy not done 
    M0 


 3.9.  S  ECONDARY  O  BJECTIVE  1  A : B  LADDER  PRESERVATION  AT  6 
 WEEKS  AFTER  RT 
 Bladder  preservation.  Rate  of  patients  with  bladder  preserved  (at  6  weeks 
 after RT) 
 Table  50:  Response  Evaluation:  Post  therapy  radical  surgery/salvage  cystectomy 
 required (aprox. 6 weeks after RT). Immediate salvage cystectomies 
 (N=) 
 Radical Surgery. Immediate salvage cystectomies 
    No 
 Radical Surgery (including Not evaluated). Immediate salvage cystectomies 
    Cytoscopy not done 
    No 
 Details of Response Evaluation 
 Table  51:  List  of  patients  with  Response  Evaluation  Non-invasive  Invasive  Bladder 
 or without Cystoscopy (6 weeks after end of RT) 
 Patient 
 ID 
 Hospital 
 Muscle 
 Invasive 
 Bladder 
 Non 
 Invasive 
 Bladder 
 Cancer 
 T Stage 
 N Stage 
 M Stage 
 Radical 
 Surgery 


 3.10. S  ECONDARY  OBJECTIVE  1  B : B  LADDER  PRESERVATION 
 IMMEDIATE  AND  LATE  SALVAGE  CYSTECTOMIES 
 Bladder  preservation:  Rate  of  immediate  and  late  salvage  cystectomies.  “Post 
 therapy  radical/surgery  cystectomy”  is  used  to  calculate  the  rate  at  3,  6  and  9 
 months (assuming a margin of one week, 7 days). 
 • 
 Immediate salvage cystectomies 
 • 
 Late salvage cystectomies 
 Table 52: Late salvages cystectomies at 3 months 
 Late salvages cystectomies at 3 months (all patients) 
 N 
 % 
 95%CI 
 No (Follow-up>=3m) 
 Death before 3m 
 Total 
 Table 53: Late salvages cystectomies at 6 months 
 Late salvages cystectomies at 6 months (all patients) 
 N 
 % 
 95%CI 
 No (Follow-up>=6m) 
 Death before 6m 
 Total 
 Table  54:  Late  salvages  cystectomies  at  6  months  (excluding  patients  with 
 Follow-up less than 6 months) 
 Late salvages cystectomies at 6 months (excluding 
 patients with Follow-up less than 6 months) 
 N 
 % 
 95%CI 
 No (Follow-up>=6m) 
 Total 
 Table 55: Late salvages cystectomies at 9 months 
 Late salvages cystectomies at 9 months (all patients) 
 N 
 % 
 95%CI 
 Yes 
 No (Follow-up>=9m) 
 Death before 9m 
 Total 


 Table  56:  Late  salvages  cystectomies  at  9  months  (excluding  patients  with 
 Follow-up less than 9 months 
 Late salvages cystectomies at 9 months (excluding 
 patients with Follow-up less than 9 months) 
 N 
 % 
 95%CI 
 Yes 
 No (Follow-up>=9m) 
 Total 
 Table 57: Late salvages cystectomies at any time 
 Late salvages cystectomies at any time (all patients) 
 N 
 % 
 95%CI 
 Yes 
 No 
 Death 
 Total 
 Table 58: Late salvages cystectomies (any time) excluding deaths 
 Late salvages cystectomies at any time (excluding deaths) 
 N 
 % 
 95%CI 
 Yes 
 No 
 Total 
 Table 59: List of patients with Late salvages cystectomies (any time) 
 Patient 
 ID 
 Hospital 
 Late salvage 
 cystectomy 
 Date Late salvage 
 cystectomy 
 Time since start of treatment until late 
 salvage cystectomy (months) 


 3.11. S  ECONDARY  OBJECTIVE  1  C : B  LADDER  PRESERVATION  EFS 
 Event  Free  Survival  (EFS)  with  bladder  preserved  free  of  tumor,  defined  as 
 the  time  from  the  start  of  immunotherapy  to  either  the  date  of  cystectomy  or 
 the date of recurrence of muscle-invasive bladder carcinoma or metastasis. 
 EFS Bladder preservation 
 Table 60: Bladder preservation: Event Free Survival 
 EFS (event) 
 N 
 % 
 95%CI 
 Event/Death 
 No 
 Total 
 Table 61: Type of event: EFS bladder preserved 
 (N=) 
 Type of event: EFS bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Table 62: Survival Median/Mean EFS 
 Median 
 95%CI 
 Mean 
 95%CI 
 EFS 
 3.11.1. 
 EFS B  LADDER  PRESERVATION  ESTIMATED  AT  6, 12, 18  AND 
 24  MONTHS  (K  APLAN -M  EIER ) 
 Table 63: EFS bladder preserved at 6, 12, 18 and 24 months 
 EFS bladder 
 preserved 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 
 At 12 months 
 At 18 months 


 EFS bladder 
 preserved 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 3.11.1.1. 
 F  IGURE : EFS B  LADDER  PRESERVATION 
 List of patients. Events: EFS bladder preserved 
 Table 64: List of patients with event for EFS bladder preserved 
 Patient ID 
 Hospital 
 Event EFS bladder preserved 
 Date EFS bladder 
 preserved 


 3.12. S  ECONDARY  OBJECTIVE  1  D : E  VENT  FREE  SURVIVAL  (S  PECIFIC ) 
 Event Free Survival (EFS) specific: 
 1)  M1  o  N1  (metastases)  is  an  event  independently  of  presence  of  Salvage 
 cystectomy 
 2) Local recurrence (bladder relapse) without Salvage cystectomy. 
 EFS specific 
 Table 65: Event Free Survival specific 
 EFS (event) 
 N 
 % 
 95%CI 
 Event/Death 
 No 
 Total 
 Table 66: Type of event: EFS specific 
 (N=) 
 Type of event: EFS 
 specific 
    No 
    Bladder 
 relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Table 67: Survival Median/Mean EFS specific 
 Median 
 95%CI 
 Mean 
 95%CI 
 EFS 
 3.12.1. 
 EFS  SPECIFIC  ESTIMATED  AT  6, 12, 18  AND  24  MONTHS 
 (K  APLAN -M  EIER ) 
 Table 68: EFS specific at 6, 12, 18 and 24 months 


 EFS specific 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 
 At 12 months 
 At 18 months 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 3.12.1.1. 
 F  IGURE : EFS S  PECIFIC 
 List of patients. Events: EFS specific 
 Table 69: List of patients. EFS specific 
 Patient ID 
 Hospital 
 Event EFS specific 
 Date EFS specific 


 3.13. S  ECONDARY  OBJECTIVE  1  E : PFS (T  UMOUR  ASSESSMENT ) 
 Time from treatment start to tumour relapse or distant progression (or death) 
 PFS Tumour assessment 
 Table 70: PFS Tumour Assessment 
 EFS (event) 
 N 
 % 
 95%CI 
 PD/Death 
 Alive 
 Total 
 Table 71: Type of event: PFS Tumour assessment 
 (N=) 
 Type of event: PFS Tumour 
 assessment 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Table 72: Survival Median/Mean PFS Tumour assessment 
 Median 
 95%CI 
 Mean 
 95%CI 
 PFS 
 3.13.1. 
 PFS T  UMOUR  ASSESSMENT  ESTIMATED  AT  6, 12, 18  AND  24 
 MONTHS  (K  APLAN -M  EIER ) 
 Table 73: PFS Tumour assessment at 6, 12, 18 and 24 months 
 PFS Tumour assessment 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 
 At 12 months 
 At 18 months 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 


 3.13.1.1. 
 F  IGURE : PFS T  UMOUR  ASSESSMENT 
 List of patients. Events: PFS Tumour assessment 
 Table 74: List of patients. PFS 
 Patient ID 
 Hospital 
 Event PFS 
 Date PFS 
 3.14. S  ECONDARY  OBJECTIVE  1  F : O  VERALL  S  URVIVAL 
 Time from treatment start to Death. 
 Overall Survival 
 Table 75: Overall Survival 
 EFS (event) 
 N 
 % 
 95%CI 
 Death 
 Alive 
 Total 
 Table 76: Type of event: Overall Survival 
 (N=) 
 Type of event: Overall Survival 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Table 77: Overall Survival Median/Mean 
 Median 
 95%CI 
 Mean 
 95%CI 
 OS 
 3.14.1. 
 OS  ESTIMATED  AT  6, 12, 18  AND  24  MONTHS 
 (K  APLAN -M  EIER ) 
 Table 78: Overall Survival at 6, 12, 18 and 24 months 
 OS 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 


 OS 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 12 months 
 At 18 months 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 3.14.1.1. 
 F  IGURE : O  VERALL  S  URVIVAL 
 Table 79: Details of deaths 
 Patient ID 
 Hospital 
 Status 
 Death Reason 


 3.15. S  ECONDARY  OBJECTIVE : EFS MUSCLE INVASIVE 
 Muscle  invasive  events  (bladder  relapse)  recorded  in  follow-up  bladder  disease 
 section of the eCRD. 
 Table 80: EFS: Muscle invasive (patients with cystoscopy) 
 Muscle invasive (event) 
 N 
 % 
 95%CI 
 No 
 Yes 
 Total 
 Table 81: Survival Median/Mean EFS Muscle Invasive 
 Median 
 95%CI 
 Mean 
 95%CI 
 EFS 
 3.15.1. 
 EFS M  USCLE  I  NVASIVE  ESTIMATED  AT  6, 12, 18  AND  24 
 MONTHS  (K  APLAN -M  EIER ) 
 Table 82: EFS Muscle Invasive at 6, 12, 18 and 24 months 
 EFS Muscle Invasive 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 
 At 12 months 
 At 18 months 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 3.15.1.1. 
 F  IGURE : EFS M  USCLE  I  NVASIVE 
 Table 83: List of patients with EFS Muscle Invasive 
 Patient 
 Number 
 Hospital 
 Response 
 evaluation at 6w 
 after RDT: 
 Muscle-invasive 
 bladder cancer 
 Muscle invasive 
 (patients with 
 cystoscopy - 
 bladder disease 
 FU) 
 Date Muscle 
 invasive 
 Non-Muscle 
 invasive (patients 
 with cystoscopy - 
 bladder disease 
 FU) 
 Date 
 Non-Muscle 
 invasive 
 Response evaluation: 
 Non-Invasive bladder 
 cancer (including 
 Muscle invasive) 


 3.16. S  ECONDARY  OBJECTIVE : EFS NON MUSCLE INVASIVE 
 Non-muscle  invasive  events  (bladder  relapse)  recorded  in  follow-up  bladder 
 disease section of the eCRD. 
 Table 84: EFS: Non-Muscle invasive (patients with cystoscopy) 
 Non-Muscle invasive (event) 
 N 
 % 
 95%CI 
 No 
 Yes 
 Total 
 Table 85: Survival Median/Mean EFS NON MUSCLE Invasive 
 Median 
 95%CI 
 Mean 
 95%CI 
 EFS 
 3.16.1. 
 EFS NON MUSCLE I  NVASIVE  ESTIMATED  AT  6, 12, 18 
 AND  24  MONTHS  (K  APLAN -M  EIER ) 
 Table 86: EFS Non-Muscle invasive at 6, 12, 18 and 24 months 
 EFS NON MUSCLE Invasive 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 
 At 12 months 
 At 18 months 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 3.16.1.1. 
 F  IGURE : EFS NON MUSCLE I  NVASIVE 
 Table 87: List of patients with EFS Non-Muscle Invasive 
 Patient 
 Number 
 Hospital 
 Response 
 evaluation at 6w 
 after RDT: 
 Muscle-invasive 
 bladder cancer 
 Muscle invasive 
 (patients with 
 cystoscopy - 
 bladder disease 
 FU) 
 Date Muscle 
 invasive 
 Non-Muscle 
 invasive (patients 
 with cystoscopy - 
 bladder disease 
 FU) 
 Date 
 Non-Muscle 
 invasive 
 Response 
 evaluation: 
 Non-Invasive 
 bladder cancer 
 (including Muscle 
 invasive) 


 3.17. S  ECONDARY  OBJECTIVE : METASTASES 
 Metastases events recorded in follow-up metastases section of the eCRD. 
 Table 88: EFS: Metastases 
 Metatases (event, includes death due to PD) 
 N 
 % 
 95%CI 
 Yes 
 No 
 Total 
 Table 89: Survival Median/Mean EFS METASTASES 
 Median 
 95%CI 
 Mean 
 95%CI 
 EFS 
 3.17.1. 
 EFS METASTASES  ESTIMATED  AT  6, 12, 18  AND  24 
 MONTHS  (K  APLAN -M  EIER ) 
 Table 90: EFS METASTASES at 6, 12, 18 and 24 months 
 EFS METASTASES 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative survival ratio 
 95% IC 
 At 6 months 
 At 12 months 
 At 18 months 
 At 24 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 3.17.1.1. 
 F  IGURE : EFS METASTASES 
 Table 91: List of patients with EFS Metastases 
 Patient 
 Number 
 Hospital 
 Response 
 evaluation at 6w 
 after RDT: 
 Muscle-invasive 
 bladder cancer 
 Muscle invasive 
 (patients with 
 cystoscopy - 
 bladder disease 
 FU) 
 Date Muscle 
 invasive 
 Non-Muscle 
 invasive (patients 
 with cystoscopy - 
 bladder disease 
 FU) 
 Date 
 Non-Muscle 
 invasive 
 Response evaluation: 
 Non-Invasive bladder 
 cancer (including 
 Muscle invasive) 


 3.18. ESTIMATION OF CUMULATIVE INCIDENCE 
 (COMPETING RISKS ANALYSIS) 
 3.18.1. 
 CIF: MUSCLE INVASIVE BLADDER CANCER 
 In  this  section  the  event  of  interest  was  the  relapse  due  to  the  presence  of  muscle 
 invasive  bladder  cancer  and  the  cumulative  incidence  is  estimated  in  the 
 presence of the following competitive events: 
 • 
 Death 
 • 
 Cystectomy 
 Table 92: Muscle Invasive Bladder Cancer and competitive events 
 (N=) 
 Events (Muscle Invasive Bladder 
 Cancer) 
    Event=Death 
    Event=Muscle Invasive Bladder Cancer 
    No 
 Table 93: List of patients with cumulative event: muscle invasive bladder cancer 
 Patient 
 Number 
 Date 
 treatment 
 intiation 
 Events (Muscle 
 Invasive Bladder 
 Cancer) 
 Date 
 Event/Follow- 
 up 
 Time from 
 treatment 
 initiation 
 Cytoscopy 
 Exitus Reason 
 Last 
 available 
 date 
 Late salvage 
 cystectomy 
 date 
 Table  94:  Cumulative  Incidence  of  Muscle  Invasive  Bladder  Cancer  (in  the 
 presence of competitive events) 
 Time 
 Estimated Cumulative Incidence (95% CI) 
 6 months 
 12 months 
 18 months 
 24 months 
 36 months 
 3.18.1.1. 
 F  IGURE : CIF M  USCLE  I  NVASIVE  B  LADDER  C  ANCER  AND  COMPETITIVE 
 EVENTS 


 3.18.2. 
 CIF: MUSCLE NON INVASIVE BLADDER CANCER 
 In  this  section  the  event  of  interest  was  the  relapse  due  to  the  presence  of  muscle 
 non  invasive  bladder  cancer  and  the  cumulative  incidence  is  estimated  in  the 
 presence of the following competitive events: 
 • 
 Death 
 • 
 Cystectomy 
 • 
 Muscle Invasive Bladder Cancer 
 Table 95: Muscle Non Invasive Bladder Cancer and competitive events 
 (N=) 
 Events (Muscle Non Invasive Bladder Cancer) 
    Event=Death 
    Event=Muscle Invasive Bladder Cancer 
    Event=Muscle Non Invasive Bladder Cancer 
    No 
 Table  96:  List  of  patients  with  cumulative  event:  Non-invasive  muscle  bladder 
 cancer 
 Patient 
 Number 
 Date 
 treatment 
 intiation 
 Events (Muscle Non 
 Invasive Bladder 
 Cancer) 
 Date 
 Event/Follow 
 -up 
 Time from 
 treatment 
 initiation 
 Cytoscopy 
 Exitus Reason 
 Last 
 available 
 date 
 Late salvage 
 cystectomy 
 date 
 Table  97:  Cumulative  Incidence  of  Muscle  Non  Invasive  Bladder  Cancer  (in  the 
 presence of competitive events) 
 Time 
 Estimated Cumulative Incidence (95% CI) 
 6 months 
 12 months 
 18 months 
 24 months 
 36 months 
 3.18.2.1. 
 F  IGURE : CIF M  USCLE  N  ON  I  NVASIVE  B  LADDER  C  ANCER  AND 
 COMPETITIVE  EVENTS 


 3.18.3. 
 CIF: RELAPSE BLADDER CANCER 
 In  this  section  the  event  of  interest  was  the  relapse  bladder  cancer  and  the 
 cumulative  incidence  is  estimated  in  the  presence  of  the  following  competitive 
 events: 
 • 
 Death 
 • 
 Cystectomy 
 Table 98: Relapse Bladder Cancer and competitive events 
 (N=) 
 Events (Any Bladder 
 Cancer) 
    Event= Any Bladder 
 Cancer 
    Event=Death 
    No 
 Table 99: List of patients with cumulative event: Bladder cancer (Any type) 
 Patient 
 Number 
 Date 
 treatment 
 intiation 
 Events (Any 
 Bladder Cancer) 
 Date 
 Event/Follow 
 -up 
 Time from 
 treatment 
 initiation 
 Cytoscopy 
 Exitus Reason 
 Last 
 available 
 date 
 Late salvage 
 cystectomy 
 date 
 Table  100:  Cumulative  Incidence  of  Relapse  Bladder  Cancer  (in  the  presence  of 
 competitive events) 
 Time 
 Estimated Cumulative Incidence (95% CI) 
 6 months 
 12 months 
 18 months 
 24 months 
 36 months 
 3.18.3.1. 
 F  IGURE : CIF R  ELAPSE  B  LADDER  C  ANCER  AND  COMPETITIVE  EVENTS 


 3.18.4. 
 CIF: METASTASES 
 In  this  section  the  event  of  interest  was  the  Metastases  and  the  cumulative 
 incidence is estimated in the presence of the following competitive events: 
 • 
 Death 
 Table 101: Metastases and competitive events 
 (N=) 
 Events (Metastases) 
    Event = Metastases 
    Event=Death 
    No 
 Table  102:  Cumulative  Incidence  of  Metastases  (in  the  presence  of  competitive 
 events) 
 Time 
 Estimated Cumulative Incidence (95% CI) 
 6 months 
 12 months 
 18 months 
 24 months 
 36 months 
 3.18.4.1. 
 F  IGURE : CIF M  ETASTASES  AND  COMPETITIVE  EVENTS 


 4.  PROGNOSIS FACTORS FOR EFS BLADDER 
 PRESERVATION, EFS (  SPECIFIC ), PFS AND OS 
 4.1.  EFS  BLADDER  PRESERVATION 
 4.1.1. A  GE 
 Table 103: EFS bladder preservation by age 
 Age at start of treatment 
 Age < 71 (N=) 
 Age ≥ 71 (N=) 
 Total (N=) 
 p value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 2. 
 Pearson’s Chi-squared test 
 Table  104:  Median/mean  EFS  bladder  preservation  by  age  (estimated  by 
 Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Age < 71 
 Age ≥ 71 
 Table 105: EFS bladder preservation by age estimated survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Age < 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Age ≥ 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 4.1.1.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  A  GE  (  ABOWE  OR  BELOW 
 71) 


 4.1.2. G  ENDER 
 Table 106: EFS bladder preservation by gender 
 Sex 
 Female (N=) 
 Male (N=) 
 Total (N=) 
 p value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder 
 relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  107:  Median/mean  EFS  bladder  preservation  by  gender  (estimated  by 
 Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Female 
 Male 
 Table 108: EFS bladder preservation by gender estimated survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Female 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Male 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 4.1.2.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  GENDER 


 4.1.3. S  TAGE : T2  VS . T3/T4 
 Table 109: EFS bladder preservation by Stage: T2 vs T3/T4 
 T Stage 
 T2 (N=) 
 T3/T4 (N=) 
 Total (N=) 
 p 
 value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  110:  Median/mean  EFS  bladder  preservation  by  Stage:  T2  vs  T3/T4 
 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 T2 
 T3/T4 
 Table 111: EFS bladder preservation by Stage: T2 vs T3/T4 estimated survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 T2 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 T3/T4 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 4.1.3.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  S  TAGE : T2  VS  T3/T4 


 4.1.4. ECOG: 0  VS . 1 
 Table 112: EFS bladder preservation by ECOG: 0 vs. 1 
 ECOG.BasDatDem 
 0 (N=) 
 1 (N=) 
 Total (N=) 
 p value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  113:  Median/mean  EFS  bladder  preservation  by  ECOG:  0  vs. 1  (estimated 
 by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 0 
 1 
 Table 114: EFS bladder preservation by ECOG: 0 vs. 1 estimated survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 0 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 4.1.4.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  ECOG: 0  VS . 1 


 4.1.5. N  ON  I  NVASIVE  C  ANCER  H  ISTORY : Y  ES  VS . N  O 
 Table 115: EFS bladder preservation by Non invasive Cancer History: Yes vs. No 
 NonInvasiveCancerHistory.BasCancer 
 Yes (N=) 
 No (N=) 
 Total (N=) 
 p 
 value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 2. 
 Pearson’s Chi-squared test 
 Table  116:  Median/mean  EFS  bladder  preservation  by  Non  invasive  Cancer 
 History: Yes vs. No (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Yes 
 No 
 Table  117:  EFS  bladder  preservation  by  Non  invasive  Cancer  History:  Yes  vs. No 
 estimated survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Yes 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 No 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 4.1.5.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  N  ON  INVASIVE  C  ANCER 
 H  ISTORY : Y  ES  VS . N  O 


 4.1.6. PD-L1: H  IGH  VS . L  OW /N  EGATIVE 
 Table 118: EFS bladder preservation by PD-L1: High vs. Low/Negative 
 PD-L1 High status 
 Low/Negative (N=) 
 High (N=) 
 Total (N=) 
 p value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 2. 
 Pearson’s Chi-squared test 
 Table 
 119: 
 Median/mean 
 EFS 
 bladder 
 preservation 
 by 
 PD-L1: 
 High 
 vs. Low/Negative (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Low/Negative 
 High 
 Table  120:  EFS  bladder  preservation  by  PD-L1:  High  vs. Low/Negative  estimated 
 survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Low/Negative 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 High 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 4.1.6.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  PD-L1: H  IGH 
 VS . L  OW /N  EGATIVE 


 4.1.7. C  REATININE  CLEARANCE : < 60  VS  ≥ 60 (  M L/  MIN ) 
 Table  121:  EFS  bladder  preservation  by  Creatinine  clearance:  <  60  vs  ≥  60 
 (mL/min) 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 Event Free Survival bladder preserved 
    No 
    Late salvage cystectomy/Bladder relapse 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival bladder preserved 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  122:  Median/mean  EFS  bladder  preservation  by  Creatinine  clearance:  <  60 
 vs ≥ 60 (mL/min) (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 < 60 
 ≥ 60 
 Table  123:  EFS  bladder  preservation  by  Creatinine  clearance:  <  60  vs  ≥  60 
 (mL/min) estimated survival ratio 
 EFS bladder 
 preservation 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 < 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 ≥ 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 4.1.7.1. 
 F  IGURE : EFS  BLADDER  PRESERVATION  VS  C  REATININE  CLEARANCE : 
 < 60  VS  ≥ 60 (  M L/  MIN ) 


 1.1.  EFS  BLADDER  PRESERVATION  UNIVARIATE  AND  MULTIVARIATE  C  OX  MODEL 
 Table 124: EFS bladder preservation univariate and multivariate Cox model 
 Univariate Cox Regression 
 Multivariate Cox Regression 
 Multivariate Cox Regression (Excluding PD-L1) 
 N  Event N  HR  1  95% CI  1 
 p-value 
 N  Event N  HR  1  95% CI  1 
 p-value 
 N 
 Event N  HR  1  95% CI  1 
 p-value 
Age at start of treatment 
 Age < 71 
 Age ≥ 71 
Sex 
 Female 
 Male 
T Stage 
 T2 
 T3/T4 
ECOG 
 0 
 1 
Non Invasive Cancer 
History 
 Yes 
 No 
PD-L1 High status 
 Low/Negative 
 High 
Creatinine clearance 
 < 60 
 ≥ 60 
1  HR = Hazard Ratio, CI = Confidence Interval;  2  Wald  test 


 1.1.1.1. 
 F  IGURE : FOREST PLOT EFS  BLADDER  PRESERVATION  UNIVARIATE  COX MODEL 


 Table  125:  Creatinine  clearance  and  ECOG  contingency  table,  only  patients  with 
 EFS bladder preservation 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 ECOG 
    0 
    1 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  126:  Creatinine  clearance  and  ECOG  contingency  table,  only  patients 
 without EFS bladder preservation 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 ECOG 
    0 
    1 
 1. 
 Fisher’s Exact Test for Count Data 


 Table 127: EFS bladder preservation multivariate model 
 Multivariate Cox Regression 
 Multivariate Cox Regression 
 (Excluding PD-L1) 
 Characteristic 
 N 
 Event N 
 HR  1 
 95% CI  1 
 p-value  N  Event N  HR  1 
 95% CI  1 
 p-value 
 Sex 
 Female 
 Male 
 T Stage 
 T2 
 T3/T4 
 ECOG 
 0 
 1 
 Non Invasive Cancer 
 History 
 Yes 
 No 
 PD-L1 High status 
 Low/Negative 
 High 
 1  HR = Hazard Ratio, CI = Confidence Interval 


 1.2.  EFS (  SPECIFIC ) 
 1.2.1. A  GE 
 Table 128: EFS (specific) by age 
 Age at start of treatment 
 Age < 71 (N=) 
 Age ≥ 71 (N=) 
 Total (N=) 
 p value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 129: Median/mean EFS (specific) by age (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Age < 71 
 Age ≥ 71 
 Table 130: EFS (specific) by age estimated survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Age < 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Age ≥ 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 1.2.1.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  A  GE  (  ABOWE  OR  BELOW  71) 


 1.2.2. G  ENDER 
 Table 131: EFS (specific) by gender 
 Sex 
 Female (N=) 
 Male (N=) 
 Total (N=) 
 p value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 132: Median/mean EFS (specific) by gender (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Female 
 Male 
 Table 133: EFS (specific) by gender estimated survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Female 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Male 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.2.2.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  GENDER 


 1.2.3. S  TAGE : T2  VS . T3/T4 
 Table 134: EFS (specific) by Stage: T2 vs T3/T4 
 T Stage 
 T2 (N=) 
 T3/T4 (N=) 
 Total (N=) 
 p value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  135:  Median/mean  EFS  (specific)  by  Stage:  T2  vs  T3/T4  (estimated  by 
 Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 T2 
 T3/T4 
 Table 136: EFS (specific) by Stage: T2 vs T3/T4 estimated survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 T2 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 T3/T4 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.2.3.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  S  TAGE : T2  VS  T3/T4 


 1.2.4. ECOG: 0  VS . 1 
 Table 137: EFS (specific) by ECOG: 0 vs. 1 
 ECOG 
 0 (N=) 
 1 (N=) 
 Total (N=) 
 p value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  138:  Median/mean  EFS  (specific)  by  ECOG:  0  vs. 1  (estimated  by 
 Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 0 
 1 
 Table 139: EFS (specific) by ECOG: 0 vs. 1 estimated survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 0 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.2.4.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  ECOG: 0  VS . 1 


 1.2.5. N  ON  I  NVASIVE  C  ANCER  H  ISTORY : Y  ES  VS . N  O 
 Table 140: EFS (specific) by Non invasive Cancer History: Yes vs. No 
 Non Invasive Cancer History 
 Yes (N=) 
 No (N=) 
 Total (N=) 
 p value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 2. 
 Pearson’s Chi-squared test 
 Table  141:  Median/mean  EFS  (specific)  by  Non  invasive  Cancer  History:  Yes 
 vs. No (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Yes 
 No 
 Table  142:  EFS  (specific)  by  Non  invasive  Cancer  History:  Yes  vs. No  estimated 
 survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Yes 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 No 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 1.2.5.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  N  ON  INVASIVE  C  ANCER  H  ISTORY : Y  ES 
 VS . N  O 


 1.2.6. PD-L1: H  IGH  VS . L  OW /N  EGATIVE 
 Table 143: EFS (specific) by PD-L1: High vs. Low/Negative 
 PD-L1 High status 
 Low/Negative (N=) 
 High (N=) 
 Total (N=) 
 p 
 value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  144:  Median/mean  EFS  (specific)  by  PD-L1:  High  vs. Low/Negative 
 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Low/Negative 
 High 
 Table 145: EFS (specific) by PD-L1: High vs. Low/Negative estimated survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Low/Negative 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 High 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.2.6.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  PD-L1: H  IGH  VS . L  OW /N  EGATIVE 


 1.2.7. C  REATININE  CLEARANCE : < 60  VS  ≥ 60 (  M L/  MIN ) 
 Table 146: EFS (specific) by Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 Creatinine clearance 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 Event Free Survival specific 
    No 
    Bladder relapse/Metastases 
    Bladder relapse 
    Metastases 
    Death 
 Event Free Survival specific 
    Event/Death 
    No 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  147:  Median/mean  EFS  (specific)  by  Creatinine  clearance:  <  60  vs  ≥  60 
 (mL/min) (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 < 60 
 ≥ 60 
 Table  148:  EFS  (specific)  by  Creatinine  clearance:  <  60  vs  ≥  60  (mL/min)  estimated 
 survival ratio 
 EFS (specific) 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 < 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 ≥ 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 1.2.7.1. 
 F  IGURE : EFS (  SPECIFIC )  VS  C  REATININE  CLEARANCE : < 60  VS  ≥ 60 
 (  M L/  MIN ) 


 1.3.  EFS (  SPECIFIC )  UNIVARIATE  AND  MULTIVARIATE  C  OX  MODEL 
 Table 149: EFS (specific) univariate and multivariate Cox model 
 Univariate Cox Regression 
 Multivariate Cox Regression 
 Multivariate Cox Regression 
 (Excluding PD-L1) 
 Characteristic 
 N  Event N  HR  1 
 95% CI  1  p-value  N  Event N  HR  1 
 95% CI  1  p-value  N  Event N  HR  1 
 95% CI  1  p-value 
 Age at start of treatment 
 Age < 71 
 Age ≥ 71 
 Sex 
 Female 
 Male 
 T Stage 
 T2 
 T3/T4 
 ECOG 
 0 
 1 
 Non Invasive Cancer 
 History 
 Yes 
 No 
 PD-L1 High status 
 Low/Negative 
 High 
 Creatinine clearance 
 < 60 
 ≥ 60 
 1  HR = Hazard Ratio, CI = Confidence Interval;  2  Wald  test 
 1.3.1.1. 
 F  IGURE : FOREST PLOT EFS (SPECIFIC)  UNIVARIATE  COX MODEL 


 Table  150:  Creatinine  clearance  and  ECOG  contingency  table,  only  patients  with 
 EFS (specific) 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 ECOG 
    0 
    1 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  151:  Creatinine  clearance  and  ECOG  contingency  table,  only  patients 
 without EFS (specific) 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 ECOG 
    0 
    1 
 1. 
 Fisher’s Exact Test for Count Data 


 1.4.  PFS 
 1.4.1. A  GE 
 Table 152: PFS by age 
 Age at start of treatment 
 Age < 71 
 (N=) 
 Age ≥ 71 
 (N=) 
 Total (N=) 
 p value 
 Progression Free Survival (tumour 
 assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour 
 assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 2. 
 Pearson’s Chi-squared test 
 Table 153: Median/mean PFS by age (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Age < 71 
 Age ≥ 71 
 Table 154: PFS by age estimated survival ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Age < 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Age ≥ 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 


 1.4.1.1. 
 F  IGURE : PFS  VS  A  GE  (  ABOWE  OR  BELOW  71) 


 1.4.2. G  ENDER 
 Table 155: PFS by gender 
 Sex 
 Female 
 (N=) 
 Male (N=) 
 Total (N=) 
 p value 
 Progression Free Survival (tumour 
 assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour 
 assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 156: Median/mean PFS by gender (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Female 
 Male 
 Table 157: PFS by gender estimated survival ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Female 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Male 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.4.2.1. 
 F  IGURE : PFS  VS  GENDER 


 1.4.3. S  TAGE : T2  VS . T3/T4 
 Table 158: PFS by Stage: T2 vs T3/T4 
 T Stage 
 T2 (N=) 
 T3/T4 
 (N=) 
 Total (N=) 
 p value 
 Progression Free Survival (tumour assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 159: Median/mean PFS by Stage: T2 vs T3/T4 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 T2 
 T3/T4 
 Table 160: PFS by Stage: T2 vs T3/T4 estimated survival ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 T2 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 T3/T4 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.4.3.1. 
 F  IGURE : PFS  VS  S  TAGE : T2  VS  T3/T4 


 1.4.4. ECOG: 0  VS . 1 
 Table 161: PFS by ECOG: 0 vs. 1 
 ECOG 
 0 (N=) 
 1 (N=) 
 Total (N=) 
 p 
 value 
 Progression Free Survival (tumour 
 assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour 
 assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 162: Median/mean PFS by ECOG: 0 vs. 1 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 0 
 1 
 Table 163: PFS by ECOG: 0 vs. 1 estimated survival ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 0 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.4.4.1. 
 F  IGURE : PFS  VS  ECOG: 0  VS . 1 


 1.4.5. N  ON  I  NVASIVE  C  ANCER  H  ISTORY : Y  ES  VS . N  O 
 Table 164: PFS by Non invasive Cancer History: Yes vs. No 
 Non Invasive Cancer History 
 Yes (N=) 
 No (N=) 
 Total (N=) 
 p value 
 Progression Free Survival (tumour assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 2. 
 Pearson’s Chi-squared test 
 Table  165:  Median/mean  PFS  by  Non  invasive  Cancer  History:  Yes  vs. No 
 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Yes 
 No 
 Table  166:  PFS  by  Non  invasive  Cancer  History:  Yes  vs. No  estimated  survival 
 ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Yes 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 No 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.4.5.1. 
 F  IGURE : PFS  VS  N  ON  INVASIVE  C  ANCER  H  ISTORY : Y  ES  VS . N  O 


 1.4.6. PD-L1: H  IGH  VS . L  OW /N  EGATIVE 
 Table 167: PFS by PD-L1: High vs. Low/Negative 
 PD-L1 High status 
 Low/Negative 
 (N=) 
 High 
 (N=) 
 Total 
 (N=) 
 p value 
 Progression Free Survival (tumour 
 assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour 
 assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  168:  Median/mean  PFS  by  PD-L1:  High  vs. Low/Negative  (estimated  by 
 Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Low/Negative 
 High 
 Table 169: PFS by PD-L1: High vs. Low/Negative estimated survival ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Low/Negative 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 High 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.4.6.1. 
 F  IGURE : PFS  VS  PD-L1: H  IGH  VS . L  OW /N  EGATIVE 


 1.4.7. C  REATININE  CLEARANCE : < 60  VS  ≥ 60 (  M L/  MIN ) 
 Table 170: PFS by Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 Creatinine clearance 
 < 60 
 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 Progression Free Survival (tumour assessment) 
    Alive without PD 
    PD (tumour assessment) 
    Death 
 Progression Free Survival (tumour assessment) 
    PD/Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  171:  Median/mean  PFS  by  Creatinine  clearance:  <  60  vs  ≥  60  (mL/min) 
 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 < 60 
 ≥ 60 
 Table  172:  PFS  by  Creatinine  clearance:  <  60  vs  ≥  60  (mL/min)  estimated  survival 
 ratio 
 PFS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 < 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 ≥ 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.4.7.1. 
 F  IGURE : PFS  VS  C  REATININE  CLEARANCE : < 60  VS  ≥ 60 (  M L/  MIN ) 


 1.5.  PFS  UNIVARIATE  AND  MULTIVARIATE  C  OX  MODEL 
 Table 173: PFS univariate and multivariate Cox model 
 Univariate Cox Regression 
 Multivariate Cox Regression 
 Multivariate Cox Regression 
 (Excluding PD-L1) 
Characteristic 
 N  Event N  HR  1 
 95% CI  1 
 p-value 
 N  Event N  HR  1 
 95% CI  1 
 p-value 
 N  Event N  HR  1 
 95% CI  1  p-value 
Age at start of 
treatment 
 Age < 71 
 Age ≥ 71 
Sex 
 Female 
 Male 
T Stage 
 T2 
 T3/T4 
ECOG 
 0 
 1 
Non Invasive Cancer 
History 
 Yes 
 No 
PD-L1 High status 
 Low/Negative 
 High 
Creatinine clearance 
 < 60 
 ≥ 60 
1  HR = Hazard Ratio, CI = Confidence Interval;  2  Wald  test 


 1.5.1.1. 
 F  IGURE : FOREST PLOT PFS  UNIVARIATE  COX MODEL 


 Table  174:  Creatinine  clearance  and  ECOG  contingency  table,  only  patients  with 
 PFS 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 ECOG 
    0 
    1 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  175:  Creatinine  clearance  and  ECOG  contingency  table,  only  patients 
 without PFS 
 Creatinine clearance (mL/min) 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p value 
 ECOG 
    0 
    1 
 1. 
 Fisher’s Exact Test for Count Data 


 1.6.  OS 
 1.6.1. A  GE 
 Table 176: OS by age 
 Age at start of treatment 
 Age < 71 (N=) 
 Age ≥ 71 (N=) 
 Total (N=) 
 p value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 177: Median/mean OS by age (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Age < 71 
 Age ≥ 71 
 Table 178: OS by age estimated survival ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Age < 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Age ≥ 71 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.1.1. 
 F  IGURE : OS  VS  A  GE  (  ABOWE  OR  BELOW  71) 


 1.6.2. G  ENDER 
 Table 179: OS by gender 
 Sex 
 Female (N=) 
 Male (N=) 
 Total (N=) 
 p 
 value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 180: Median/mean OS by gender (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Female 
 Male 
 Table 181: OS by gender estimated survival ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Female 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 Male 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.2.1. 
 F  IGURE : OS  VS  GENDER 


 1.6.3. S  TAGE : T2  VS . T3/T4 
 Table 182: OS by Stage: T2 vs T3/T4 
 T Stage 
 T2 (N=) 
 T3/T4 (N=) 
 Total (N=) 
 p 
 value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 183: Median/mean OS by Stage: T2 vs T3/T4 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 T2 
 T3/T4 
 Table 184: OS by Stage: T2 vs T3/T4 estimated survival ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 T2 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 T3/T4 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.3.1. 
 F  IGURE : OS  VS  S  TAGE : T2  VS  T3/T4 


 1.6.4. ECOG: 0  VS . 1 
 Table 185: OS by ECOG: 0 vs. 1 
 ECOG 
 0 (N=) 
 1 (N=) 
 Total (N=) 
 p value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table 186: Median/mean OS by ECOG: 0 vs. 1 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 0 
 1 
 Table 187: OS by ECOG: 0 vs. 1 estimated survival ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 0 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.4.1. 
 F  IGURE : OS  VS  ECOG: 0  VS . 1 


 1.6.5. N  ON  I  NVASIVE  C  ANCER  H  ISTORY : Y  ES  VS . N  O 
 Table 188: OS by Non Invasive Cancer History: Yes vs. No 
 Non Invasive Cancer History 
 Yes (N=) 
 No (N=) 
 Total (N=) 
 p 
 value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  189:  Median/mean  OS  by  Non  invasive  Cancer  History:  Yes  vs. No 
 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Yes 
 No 
 Table 190: OS by Non invasive Cancer History: Yes vs. No estimated survival ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Yes 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 No 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.5.1. 
 F  IGURE : OS  VS  N  ON  INVASIVE  C  ANCER  H  ISTORY : Y  ES  VS . N  O 


 PD-L1: High vs. Low/Negative 
 Table 191: OS by PD-L1: High vs. Low/Negative 
 PD-L1 High status 
 Low/Negative (N=) 
 High (N=) 
 Total (N=) 
 p value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  192:  Median/mean  OS  by  PD-L1:  High  vs. Low/Negative  (estimated  by 
 Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Low/Negative 
 High 
 Table 193: OS by PD-L1: High vs. Low/Negative estimated survival ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 Low/Negative 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 High 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.5.2. 
 F  IGURE : OS  VS  PD-L1: H  IGH  VS . L  OW /N  EGATIVE 


 1.6.6. C  REATININE  CLEARANCE : < 60  VS  ≥ 60 (  M L/  MIN ) 
 Table 194: OS by Creatinine clearance: < 60 vs ≥ 60 (mL/min) 
 Creatinine clearance 
 < 60 (N=) 
 ≥ 60 (N=) 
 Total (N=) 
 p 
 value 
 Status 
    Alive at end of trial: Patient’s decision 
    Alive at end of trial according to protocol 
    Death 
 Patient status 
    Death 
    Alive 
 1. 
 Fisher’s Exact Test for Count Data 
 Table  195:  Median/mean  OS  by  Creatinine  clearance:  <  60  vs  ≥  60  (mL/min) 
 (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 < 60 
 ≥ 60 
 Table  196:  OS  by  Creatinine  clearance:  <  60  vs  ≥  60  (mL/min)  estimated  survival 
 ratio 
 OS 
 Events (%, total 
 N) 
 Patients at 
 risk 
 % estimated cumulative survival 
 ratio 
 CI 95% 
 < 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 ≥ 60 
 At 6 months 
 At 12 months 
 At 24 months 
 At 36 months 
 1.6.6.1. 
 F  IGURE : OS  VS  C  REATININE  CLEARANCE : < 60  VS  ≥ 60 (  M L/  MIN ) 


 1.7.  OS  UNIVARIATE  AND  MULTIVARIATE  C  OX  MODEL 
 Table 197: OS univariate and multivariate Cox model 
 Univariate Cox Regression 
 Multivariate Cox Regression 
 Multivariate Cox Regression 
 (Excluding PD-L1) 
 N 
 Event N  HR  1 
 95% CI  1 
 p-value 
 N 
 Event N  HR  1 
 95% CI  1 
 p-value 
 N 
 Event N  HR  1 
 95% CI  1  p-value 
Age at start of treatment 
 Age < 71 
 Age ≥ 71 
Sex 
 Female 
 Male 
T Stage 
 T2 
 T3/T4 
ECOG 
 0 
 1 
Non Invasive Cancer History 
 Yes 
 No 
PD-L1 High status 
 Low/Negative 
 High 
Creatinine clearance 
 < 60 
 ≥ 60 
1  HR = Hazard Ratio, CI = Confidence Interval;  2  Wald  test 


 1.7.1.1. 
 F  IGURE : FOREST PLOT OS  UNIVARIATE  COX MODEL 


 2.  SAFETY ANALYSIS 
 2.1.  SAFETY SUMMARY: ALL EVENTS IN OVERALL 
 (SAFETY POPULATION) 
 Table 198: Safety 
 N 
 % 
 LL IC 95% 
 UL IC 95% 
 SAE 
 No 
 Yes 
 Total 
 SAE related 
 No 
 Yes 
 Total 
 AE relationship to treatment (any 
 treatment) 
 No 
 Yes 
 Total 
 AE Grade≥3 related to any 
 treatment 
 No 
 Yes 
 Total 
 AE related to both treatments 
 (Durva-Treme) 
 No 
 Yes 
 Total 
 AE related to all treatments 
 (Durva-Treme-Radiotherapy) 
 No 
 Yes 
 Total 
 Adverse Events Related 
 Durvalumab 
 No 
 Yes 
 Total 
 Adverse Events Related RT 
 No 
 Yes 
 Total 
 Adverse Events Related 
 Tremelimumab 
 No 
 Yes 
 Total 
 AE 
 Yes 
 Total 
 AE Grade≥3 
 No 
 Yes 
 Total 


 2.2.  SAES 
 Table 199: SAEs 
 N (%) 
 Adverse 
 Event 
 (CTC) 
 Table 200: List of all SAEs with details 
 Patient 
 Number 
 AE/GRADE 
 Adverse Events 
 CTCAE Other 
 Adverse 
 Events 
 Intensity 
 Adverse 
 Events 
 Related 
 Adverse 
 Events 
 Related 
 Durvalumab 
 Adverse 
 Events 
 Related 
 RT 
 Adverse 
 Events Related 
 Tremelimumab 
 Adverse 
 Events 
 Start Date 
 Adverse 
 Events 
 Stop Date 
 1 
 2 
 2.3.  TOXICITIES 
 2.3.1. M  OST  FREQUENT  TOXICITIES  (  RELATED  TO  ANY  TREAT .) 
 Table 201: Most frequent toxicities (at least 3 pts aprox. ≥10%) 
 N 
 % 
 LL IC 95% 
 UL IC 95% 
 No 
 Sí 
 Total 
 No 
 Sí 
 Total 
 Table 202: Most frequent toxicities (at least 3 pts aprox. ≥10%) according to grade 
 NO 
 G1 
 G2 
 G3 
 G5 
 Total 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 


 2.3.2. T  OXICITIES  GRADE  ≥ 3 
 Table 203: Toxicities with grade 3 or higher 
 N (%) 
 Adverse 
 Event 
 (CTC) 
 Table 204: List of all toxicities with grade 3 or higher 
 Patient 
 ID 
 Adverse Event 
 (CTC) 
 Adverse Event 
 (CTC specify) 
 AE intensity 
 Adverse 
 Events 
 Related 
 Durva. 
 Adverse 
 Events 
 Related 
 RT 
 Adverse 
 Events 
 Related 
 Treme. 
 Date AE 
 started 
 Date AE 
 ended 
 Duration 
 (days)  Continuous  SAE 
 1 
 2 
 1.1.1. AES 
 1.1.1.1. 
 Most frequent AES 
 Table 205: Most frequent AEs (related or not to treatment) (at least 3 pts aprox. ≥ 
 10%) 
 N 
 % 
 LL IC 95% 
 UL IC 95% 
 No 
 Sí 
 Total 
 No 
 Sí 
 Total 
 Table 206: Most frequent AEs (at least 3 pts aprox. ≥10%) according to grade 
 No 
 G1 
 G2 
 G3 
 G5 
 Total 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 


 1.1.2. AES  GRADE  ≥ 3 
 Table 207: AEs with grade 3 or higher 
 N (%) 
 Adverse 
 Event 
 (CTC) 
 Table 208: List of all AEs with grade 3 or higher 
 Patient 
 ID 
 Adverse Event (CTC)  Adverse Event 
 (CTC specify)  AE intensity 
 Adverse 
 Events 
 Related 
 Durva. 
 Adverse 
 Events 
 Related 
 RT 
 Adverse 
 Events 
 Related 
 Treme. 
 Date AE 
 started 
 Date AE 
 ended 
 Duration 
 (days)  Continuous 
 1 
 2