Conditions: Neuroendocrine Tumor Anaplastic Thyroid Cancer Adenocarcinoma Pheochromocytoma Paraganglioma
Keywords: Cabozantinib Atezolizumab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 93
Healthy volunteers: no

Brief summary:
CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and progressive tumors from endocrine system.

The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) evaluated following RECIST v1.1 criteria in advanced endocrine tumors.

Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal gland and paraganglia) are characterized by being remarkably vascular and expressing several growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF), and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the resistance to prior antiangiogenic drugs.

The trial will include patients with advanced and refractory tumors of endocrine system and patients would be allocated to six different cohorts according to the following tumor types.

Detailed description:
CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and progressive tumors from endocrine system.

Hypothesis:

The main hypothesis is that the administration of cabozantinib plus atezolizumab will improve the probability of expected objective response rate in advanced and refractory tumors of the endocrine system.

Objectives:

The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) evaluated following RECIST v1.1 criteria in advanced endocrine tumors. Secondary objectives include:

* To evaluate the safety profile of cabozantinib and atezolizumab combination, according to NCI-CTCAE V5.0.
* Duration of response (DoR) as per RECIST V1.1.
* Progression-free survival (PFS): median PFS as per RECIST V1.1.
* Overall Survival (OS): median OS as per RECIST V1.1.
* Tumor biomarkers: translational sub-study (optional).

Treatment:

All the subjects will be treated with the combination until disease progression, unacceptable toxicity, or patient consent withdrawal (whichever occurs first):

* Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously.
* Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle).

Rationale:

Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal gland and paraganglia) are characterized by being remarkably vascular and expressing several growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF), and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the resistance to prior antiangiogenic drugs.

Patients allocation:

The trial will include patients with advanced and refractory tumors of endocrine system and patients would be allocated to six different cohorts according to the following tumor types:

Cohort 1: Well-differentiated neuroendocrine tumors of the lung and thymus (grades 1 and 2) after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

Cohort 2: Anaplastic thyroid cancer in first-line or after progression to chemotherapy or investigational drugs.

Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane.

Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide receptor radionuclide therapy (PRRT) if indicated, prior chemotherapy and biological therapy, such as somatostatin analogs, are allowed.

Cohort 5: Well-differentiated neuroendocrine tumors of digestive system after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

Cohort 6: Grade 3 neuroendocrine neoplasm of any origin, excluding small cell lung cancer, after progression to chemotherapy or targeted agents/PRRT.

Arms:
arm 1: * Cabozantinib 40 mg tablets, oral administration, once daily, continuously.
* Atezolizumab 1200 mg administered intravenously, every three weeks (cycle).

Interventions: intervention 1: Cabozantinib 40 mg
Intervention descriptions: intervention 1: All the subjects will be treated with the combination of cabozantinib and atezolizumab until disease progression, unacceptable toxicity or patient consent withdrawal (whichever occurs first).

Protocol document:
Prot_SAP_000.pdf: 
 Study Title: 
 Exploratory basket trial of cabozantinib plus atezolizumab in advanced and 
 progressive neoplasms of the endocrine system – The CABATEN study 
 Protocol Number:  GETNE-T1914 
 EudraCT:  2019-002279-32 
 Acronym: CABATEN STUDY 
 Sponsor:  Grupo Español de Tumores Neuroendocrinos  y Endocrinos (GETNE) 
 C/ Balmes 243, Escalera A 5º1ª 
 08006 Barcelona 
 Phone: +34 93 434 44 12 
 E-mail: getne@getne.org 
 Coordinating Investigators: 
 Jaume Capdevila, M.D., Ph.D. 
 Vall d’Hebrón University Hospital 
 Medical Oncology Department 
 P. Vall d’Hebron, 119-129 
 08035 - Barcelona 
 Phone: +34 93 274 60 85 
 E-mail:  jcapdevila@vhio.net 
 Enrique Grande. M.D., Ph.D. 
 MD Anderson Cancer Center Madrid 
 Medical Oncology Department. 
 Calle de Arturo Soria, 270, 
 28033 - Madrid 
 Phone: +34 91 787 86 00 
 e-mail:  egrande@mdanderson.es 
 This document is confidential and proprietary to the Sponsor. Acceptance of this document constitutes agreement by the 
 recipient that no unpublished information contained herein will be reproduced, published, or otherwise disseminated or 
 disclosed without prior written approval of sponsor except that this document may be disclosed in any media to investigators, 
 Ethics Committee, Competent Authorities or Institutional Review Boards. 
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 Page  1  of  100 


 Sponsor Signature Page 
 Protocol Number:  GETNE-T1914 
 Study  Title:  Exploratory  basket  trial  of  cabozantinib  plus  atezolizumab  in  advanced  and  progressive 
 neoplasms of the endocrine system –  The CABATEN study 
 EudraCT Number:  2019-002279-32 
 Version number and date:  Protocol version 4.0 February 18th 2022 
 I  have  received  and  read  the  Investigator’s  Brochure  for  Cabozantinib  and  Atezolizumab.  I  have  read  the 
 GETNE-T1914  -  CABATEN  STUDY  protocol  and  agree  to  conduct  the  study  as  outlined.  I  agree  to 
 maintain  the  confidentiality  of  all  information  received  or  developed  in  connection  with  this  protocol  and  I 
 agree  to  conduct  this  trial  in  accordance  with  all  provisions  of  the  protocol,  GCPs  and  the  Declaration  of 
 Helsinki. 
 Dr. Jaume Capdevila 
 __________________________________________ 
 ____________________________ 
 Sponsor signature 
 Signature date (DD-MM-YYYY) 
 Dr. Jaume Capdevila 
 ______________________________ 
 ____________________________ 
 Coordinating Investigator signature 
 Signature date  (DD-MM-YYYY) 
 Dr. Enrique Grande 
 _________________________________________ 
 ____________________________ 
 Coordinating Investigator signature 
 Signature date  (DD-MM-YYYY) 
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 Investigator’s Agreement 
 Protocol Number:  GETNE-T1914 
 Study  Title:  Exploratory  basket  trial  of  cabozantinib  plus  atezolizumab  in  advanced  and  progressive 
 neoplasms of the endocrine system –  The CABATEN study 
 EudraCT Number:  2019-002279-32 
 Version number and date:  Protocol version 4.0 February 18th 2022 
 I  have  received  and  read  the  Investigator’s  Brochure  for  Cabozantinib  and  Atezolizumab.  I  have  read  the 
 GETNE  T1914  -  CABATEN  STUDY  protocol  and  agree  to  conduct  the  study  as  outlined.  I  agree  to 
 maintain  the  confidentiality  of  all  information  received  or  developed  in  connection  with  this  protocol  and  I 
 agree  to  conduct  this  trial  in  accordance  with  all  provisions  of  the  protocol,  GCPs  and  the  Declaration  of 
 Helsinki. 
 Investigator Printed Name 
 Investigator Signature 
 Date: 
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 1. 
 Synopsis 
 Sponsor: 
 GETNE (Spanish Group of Neuroendocrine and Endocrine Tumors) 
 C/ Balmes 243, Escalera A 5º1ª 
 08006 Barcelona 
 Phone: +34 93 434 44 12 
 E-mail: getne@getne.org 
 Investigational Products: 
 ●  Cabozantinib - 40 mg and 20 mg film-coated tablets 
 ●  Atezolizumab - Atezolizumab 1200 mg concentrate for solution for infusion 
 Title of Study: 
 Exploratory  basket  trial  of  cabozantinib  plus  atezolizumab  in  advanced  and  progressive  neoplasms  of  the 
 endocrine system – The CABATEN study 
 Protocol number:  GETNE-T1914 
 EudraCT:  2019-002279-32 
 Coordinating Investigators: 
 Jaume Capdevila, M.D., Ph.D. 
 Vall d’Hebrón University Hospital 
 Medical Oncology Department 
 P. Vall d’Hebron, 119-129 
 08035 - Barcelona 
 Phone: +34 93 274 60 85 
 E-mail:  jcapdevila@vhio.net 
 Enrique Grande. M.D., Ph.D. 
 MD Anderson Cancer Center Madrid 
 Medical Oncology Department. 
 Calle de Arturo Soria, 270, 
 28033 - Madrid 
 Phone: +34 91 787 86 00 
 e-mail:  egrande@mdanderson.es 
 Principal Investigators: 
 In attached document 
 Study center(s): 
 15 sites in Spain, detailed in attached document 
 Studied period: 
 First patient recruited:  8/10/2020 
 Phase of development: 
 2 
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 Recruitment Period:  24 months: 8 months (Stage 1),  16 months (stage 2) 
 Last patient out:  1Q 2023 (Stage I); 2023 (stage 2) 
 Estimated End of Study:  1Q 2024 
 Objectives: 
 Primary objective: 
 ●  To assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological 
 objective response rate (ORR) in advanced endocrine tumors. 
 Secondary objectives: 
 ● 
 Safety Profile 
 ● 
 Duration of Response (DoR) 
 ● 
 Progression-free Survival (PFS) 
 ● 
 Overall Survival (OS) 
 ● 
 Biomarkers 
 ●  Quality of Life (QoL) 
 Study Design: 
 This  is  a  multicohort  phase  II  study  of  cabozantinib  plus  atezolizumab  in  advanced  and  progressive 
 tumors from the endocrine system. 
 Dosing scheme: 
 ●  Level  0  (starting  dose):  cabozantinib  40  mg  qd  +  atezolizumab  1200  mg  iv  every  21  days  (one 
 cycle). 
 ●  Level -1: cabozantinib 20 mg qd + atezolizumab 1200 mg iv every 21 days (one cycle). 
 Cohorts of tumor types: 
 1.  Well-differentiated  neuroendocrine  tumors  of  lung  origin  or  thymus  (WHO  grade  1  and  2,  typical 
 and atypical carcinoids) 
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 2.  Anaplastic thyroid cancer 
 3.  Adrenocortical carcinoma 
 4.  Pheochromocytoma and paraganglioma 
 5.  Well-differentiated neuroendocrine tumors of gastroenteropancreatic origin (WHO grade 1 and 2) 
 6.  Poorly differentiated neuroendocrine tumors (WHO grade 3), excluding small cell lung cancer 
 Number of patients (planned): 
 Minimum of 54 patients and maximum of 144 patients, depending on the efficacy results, following the 
 Simon-II optimal two-stage design, as further described in this protocol. 
 Eligibility criteria: 
 1. Inclusion criteria: 
 Patients eligible for inclusion in this study must meet all the following criteria: 
 1.  Male or female subjects ≥ 18 years old. 
 2.  Willingness  to  participate  in  the  study  by  signing  ICF  approved  by  the  trial  Central  Ethic 
 Committee (CEIm). 
 3.  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 4.  Measurable disease per RECIST 1.1 as determined by the investigator. 
 5.  Patients  with  advanced  and  progressive  neuroendocrine  tumors  histopathologically  confirmed  (as 
 per  local  pathology  report),  meeting  one  of  the  following  (according  to  WHO  2010 
 classification): 
 a.  Cohort  1:  Well-differentiated  neuroendocrine  tumours  of  the  lung  and  thymus  (WHO 
 grade  1  and  2,  typical  and  atypical  carcinoids)  after  progression  to  somatostatin  analogs, 
 targeted agents, PRRT, and/or chemotherapy. 
 b.  Cohort  2:  Advanced  anaplastic  thyroid  cancer  in  first-line  or  after  progression  to 
 chemotherapy  or  investigational  drugs,  that  underwent  prior  primary  tumor  surgical 
 resection  or  not.  In  patients  that  primary  tumor  has  not  been  resected,  the  risk  of 
 aerodigestive  compression  or  bleeding  should  be  ruled  out  to  ensure  no  interference  with 
 the  administration  of  the  investigational  product  and  undesirable  potential  side  effects 
 related to the route of administration. 
 c.  Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane. 
 d.  Cohort  4:  Pheochromocytoma  and  paraganglioma  after  progression  to  peptide  receptor 
 radionuclide  therapy  (PRRT)  if  indicated.  Prior  chemotherapy  and  biological  therapy, 
 such as somatostatin analogs, are allowed. 
 e.  Cohort  5:  Well-differentiated  neuroendocrine  tumours  of  digestive  system  (WHO  grade  1 
 and  2)  after  progression  to  somatostatin  analogs,  targeted  agents,  PRRT,  and/or 
 chemotherapy. 
 f. 
 Cohort  6:  Grade  3  neuroendocrine  neoplasm  (WHO  grade  3,  including  NET  and  NEC 
 G3)  of  any  origin,  excluding  small  cell  lung  cancer,  after  progression  to  chemotherapy  or 
 targeted agents/PRRT. 
 Note :  Patients  will  be  eligible  for  inclusion  after  progression  to  one  of  the  lines  aforementioned, 
 without limit in the number of treatment lines. 
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 6.  Recovery  from  toxicity  related  to  any  prior  treatments  to  ≤  Grade  1,  unless  the  AE(s)  are 
 clinically non-significant and/or stable on supportive therapy. 
 7.  Ability to swallow tablets. 
 8.  Adequate normal organ and marrow function as defined below: 
 a.  Haemoglobin ≥ 9.0 g/dL. 
 b.  Absolute neutrophil count (ANC)  >  1500 per mm  3  . 
 c.  Platelet count ≥ 100,000 per mm  3  . 
 d.  Serum  bilirubin  ≤  1.5X  institutional  upper  limit  of  normal  (ULN)  unless  liver  metastases 
 are  present,  in  which  case  it  must  be  ≤  2X  ULN.  This  will  not  apply  to  patients  with 
 confirmed  Gilbert’s  syndrome  (persistent  or  recurrent  hyperbilirubinemia  that  is 
 predominantly  unconjugated  in  the  absence  of  haemolysis  or  hepatic  pathology); 
 however, they will be allowed only in consultation with their physician. 
 e.  AST  (SGOT)/ALT  (SGPT)  ≤  2.5X  institutional  upper  limit  of  normal  unless  liver 
 metastases are present, in which case it must be ≤ 3X ULN. 
 f. 
 Measured  creatinine  clearance  (CL)  >  40  mL/min  or  Calculated  creatinine  CL  >  40 
 mL/min  by  the  Cockcroft-Gault  formula  (Cockcroft  and  Gault  1976)  or  by  24-hour  urine 
 collection for the determination of creatinine clearance: 
 Males: 
 Creatinine CL (mL/min)  = 
 Weight (kg) × (140 – Age) 
 72 x serum creatinine (mg/dL) 
 Females: 
 Creatinine CL (mL/min)  = 
 Weight (kg) × (140 – Age)  ×0.85 
 72 x serum creatinine (mg/dL) 
 9.  Female  subjects  of  childbearing  potential  (not  surgically  sterile  or  at  least  2  years 
 postmenopausal)  must  provide  a  negative  urine  pregnancy  test  at  Screening,  and  use  a  medically 
 accepted  double  barrier  method  of  contraception  from  their  inclusion  in  the  study  and  until  5 
 months  after  the  last  dose  of  study  treatment  (i.e  condom  with  spermicide  +  IUD  or  cervical 
 caps)(see section 9.6.1 of this protocol). 
 10.  Males  should  agree  to  abstain  from  sexual  intercourse  with  a  female  partner  or  agree  to  use  a 
 double  barrier  method  of  contraception  (i.e.condom  with  spermicide,  in  addition  to  having  their 
 female  partner  use  some  contraceptive  measures  such  as,  intrauterine  device  (IUD)  or  cervical 
 caps), for the duration of the study and for 4 months after participation in the study. 
 11.  Willingness  and  ability  of  patients  to  comply  with  the  protocol  for  the  duration  of  the  study 
 including  undergoing  treatment  as  well  as  availability  for  scheduled  visits  and  examinations 
 including follow up. 
 2. Exclusion criteria 
 Patients that meet any of the following criteria will be excluded from the study: 
 1.  Prior  treatment  with  cabozantinib  or  any  immune  checkpoint  inhibitor  therapy  (e.g,  CTLA4, 
 PD-1, or PD-L1 targeting agent). 
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 2.  Receipt  of  any  type  of  small  molecule  kinase  inhibitor  (including  investigational  kinase  inhibitor) 
 within  2  weeks  or  5  half-lives  of  the  agent,  whichever  is  longer.  Patients  should  have  been  out  of 
 mitotane for at least 4 weeks. 
 3.  Receipt  of  any  type  of  anticancer  antibody  (including  investigational  antibody)  or  systemic 
 chemotherapy within 2 weeks before starting treatment. 
 4.  Current  or  prior  use  of  immunosuppressive  medication  within  2  weeks  before  the  first  dose  of 
 cabozantinib  and  atezolizumab,  with  the  exceptions  of  intranasal  and  inhaled  corticosteroids  or 
 systemic  corticosteroids  at  physiological  doses,  which  are  not  to  exceed  10  mg/day  of  prednisone, 
 or an equivalent corticosteroid. 
 5.  Active or prior documented autoimmune disease within the past 2 years 
 Note :  Subjects  with  vitiligo,  Grave's  disease,  or  psoriasis  not  requiring  systemic  treatment  (within 
 the past 2 years) are not excluded. 
 6.  Active  or  prior  documented  inflammatory  bowel  disease  (e.g.,  Crohn's  disease  and  ulcerative 
 colitis). 
 7.  History of allogeneic organ transplant. 
 8.  Subjects  having  a  diagnosis  of  immunodeficiency  or  receiving  systemic  steroid  therapy  or  any 
 other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment. 
 9.  Receipt  of  radiation  therapy  for  bone  metastasis  within  2  weeks  or  any  other  radiation  therapy 
 within  4  weeks  before  inclusion.  Subjects  with  clinically  relevant  ongoing  complications  from 
 prior  radiation  therapy  that  have  not  completely  resolved  are  not  eligible  (e.g,  radiation 
 esophagitis or other inflammation of the viscera). 
 10.  Known  brain  metastases  or  cranial  epidural  disease  unless  adequately  treated  with  radiotherapy 
 and/or  surgery  (including  radiosurgery)  and  stable  for  at  least  4  weeks  before  inclusion.  Eligible 
 subjects  must  be  neurologically  asymptomatic  and  without  corticosteroid  treatment  at  the  time  of 
 study treatment. 
 11.  Concomitant  anticoagulation  with  oral  anticoagulants  (e.g,  warfarin,  direct  thrombin  and  factor 
 Xa  inhibitors)  or  platelet  inhibitors  (e.g,  clopidogrel),  except  for  the  following  allowed 
 anticoagulants: 
 ●  Low-dose  aspirin  for  cardioprotection  (per  local  applicable  guidelines)  and  low-dose  low 
 molecular weight heparins (LMWH). 
 ●  Anticoagulation  with  therapeutic  doses  of  LMWH  in  subjects  without  known  brain 
 metastases  and  who  are  on  a  stable  dose  of  LMWH  for  at  least  6  weeks  before  inclusion 
 and  who  have  had  no  clinically  significant  hemorrhagic  complications  from  the 
 anticoagulation regimen or the tumour. 
 12.  The  subject  has  uncontrolled,  significant  intercurrent  or  recent  illness  including,  but  not  limited 
 to, the following conditions: 
 a.  Cardiovascular disorders: 
 i. 
 Class  3  or  4  congestive  heart  failure  as  defined  by  the  New  York  Heart 
 Association, unstable angina pectoris, and serious cardiac arrhythmias. 
 ii. 
 Uncontrolled  hypertension,  defined  as  sustained  blood  press  >  150  mm  hg 
 systolic or > 100 mm hg diastolic despite optimal antihypertensive treatment. 
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 iii. 
 Stroke  (including  transient  ischemic  attack  [TIA]),  myocardial  infarction,  other 
 ischemic  event,  or  thromboembolic  event  (e.g,  deep  venous  thrombosis  [DVT] 
 and  pulmonary  embolism)  within  6  months  before  inclusion.  Subjects  with  a 
 more  recent  diagnosis  of  DVT  are  allowed  if  stable,  asymptomatic,  and  treated 
 with LMWH for at least 6 weeks before study treatment. 
 b.  Gastrointestinal  disorders  (e.g,  malabsorption  syndrome  or  gastric  outlet  obstruction) 
 including those associated with a high risk of perforation or fistula formulation: 
 i. 
 Tumours  invading  the  GI  tract,  active  peptic  ulcer  disease,  inflammatory  bowel 
 disease,  ulcerative  colitis,  diverticulitis,  cholecystitis,  symptomatic  cholangitis  or 
 appendicitis,  acute  pancreatitis  or  acute  obstruction  of  the  pancreatic  or  biliary 
 duct, or gastric outlet obstruction. 
 ii. 
 Abdominal  fistula,  GI  perforation,  bowel  obstruction,  or  intra-abdominal  abscess 
 within  6  months  before  inclusion.  Note:  complete  healing  of  an  intra-abdominal 
 abscess must be confirmed prior to start of the treatment. 
 c.  Clinically  significant  hematemesis  or  hemoptysis  of  >  0.5  teaspoon  (>  2.5  ml)  of  red 
 blood or history of other significant bleeding within 3 months before treatment. 
 d.  Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. 
 e.  Lesions invading major pulmonary blood vessels. 
 f. 
 Other clinically significant disorders such as: 
 i. 
 Active 
 infection 
 requiring 
 systemic 
 treatment,  infection  with  human 
 immunodeficiency  virus  or  acquired  immunodeficiency  syndrome-related  illness, 
 or chronic hepatitis B or C infection. 
 ii. 
 Serious non-healing wound/ulcer/bone fracture. 
 iii. 
 Moderate to severe hepatic impairment (child-pugh B or C). 
 iv. 
 Requirement for hemodialysis or peritoneal dialysis. 
 v. 
 Uncontrolled diabetes mellitus. 
 vi. 
 History of solid organ transplantation. 
 13.  Major  surgery  (e.g,  GI  surgery  and  removal  or  biopsy  of  brain  metastasis)  within  8  weeks  before 
 inclusion.  Complete  wound  healing  from  major  surgery  must  have  occurred  4  weeks  before  study 
 treatment  and  from  minor  surgery  (e.g,  simple  excision,  tooth  extraction)  at  least  10  days  before 
 study  treatment.  Subjects  with  clinically  relevant  ongoing  complications  from  prior  surgery  are 
 not eligible. 
 14.  Corrected  QT  interval  calculated  by  the  Fridericia  formula  (QTcf)  >  500  ms  within  28  days  before 
 study treatment. 
 Note :  if  a  single  ECG  shows  a  QTCf  with  an  absolute  value  >  500  ms,  two  additional  EGGs  at 
 intervals  of  approximately  3  min  must  be  performed  within  30  min  after  the  initial  ECG,  and  the 
 average of these 3 consecutive results for qtcf will be used to determine eligibility. 
 15.  Pregnant or lactating females. 
 16.  Inability to swallow tablets. 
 17.  Previously  identified  allergy  or  hypersensitivity  to  components  of  the  study  treatment 
 formulations. 
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 18.  Diagnosis  of  another  malignancy  within  3  years  before  study  treatment,  except  for  superficial 
 skin cancers, or localised, low grade tumours deemed cured and not treated with systemic therapy. 
 Investigational products, dosage and mode of administration: 
 ●  Cabozantinib 40 mg or 20 mg tablets, oral administration, once daily, continuously. 
 ●  Atezolizumab 1200 mg administered intravenously, every three weeks (cycle). 
 Duration of treatment: 
 All  the  subjects  will  be  treated  with  the  combination  of  cabozantinib  and  atezolizumab  until  disease 
 progression, unacceptable toxicity or patient consent withdrawal (whichever occurs first). 
 Reference therapy, dosage and administration: 
 Not applicable, this is a single arm study that will include patients receiving the same treatment. 
 Criteria for evaluation: 
 Efficacy  assessments:  RECIST  V1.1  assessments  will  be  performed  on  images  from  CT  scans 
 (preferred)  or  MRI,  both  preferably  with  intravenous  (i.v.)  contrast,  of  the  neck,  chest,  abdomen 
 (including  liver  and  adrenal  glands)  and  pelvis.  Pelvic  imaging  is  recommended  only  when  primary  or 
 metastatic  disease  in  the  pelvic  region  is  likely.  Additional  anatomy  should  be  imaged  based  on  signs  and 
 symptoms  of  individual  patients  at  baseline  and  through  follow-up.  Baseline  assessments  should  be 
 performed  no  more  than  28  days  before  the  date  of  inclusion  and,  ideally,  as  close  as  possible  to  the  start 
 of  treatment  and  q12w  ±  2w  until  objective  disease  progression/death  (whichever  comes  first).  Image 
 assessments  by  CT  scan  or  MRI  may  be  performed  q8w  ±  2w  if  required  by  local  standard  clinical 
 practice  or  by  investigator  criteria,  as  long  as  the  frequency  of  assessments  is  maintained.  If  an 
 unscheduled  assessment  was  performed  and  the  patient  has  not  progressed,  every  attempt  should  be  made 
 to perform the subsequent assessments at their next scheduled visit. 
 The primary endpoint definition is as follows: 
 ●  Overall  Response  Rate  (ORR):  includes  patients  with  partial  (PR)  and  complete  response  (CR) 
 as best response according to RECIST v 1.1. 
 The  efficacy secondary endpoints will be studied as follows: 
 ●  Duration  of  response  (DoR)  as  per  RECIST  1.1:  DOR  calculated  as  the  time  from  the  date  of 
 first documented CR or PR to the first documented progression or death due to underlying cancer. 
 ●  Progression-free  Survival  (PFS):  Median  Progression  free  survival  (mPFS)  is  defined  as  the 
 time  from  the  date  of  inclusion  to  the  date  of  the  first  documented  disease  progression  or  death 
 due  to  any  cause,  whichever  occurs  first.  PFS  will  be  determined  based  on  tumour  assessment 
 (RECIST  version  1.1  criteria).  The  local  Investigator's  assessments  will  be  used  for  analyses. 
 Those  patients  who  are  alive  and  have  not  progressed  at  the  last  follow-up  will  be  censored  at  the 
 date  of  the  last  image  available.  Patient  with  no  additional  image  test  other  than  that  at  baseline 
 will be censored to the day after inclusion. 
 ●  Overall  Survival  (OS) :  Median  Overall  Survival  (mOS)  is  calculated  as  the  time  from  date  of 
 inclusion to date of death due to any cause. 
 ●  Quality  of  Life  (QoL):  Quality  of  Life  will  be  analyzed  descriptively  by  QoL  questionnaires 
 (EQ-5D-5L, EORTC QLQ-C30 see appendix 2 and 3). 
 Safety  assessments:  The  assessment  of  adverse  events  will  include  the  type  of  event  (including 
 symptoms,  physical  exam  findings  and  laboratory  abnormalities),  the  incidence,  the  severity,  the  timing, 
 the  seriousness,  and  the  relatedness  regarding  the  treatment  under  study.  Adverse  events  will  be  recorded 
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 and  reported  in  the  corresponding  section  of  the  case  report  form.  The  grade  of  adverse  event  will  be 
 coded  according  to  the  National  Cancer  Institute’s  Common  Toxicity  criteria  (NCI-CTCAE  v5.0  scoring 
 system).  The  worst  toxicity  score  will  be  recorded.  In  case  of  SAE  and  AESI  the  investigator  should 
 immediately fill in the dedicated SAE form and send it by as detailed in section 9.3.2. 
 Translational substudy (optional): 
 ●  Tumor  biopsies:  Collection  of  the  most  recent  archived,  tumor-biopsy  sections  for  identification 
 of predictive biomarkers. 
 ●  Blood  samples:  Somatic  alterations  in  tumours  including  proteomics,  transcriptomics,  metabolics 
 i.e.  metabolic  pathways  of  insulin  growth  factor,  among  others.  No  germinal  line  determinations 
 will  be  performed.  The  levels  of  IGF-1  in  serum  (others  biomarkers  may  be  analysed)  will  be 
 measured  using  the  blood  samples  collected  from  the  patients  at  the  different  time-points, 
 according  to  table  2  “Schedule  of  assessments”.  The  evolution  of  biomarkers  will  be  evaluated 
 individually and for the different groups of patients. 
 Statistical methods: 
 Simon-II  optimal  two-stage  design  was  applied  for  sample  size  estimation.  We  hypothesize  that  the 
 experimental  therapy  will  improve  the  probability  of  expected  objective  response  rate  in  refractory 
 settings  less  than  5%  in  historical  cohorts  to  20%  in  the  current  study.  With  80%  of  power  (0.2)  and 
 unilateral  alpha  (0.1),  24  patients  per  cohort  are  needed  to  demonstrate  the  primary  hypothesis.  The 
 Simon-II  design  suggested  to  observe  ≥  1  patient  with  objective  response  within  the  first  9  patients 
 included  in  the  first  stage.  If  ≥  1  out  of  9  patients  in  each  cohort  achieve  an  objective  radiological 
 response  in  the  first  stage,  study  will  continue  recruiting  15  additional  patients  up  to  24  patients  per 
 cohort.  if  ≥3  out  of  a  total  of  24  patients  achieve  a  radiological  objective  response  at  the  final  analysis,  the 
 study  should  be  declared  positive.  If  stage  I  is  reached  only  in  one  cohort,  recruitment  will  continue  in  the 
 successful cohort and stopped in the non-effective cohorts. 
 An  overall  description  will  be  made  of  the  variables  included  in  the  study.  Absolute  and  relative 
 frequency  distributions  (percentages)  of  qualitative  variables  will  be  presented,  as  well  as  measures  of 
 central  tendency  and  dispersion  (mean,  standard  deviation,  median,  minimum,  and  maximum  values)  of 
 quantitative  variables.  The  missing  data  will  not  be  inputed  and  will  be  left  as  lost  (missing  value), 
 however it will be presented. 
 The  individual  and  summary  on  results  of  vital  signs,  ECG  parameters,  clinical  laboratory  data 
 (haematology,  serum  biochemistry,  and  urinalysis)  will  be  presented  in  tabular  form.  The  values  outside 
 the  reference  range  will  be  flagged.  Clinically  significantly  abnormal  values  will  be  listed  in  tabular  form. 
 AEs  will  be  tabulated  by  system  organ  class  and  preferred  term  after  medical  coding  using  the  latest 
 version of the NCI-CTCAE v5.0. 
 Main analyses populations: 
 ●  Intent-to-Treat (ITT) 
 ●  Per Protocol (PP) 
 ●  Safety population (SP) 
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 INDEX 
 2. Introduction 
 19 
 2.1. Disease background 
 19 
 2.2. Systemic therapy for advanced and refractory tumours from endocrine system 
 22 
 3. Trial rationale 
 24 
 3.1. Rationale for dose 
 25 
 4. Hypothesis and Objectives 
 25 
 4.1. Study Hypothesis 
 25 
 4.2. Study Objectives 
 25 
 5. Study Design 
 25 
 5.1. Overall Study Design 
 25 
 5.2. Patient Screening 
 27 
 5.3. Patient Inclusion and Cohort Assignment 
 27 
 5.4. Patient Treatment 
 27 
 5.5. Patient Follow up After Treatment 
 27 
 5.5.1. End of treatment without progression 
 27 
 5.5.2. End of treatment due to progression 
 28 
 5.6.  Translational Research 
 28 
 5.7. Study Calendar 
 28 
 6. Eligibility Criteria 
 28 
 6.1. Inclusion Criteria 
 28 
 6.2. Exclusion Criteria 
 30 
 6.3. Patient Withdrawal From the Trial 
 32 
 6.4. Premature Termination of the Trial 
 32 
 6.5. Definition of End of Trial 
 33 
 7. Treatment of Subjects 
 33 
 7.1. Cabozantinib 
 33 
 7.1.1. Cabozantinib presentation and administration 
 33 
 Administration instructions 
 33 
 7.1.2. Dose modifications 
 34 
 7.1.3. Cabozantinib Special warnings and precautions for use 
 34 
 7.2. Atezolizumab 
 37 
 7.2.1. Atezolizumab presentation and administration 
 37 
 7.2.2. Atezolizumab dose modifications 
 38 
 7.2.3. Atezolizumab Special warnings and precautions for use 
 38 
 7.3. Concomitant Medications 
 43 
 7.3.1. Allowed concomitant treatment 
 44 
 7.3.2. Prohibited concomitant treatment 
 44 
 7.4  Potential Drug Interactions 
 46 
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 7.4.1 Potential Drug Interactions with Cabozantinib 
 46 
 7.4.2 Potential Drug Interactions with Atezolizumab 
 47 
 7.5. Treatment Compliance 
 47 
 7.6. Study Drug Supply, Labelling, Dispensing and Handling 
 47 
 7.6.1. Study Drug Supply 
 47 
 7.6.2. Study drug labelling 
 48 
 7.6.3. Study drug storage 
 48 
 8. Study Assessments 
 49 
 8.1. Schedule for tests and determinations 
 49 
 8.2.  Clinical Evaluation, Laboratory Tests and Follow-up 
 51 
 8.2.1. Before treatment start 
 51 
 Eligibility Criteria 
 53 
 Laboratory Assessments 
 53 
 Eastern Cooperative Oncology Group (ECOG) Performance Status 
 53 
 Biological samples collection 
 53 
 Tumour Imaging 
 53 
 8.2.2. Assessment during treatment 
 54 
 8.2.3. End of treatment Visit 
 55 
 8.2.4. Post-treatment (Follow-up) 
 57 
 8.2.4.1. Progression Free Survival follow-up 
 57 
 8.2.4.2. Overall Survival (Long term follow-up) 
 57 
 9. Assessment of Safety 
 58 
 9.1. Safety Parameters 
 58 
 9.2. Adverse and Serious Adverse Events 
 58 
 9.2.1. Definitions 
 58 
 9.2.1.1. Adverse Event (AE) 
 58 
 9.2.1.2. Severity of Events 
 59 
 9.2.1.3.  Laboratory Abnormalities 
 59 
 9.3. Serious Adverse Event (SAE) 
 59 
 9.3.1. Definitions 
 59 
 9.3.2. SAE Reporting 
 60 
 9.3.2.  SAE Regulatory Reporting 
 61 
 9.4. Adverse Events of Special Interest 
 62 
 9.4.1 General Information on Immune-Related Adverse Events 
 63 
 9.5. Follow-Up of Adverse Events 
 63 
 9.6. Other Safety Considerations 
 64 
 9.6.1. Pregnancy 
 64 
 9.6.2. Medication Errors/Overdose/Drug abuse/Drug misuse 
 64 
 10. Statistics 
 65 
 10.1. Sample Size Calculation 
 65 
 10.2. Study Endpoints 
 65 
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 10.2.1. Primary endpoint 
 65 
 10.2.2.  Secondary endpoints 
 65 
 10.3. Efficacy Assessment 
 65 
 10.3.1. Time-point efficacy assessment 
 66 
 10.4. Definition of Study Populations 
 66 
 10.5. Safety Analysis 
 67 
 10.6. Statistical Analysis 
 67 
 10.7. Statistical Methods 
 67 
 11. Direct access to source data/documents 
 67 
 11.1. Source Data Definition 
 67 
 11.2. Study Oversight and Study Monitoring 
 68 
 12. Regulatory 
 69 
 12.1. Audits and Inspections 
 69 
 12.2. Independent Ethical Committee (IEC) or Institutional Review Board (IRB) Review 
 69 
 12.3. Ethical Conduct of the Study 
 69 
 12.4. Written Informed Consent 
 69 
 12.5. Insurance 
 70 
 13. Quality Control and Quality Assurance 
 70 
 14. Data Handling and Record Keeping 
 70 
 14.1. Inspection of Records 
 70 
 14.2. Retention of Records 
 71 
 15. Publication Policy 
 71 
 16. List of References 
 72 
 APPENDICES 
 76 
 Appendix 1. Management of Atezolizumab-specific Adverse Events 
 76 
 Management Guidelines for Pulmonary Events, Including Pneumonitis 
 76 
 Management Guidelines for Hepatic Events 
 77 
 Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
 79 
 Management Guidelines for Endocrine Events 
 80 
 Management Guidelines for Ocular Events 
 82 
 Management Guidelines for Immune-Mediated Myocarditis 
 83 
 Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
 84 
 Management Guidelines for Pancreatic Events, Including Pancreatitis 
 87 
 Management Guidelines for Dermatologic Events 
 89 
 Management Guidelines for Neurologic Disorders 
 90 
 Management Guidelines for Immune-Mediated Meningoencephalitis 
 91 
 Management Guidelines for Renal Events 
 92 
 Management Guidelines for Immune-Mediated Myositis 
 93 
 Appendix 2. EORTC QLQ-C30 Questionnaire (Version 3.0 Spanish) 
 97 
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 Appendix 3. EuroQol-5D questionnaire (Spanish) 
 99 
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 List of Abbreviations and Definitions of Terms 
 The following abbreviations and specialist terms are used in this study protocol. 
 Table 1. 
 Abbreviations and Specialist Terms 
 Abbreviation or 
 Specialist Term 
 Explanation 
 5-HIAA 
 5-Hydroxyindoleacetic acid 
 ADL 
 Activities of Daily Living 
 ADR 
 Adverse drug reaction 
 AE 
 Adverse event 
 AP 
 Anatomic pathology 
 ASCO 
 American Society of Clinical Oncology 
 AUC 
 Area Under Curve 
 BED 
 Biological efficacious dose 
 beta-hCG 
 Beta-human chorionic gonadotropin 
 BID 
 bis in die, (Latin for "twice daily") 
 BMI 
 Body mass index 
 BRAF 
 v-raf murine sarcoma viral oncogene homolog B1 
 CIs 
 Confidence intervals 
 CK 
 Creatine  kinase  (CK),  also  known  as  creatine  phosphokinase  (CPK)  or  phosphocreatine 
 kinase 
 CL/F 
 Apparent total clearance of the drug from plasma after administration 
 Cmax 
 Maximum (or peak) serum concentration 
 CB 
 Clinical benefit 
 CDR 
 Control disease rate 
 CEA 
 Carcinoembryonic Antigen 
 CGA 
 Chromogranin A 
 CR 
 Complete Response 
 CRF 
 Controlled Release Form 
 CSR 
 Central Serous Retinopathy 
 CTCAE 
 Common Terminology Criteria for Adverse Events 
 CT Scan 
 Computed Tomography Scan 
 DBP 
 Diastolic Blood Pressure 
 DLT 
 Dose Limiting Toxicity 
 DM 
 Distant metastasis 
 DR 
 Duration of response 
 DVP 
 Data Validation Plan 
 ECG 
 Electrocardiogram 
 ECOG 
 Eastern Cooperative Oncology Group 
 eCRF 
 Electronic Case Report Form 
 EDC 
 Electronic Data Capture 
 ECG 
 Electrocardiogram 
 EMA 
 European Medicines Agency 
 ESMO 
 European society of Medical Oncology 
 FBE 
 Full blood examination 
 FDA 
 United States Food and Drug Administration 
 FFPE 
 Formalin-fixed paraffin-embedded 
 FISH 
 Fluorescence in situ hybridization 
 FU 
 Follow-up 
 GCP 
 Good Clinical Practice 
 GEP-NET 
 Gastroenteropancreatic Neuroendocrine Tumors 
 GH 
 Growth hormone 
 Hb 
 Haemoglobin 
 H/E 
 Haematoxylin/eosin 
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 HFSR 
 Hand Foot Skin Reaction 
 IB 
 Investigator Brochure 
 ICF 
 Informed Consent Form 
 ICH 
 International Conference on Harmonization 
 IEC 
 Independent Ethics Committee 
 IFN 
 Interferon 
 IM 
 Intramuscular 
 IMP 
 Investigational Medicinal Product 
 IRB 
 Institutional Review Board 
 ISF 
 Investigator Site File 
 ITT 
 Intention To Treat 
 KA 
 Keratoacanthoma 
 Ke 
 Elimination rate constant 
 KPS 
 Karnofsky Performance Status 
 LLN 
 Lower Limit of Normality 
 LVEF 
 Left Ventricular Ejection Fraction 
 LOCF 
 Last Observation  Carried Forward 
 MAP 
 Mitogen-Activated Protein 
 MASCC 
 Multinational Association of Supportive Care 
 MDM2 
 Mouse double minute 2 homolog 
 MedDRA 
 Medical Dictionary for Regulatory Activities 
 MEK 
 Mitogen-activated protein kinase kinase 
 MEN 
 Multiple endocrine neoplasms 
 MLPA 
 Multiplex ligation-dependent probe amplification 
 MRI 
 Magnetic Resonance Imaging 
 MRT 
 Mean Residence Time 
 MTD 
 Maximum Tolerated Dose 
 MUGA 
 Multigated Acquisition Scan 
 NET 
 Neuroendocrine Tumor 
 NSE 
 Neuron-Specific Enolase 
 OAE 
 Other significant adverse event 
 ORR 
 Overall response rate 
 OS 
 Overall Survival 
 OTEL 
 Open To Enrolment Letter 
 P2RD 
 Phase two recommended dose 
 PCR 
 Polymerase Chain Reaction 
 PD 
 Progression disease 
 PE 
 Physical examination 
 PET-CT 
 Positron emission tomography–computed tomography 
 PFS 
 Progression Free Survival 
 PI 
 Principal Investigator 
 PK 
 Pharmacokinetics 
 PLGA 
 Poly (lactic-co-glycolic acid) 
 pNET 
 Pancreatic NET 
 PP 
 Per Protocol 
 PR 
 Partial Response 
 PRT 
 Primary retroperitoneal tumours 
 PS 
 Performance Status 
 QD 
 Quaque die, every day “once daily” 
 QLQ 30 
 Quality of Life Questionnaire Core 30 
 QoL 
 Quality of Life 
 RDD 
 Retinal Degenerative Disease 
 RECIST 
 Response Evaluation Criteria In Solid Tumours 
 REEC 
 Registro Español de Estudios Clínicos (Spanish Registry of Clinical Studies) 
 RLS 
 Retroperitoneal Liposarcoma 
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 RP 
 Retroperitoneum 
 RP2D 
 Recommended Phase II dose 
 RVO 
 Retinal Vein Occlusion 
 Rx 
 Radiography 
 SAE 
 Serious adverse event 
 SAP 
 Statistical Analysis Plan 
 SAR 
 Serious adverse reaction 
 SBP 
 Systolic Blood Pressure 
 SC 
 Subcutaneous 
 SCC 
 Squamous Cell Carcinoma 
 SD 
 Stable disease 
 SDV 
 Source Data Verification 
 SmPC 
 Summary of Product Characteristics 
 SP 
 Safety Population 
 SRS 
 Stereotactic Radiosurgery 
 SSAs 
 Somatostatin Analogues 
 SSTR 
 Somatostatin Receptors 
 SUSAR 
 Suspected unexpected serious adverse reaction 
 Sx 
 Surgery 
 Tmax 
 Time of the sample identified as Cmax 
 TR 
 Translational Research 
 TTLR 
 Time to Local Relapse 
 ULN 
 Upper Limit of Normality 
 Vd/F 
 Apparent volume of distribution after non-intravenous administration 
 VS 
 Vital signs 
 VMAT 
 Volumetric Modulated Arc Therapy 
 WBC 
 White Blood Count 
 WBRT 
 Whole Brain Radiotherapy 
 WHO 
 World Health Organization 
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 2. 
 I  NTRODUCTION 
 2.1. 
 D  ISEASE  BACKGROUND 
 Neuroendocrine  tumours  (NETs)  comprise  a  heterogeneous  group  of  neoplasms  originating  from  neural  crest 
 cells,  endocrine  glands,  endocrine  islets  or  the  diffuse  endocrine  system,  which  explains  the  heterogeneity  in 
 the  characteristics  of  these  tumours  and  their  clinical  presentation  (1).  Although  considered  rare 
 malignancies,  available  data  suggest  an  increase  in  the  incidence  of  NETs  over  the  past  30  years,  with  around 
 7  cases  per  100,000  populations  per  year  (2),  with  NETs  of  pancreatic,  intestinal,  and  bronchopulmonary 
 origin as the most common types. 
 Clinical  diagnoses  of  NETs  are  reliable  at  the  advanced  stages  when  many  subjects  present  with  metastases 
 and  inoperable  disease,  thereby  receiving  first  line  therapy  towards  controlling  the  progression  of  the  disease 
 and relieving associated symptoms (2). 
 Well and poorly-differentiated neuroendocrine tumours of lung origin 
 The  origin  and  tumour  development  of  neuroendocrine  neoplasms  are  discussed  controversially,  but  most 
 theories  point  to  an  association  with  Kulchitsky  cells  (or  enterochromaffin  cells),  which  are  normally  present 
 in  the  bronchial  mucosa  and  are  part  of  the  diffuse  neuroendocrine  system,  comprising  single  cells  or  clusters 
 of 4 to 10 cells (3,4,5). 
 NETs  were  first  described  as  carcinoid  tumours  by  Siegfried  Oberndorfer  in  1904,  and  are  developed  from 
 hormone  producing  (endocrine)  cells  which  can  be  found  throughout  the  foregut  (thymus,  lung,  bronchi,  and 
 trachea),  midgut  (small  intestine,  gallbladder,  and  pancreas),  and  hindgut  (Colon,  excluding  appendix, 
 rectum),  with  the  small  intestine  (30.4  %)  and  the  lung  (29.8  %)  (5,6)  as  the  most  common  locations.  NETs 
 of  the  lung  are  also  characterised  by  their  abilities  to  take  up  and  decarboxylate  the  amine  precursors  (APUD 
 system cells) (7,8,9). 
 According  to  the  World  Health  Organization  (WHO)  classification  2004,  NETs  share  common 
 morphological,  immunohistochemical  and  molecular  characteristics  and  can  be  divided  into  three  main 
 entities (10): 
 ●  Carcinoid tumours: typical (TC) or atypical (AC), 
 ●  Large cell neuroendocrine carcinomas (LCNEC), 
 ●  Small cell carcinomas (SCLC). 
 These are further summarised into two groups according to their biological aggressiveness: 
 ●  Well-differentiated low grade (G1) typical and intermediate grade (G2) atypical carcinoids, 
 ●  Poorly-differentiated high grade (G3) LCNEC and SCLC. 
 Unlike  those  of  typical  and  atypical  carcinoids,  genetic  and  epigenetic  characteristics  of  LCNEC  and  SCLC 
 are not closely related, and there are no precursor lesions known for SCLCs and LCNECs (10,11). 
 Anaplastic thyroid cancer 
 Anaplastic  thyroid  cancer  (ATC)  occurs  in  less  than  2  %  of  all  thyroid  cancer  cases  but  uniformly  lethal;  and 
 it affects 1–2 individuals per million every year in the United States. 
 Patients  are  usually  in  their  sixth  or  seventh  decade  of  life  at  the  time  of  disease  presentation,  and  average 
 median survival has been reported as 5 months, with < 20 % of survivors at 1 year after diagnosis (12,13). 
 ATC  is  thought  to  originate  from  differentiated  thyroid  cancers  of  follicular  cell  origin,  as  a  result  of 
 dedifferentiation.  Up  to  80  %  of  ATC  occurs  in  the  setting  of  a  long-standing  goitre,  possibly  in  the 
 background of an undiagnosed, well-differentiated thyroid cancer (15). 
 Dedifferentiation  is  associated  with  gains  and  deletions  in  multiple  chromosomal  regions  and  involves  a 
 complex  process  involving  multiple  events,  including  cell  cycle  derangement  and  signal  transduction 
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 pathway  disturbances  (16-18).  Due  to  its  extremely  aggressive  behaviour,  the  American  Joint  Committee  on 
 Cancer  (AJCC)  defines  all  of  ATC  stages  as  stage  IV,  which  is  further  staged  into  IVa,  IVb,  and  IVc, 
 depending  on  the  extension  of  the  primary  tumour,  lymph  node  involvement,  or  presence  of  distant 
 metastases  (DM).  Although  survival  rates  have  not  significantly  improved  in  six  decades,  multimodality 
 treatments  including  surgery,  radiation,  chemotherapy,  and  targeted  therapy  are  considered  the  best  strategy 
 for improving outcome in patients diagnosed with ATC (14). 
 Adrenocortical carcinoma 
 Adrenocortical  carcinoma  (ACC)  is  a  rare  malignancy  with  an  incidence  of  0.7–2.0  cases/million 
 inhabitants/year  (19)  whose  malignancy  features  relies  on  careful  investigations  of  the  clinical,  biological, 
 and  imaging  features  before  surgery  and  the  anatomopathological  examination  after  tumour  removal.  Most 
 patients  present  with  excess  steroid  hormone  or  abdominal  mass  effects,  but  about  15  %  of  patients  with 
 ACC are initially diagnosed incidentally (20). 
 The  stage  classification  proposed  by  the  European  Network  for  the  Study  of  Adrenal  Tumours  (ENSAT)  is 
 recommended  (21).  Pathology  reports  define  the  Weiss  score,  the  resection  status,  and  the  proliferative  index, 
 including the mitotic count and the Ki67 index. 
 As  far  as  the  treatment  is  concerned,  the  complete  resection  of  the  tumour  is  the  first  option  for  tumours  that 
 are limited to the adrenal gland. 
 In  metastatic  disease,  mitotane  is  the  cornerstone  of  initial  treatment,  and  cytotoxic  drugs  should  be  added  in 
 case  of  progression.  Recently,  the  First  International  Randomised  (FIRM-ACT)  Trial  in  metastatic  ACC 
 reported  the  association  between  mitotane  and  etoposide/doxorubicin/cisplatin  (EDP)  as  the  new  standard  in 
 first  line  treatment  of  ACC.  In  the  last  few  years,  new  targeted  therapies,  including  the  IGF-1  receptor 
 inhibitors,  have  been  investigated,  but  their  efficacy  remains  limited.  Thus,  new  treatment  concepts  are 
 urgently needed (19). 
 Pheochromocytoma and paraganglioma 
 Pheochromocytomas  and  paragangliomas  (PPGLs)  are  highly  vascular  neuroendocrine  tumours  that  arise 
 from  chromaffin  cells  of  the  adrenal  medulla  or  their  neural  crest  progenitors  located  outside  of  the  adrenal 
 gland,  respectively  (22).  PPGLs  are  estimated  to  occur  in  about  2–8  of  1  million  persons  per  year  and  about 
 0.1  %  of  hypertensive  patients  harbour  a  PPGL.  About  10  %  of  patients  with  PPGL  present  with  adrenal 
 incidentaloma  (23).  According  to  2017–WHO  classification  of  tumours  (fourth  edition)  based  on  their 
 location/origin,  the  neuroendocrine  tumours  are  classified  as  tumours  of  the  adrenal  medulla  and 
 extra-adrenal  paraganglia  (24).  These  tumours  are  derived  either  from  sympathetic  tissue  in  adrenal  or 
 extra-adrenal  abdominal  locations  (sympathetic  PPGLs)  or  from  parasympathetic  tissue  in  the  thorax  or  head 
 and  neck  (parasympathetic  PPGLs).  Sympathetic  PPGLs  frequently  produce  considerable  amounts  of 
 catecholamines,  and  in  approximately  80  %  of  patients,  they  are  found  in  the  adrenal  medulla  (22,25).  The 
 remaining  20  %  of  these  tumours  are  located  outside  of  the  adrenal  glands,  in  the  prevertebral  and 
 paravertebral  sympathetic  ganglia  of  the  chest,  abdomen,  and  pelvis.  Extra-adrenal  PPGLs  in  the  abdomen 
 most  commonly  arise  from  a  collection  of  chromaffin  tissue  around  the  origin  of  the  inferior  mesenteric 
 artery  (the  organ  of  Zuckerkandl)  or  aortic  bifurcation.  In  contrast,  most  parasympathetic  PPGLs  are 
 chromaffin-negative  tumours  mostly  confined  to  the  neck  and  at  the  base  of  the  skull  region  along  the 
 glossopharyngeal  and  vagal  nerves,  and  only  4  %  of  these  tumours  secrete  catecholamines  (25).  These  head 
 and  neck  PGLs  were  formerly  known  as  glomus  tumour  or  carotid  body  tumours.  Most  PPGLs  represent 
 sporadic  tumours  and  about  35  %  of  PPGLs  are  of  familial  origin  with  about  20  known  susceptibility  genes 
 making  them  the  most  hereditary  amongst  all  human  tumours  (26,27).  Based  on  these  genetic  mutations  and 
 pathogenetic  pathways,  PPGLs  can  be  classified  into  three  broad  clusters—cluster  1,  cluster  2,  and  cluster  3. 
 Cluster  1  includes  mutations  involving  in  overexpression  of  vascular  endothelial  growth  factor  (VEGF)  (due 
 to  pseudohypoxia)  and  impaired  DNA  methylation  leading  to  increased  vascularization.  Cluster  2  involves 
 the  activation  of  the  mutations  of  Wnt-signalling  pathway  (Wnt  receptor  signalling  and  Hedgehog 
 signalling).  The  activation  of  Wnt  and  Hedgehog  signalling  is  secondary  to  somatic  mutations  of  Cold  shock 
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 domain  containing  E1(CSDE1)  and  Mastermind  like  transcriptional  coactivator  3  (MAML3)  genes  (28). 
 Abnormal  activation  of  kinase  signalling  pathways  like  PI3Kinase/AKT,  RAS/RAF/ERK,  and  mTOR 
 pathways  account  for  cluster  3  mutations  (24).  On  the  other  hand,  based  on  biochemical  secretory  patterns, 
 PPGLs  can  be  characterised  into  three  different  phenotypical  categories—noradrenergic  phenotype 
 (predominant  norepinephrine  secreting),  adrenergic  phenotype  (predominant  epinephrine  secreting),  and 
 dopamine  secreting.  These  biochemical  phenotypes  of  PPGL  lead  to  a  constellation  of  symptoms  (based  on 
 the predominant hormone secreted) leading to different clinical manifestations. 
 Well-differentiated neuroendocrine tumours of gastroenteropancreatic origin 
 Gastroenteropancreatic  neuroendocrine  neoplasms  (NENs)  are  rare  tumours  defined  by  the  expression  of 
 specific  diagnostic  biomarkers  (29-31).  Cell  differentiation  is  a  major  prognostic  marker  of  neuroendocrine 
 neoplasms  (32,  33).  Indeed,  regardless  of  the  stage  or  the  location  of  the  primary  tumour,  it  has  been 
 highlighted  (31)  that  well-differentiated  lesions  have  a  better  prognosis  than  poorly  differentiated  ones  [32, 
 34-36). 
 In  2010,  the  World  Health  Organization  (WHO)  classification  of  neuroendocrine  neoplasms  was  reviewed 
 and  the  crucial  role  of  the  proliferative  rate  was  validated  (37-42).  The  WHO  Classification  2010  defined 
 three  groups  of  tumours  (Grades  1-3)  according  to  the  combination  of  the  morphological  characteristics, 
 mitotic  index,  and  Ki-67  index  (43).  Grades  1  and  2  corresponded  to  well-differentiated  neuroendocrine 
 tumours  (NETs),  whereas  grade  3  corresponded  to  poorly  differentiated  lesions  called  neuroendocrine 
 carcinomas  (NECs).  Initially,  it  was  assumed  that  no  NET  with  a  mitotic  or  a  Ki-67  index  above  20  %  could 
 exist. 
 The  majority  of  gastroenteropancreatic  NENs  are  classified  in  the  well-differentiated  category  because  they 
 retain  the  organoid  architecture  typical  of  neuroendocrine  organs  and  have  a  relatively  low  proliferative  rate. 
 It  is  stated  that  all  gastroenteropancreatic  NETs—with  the  exception  of  the  pancreatic  microadenomas, 
 gastrin-driven  type  1  neuroendocrine  tumours  in  the  stomach  are  potentially  malignant  neoplasms.  Different 
 classifications  have  been  used  to  distinguish  pure  neuroendocrine  tumours  from  mixed  endocrine-exocrine 
 tumours,  and  to  distinguish  within  pure  neuroendocrine  tumours  according  to  their  behaviour 
 (well-differentiated  NETs  with  benign  behaviour,  well-differentiated  NETs  with  uncertain  behaviour, 
 well-differentiated  NETs  with  malignant  behaviour,  and  poorly  differentiated  endocrine  carcinomas  with 
 high-grade  malignant  behaviour)  (44,  45).  These  classifications  are  based  on  their  site  of  origin,  size,  gross 
 and/or  microscopic  tumour  extension,  vascular  invasion,  and/or  proliferative  activity  (Ki-67  index),  as  well 
 as their syndromic clinical/functioning features. 
 High-grade  neuroendocrine  neoplasms  (WHO  G3)  of  the  pancreas  include  both  well-differentiated 
 neuroendocrine  tumour  (WD-NET)  and  poorly  differentiated  neuroendocrine  carcinoma  (PD-NEC). 
 According  to  the  WHO  classification  scheme,  the  diagnosis  of  this  group  of  tumours  is  based  on  both  the 
 histopathology  of  the  tumour  and  the  assessment  of  proliferation  fraction.  However,  the  former  can  be 
 challenging  due  to  the  lack  of  well-defined  histologic  criteria,  and  the  latter  alone  (i.e,  >  20  mitoses/10 
 high-power  fields  or  Ki67  >  20  %)  may  not  sufficiently  distinguish  WD-NETs  from  PD-NECs.  Given  the 
 considerable  differences  in  treatment  strategies  and  clinical  outcome,  additional  practical  modalities  are 
 required  to  facilitate  the  accurate  diagnosis  of  high-grade  pancreatic  neuroendocrine  neoplasms.  We 
 examined  33  cases  of  WHO  G3  neuroendocrine  neoplasms  of  the  pancreas  and  attempted  to  classify  them 
 into  WD-NET,  small  cell  PD-NEC  (PD-NEC-SCC),  and  large  cell  PD-NEC  (PD-NEC-LCC),  or  to  designate 
 them  as  "ambiguous"  when  an  uncertain  diagnosis  was  rendered  by  any  of  the  observers  or  there  was  any 
 disagreement  in  classification  among  the  three  observers.  To  simplify  the  interpretation,  both  PD-NEC-SCC 
 and  PD-NEC-LCC  were  considered  together  as  PD-NECs  in  the  final  analysis.  The  initial  approach  was  to 
 assess  microscopically  a  single  morphologically  challenging  hematoxylin  and  eosin  section  from  each  case 
 without  the  knowledge  of  Ki67  values.  This  was  performed  independently  by  three  pathologists  to  assess  the 
 degree  of  diagnostic  concordance,  and  the  immunohistochemical  staining  for  surrogate  biomarkers  of  known 
 genotypes  of  WD-NET  and  PD-NEC  was  evaluated.  Lastly,  a  clinicopathologic  review  was  completed  to 
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 establish  a  final  definitive  classification.  Loss  of  DAXX  or  ATRX  protein  expression  defined  WD-NET,  and 
 abnormal  expression  of  p53,  Rb,  SMAD4  signified  PD-NEC.  When  the  chosen  section  displayed  an  element 
 of  WD  histopathology,  or  other  tumour  sections  contained  WHO  G1/G2  components,  or  there  had  been  a 
 prior  established  diagnosis  of  a  primary  WD-NET,  the  final  diagnosis  was  considered  a  WD-NET  with 
 high-grade  (G3)  progression.  If  a  component  of  conventional  adenocarcinoma  was  present  (in  slides  not  seen 
 in  the  initial  review),  the  diagnosis  was  established  as  a  combined  adenocarcinoma  and  PD-NEC.  All  the 
 three  pathologists  agreed  on  the  morphologic  classification  of  33  %  of  the  cases  (6  WD-NET,  3 
 PD-NEC-SCC,  and  2  PD-NEC-LCC),  were  conflicted  on  two  cases,  between  PD-NEC-SCC  and 
 PD-NEC-LCC,  and  disagreed  or  were  uncertain  on  the  classification  of  the  remaining  20  cases  (61%),  which 
 were  therefore  categorised  as  ambiguous.  In  the  group  of  cases  in  which  all  pathologists  agreed  on  the 
 classification,  the  six  WD-NET  cases  had  either  loss  of  DAXX  or  ATRX  or  had  evidence  of  a  WD-NET 
 based  on  additional  or  prior  pathology  slides.  The  seven  PD-NEC  cases  had  abnormal  expression  of  p53,  Rb, 
 and/or  SMAD4  or  a  coexisting  adenocarcinoma.  In  the  ambiguous  group  (n  =  20),  14  cases  were  established 
 as  WD-NETs  based  upon  the  loss  of  DAXX  or  ATRX  in  seven  cases  and  additional  pathology  evidence  of 
 high-grade  progression  from  WD-NET  in  the  other  seven  cases;  five  cases  were  established  as  PD-NEC 
 based  upon  abnormal  expression  of  p53,  Rb,  and/or  SMAD4;  one  case  remained  undetermined  with  normal 
 expression  of  all  markers  and  no  evidence  of  entity-defining  histologic  findings  in  other  slides.  On  the  basis 
 of  the  final  pathologic  classifications,  the  disease-specific  survival  was  75  and  11  months  for  the  WD-NET 
 and  PD-NEC  groups,  respectively.  Thus,  we  conclude  that  morphologic  diagnosis  of  high-grade  pancreatic 
 neuroendocrine  neoplasms  is  challenging,  especially  when  limited  pathologic  materials  are  available,  and 
 necessitates  better  defined  criteria.  The  analysis  of  both  additional  sections  and  prior  material,  along  with  an 
 immunohistochemical  evaluation,  can  facilitate  accurate  diagnosis  in  the  majority  of  cases  and  guide  the 
 appropriate clinical management and prognosis (46). 
 2.2. 
 S  YSTEMIC  THERAPY  FOR  ADVANCED  AND  REFRACTORY  TUMOURS  FROM  ENDOCRINE  SYSTEM 
 Systemic  alternatives  for  the  treatment  of  metastatic  disease  includes  radionuclides,  ablative  locoregional 
 treatments  (for  liver  affectation),  and  other  pharmacological  options  including  somatostatin  analogs, 
 interferon,  and  chemotherapy  or  targeted  therapies  (47).  Not  all  NETs  respond  equally  to  systemic  therapy, 
 therefore  careful  selection  of  patients  is  imperative  so  as  to  maximise  the  chance  of  response  and  avoid 
 unnecessary toxicity (48). 
 The  degree  of  differentiation  can  determine  both  overall  prognosis  and  probability  of  response  to  individual 
 cytotoxic  regimens,  and  therefore  an  accurate  histological  characterisation  using  the  WHO  classification  and 
 the  TNM  system  plays  a  major  role  in  disease  management  (49).  The  proliferation  rate,  measured  by  the 
 Ki-67  index  may  be  useful  to  steer  medical  treatments  (50).  Highly  proliferative  (Ki-67  >  20  %)  and  poorly 
 differentiated  or  anaplastic  pancreatic  tumours  behave  aggressively,  with  rapid  growth  rate  and  early 
 dissemination.  However,  this  subtype  of  NET  may  be  more  sensitive  to  cytotoxic  chemotherapy,  which 
 impairs mitosis in a greater proportion of the rapidly dividing cell population (48). 
 The  foregut  tumours  (excluding  those  of  thymic  and  bronchial  origin),  particularly  the  pancreatic  NETs  are 
 most  likely  to  respond  to  conventional  cytotoxic  chemotherapy.  Midgut  tumours  often  appear  to  be  low 
 proliferating  tumours,  and  cytotoxic  chemotherapy  has  only  resulted  in  responses  of  short  duration  in  <  10  % 
 of  patients.  Therefore,  in  slow  growing  tumours,  there  is  an  interest  to  evaluate  treatment  modalities  with 
 mechanisms  of  action  other  than  cell  cycle  arrest  (48).  Immune  modulation  using  interferon-α  (IFNα) 
 administered  subcutaneously  at  doses  of  3–9  million  units  administered  3–7  days  a  week  has  been  shown  to 
 produce  RRs  up  to  50  %  measured  by  biochemical  criteria,  with  durable  reduction  in  tumour  growth  in  up  to 
 15  %  of  patients  and  symptomatic  improvement  seen  in  40–70  %  of  patients  (51).  Somatostatin  analogues 
 have  been  used  in  conjunction  with  IFN,  and  long-term  survival  gains  have  been  suggested  (52-54). 
 However,  the  benefits  of  IFN  have  not  definitively  been  shown  to  outweigh  its  toxicity  so  as  yet,  IFN  is  not 
 generally adopted as routine treatment for NETs. 
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 Borderline  tumours  with  histological  evidence  of  a  well-differentiated  phenotype  but  moderately  raised 
 Ki-67  of  2–15  %  present  management  dilemmas  that  may  be  clarified  by  future  correlative  studies  assessing 
 proliferation indices with treatment outcomes (55,56). 
 In  general,  chemotherapy  is  more  effective  in  tumours  of  pancreatic  origin  than  in  those  of  enteric  origin,  and 
 in  poorly  differentiated  tumours  (NEC)  or  with  high  proliferative  index  (Ki-67)  than  in  those  with  good 
 histological  differentiation  and  low  proliferative  index.  It  can  be  considered  for  use  in  G2  NET  in  which 
 radiological  progression  is  documented,  or  in  G1  NET  in  progression  after  failure  of  other  therapeutic 
 options,  although  the  optimal  chemotherapy  scheme  must  be  evaluated  in  appropriately  designed  clinical 
 trials for this purpose (57). 
 With  hormonal  and  immunological  therapies,  a  high  percentage  of  control  of  symptoms  related  to  hormonal 
 secretion syndrome is achieved, but the antitumour effect is limited (58). 
 Classical  cytotoxic  agents  have  also  shown  limited  activity  in  systemic  control  (59,60),  and  this  could  be 
 related to the biology of these tumours. 
 The  limited  efficacy  of  these  classic  drugs  has  led  to  the  investigation  of  new  therapeutic  agents  that  attempt 
 to  exploit  the  phenotypic  characteristics  of  endocrine  tumours.  The  more  detailed  knowledge  of  the 
 molecular  mechanisms  related  to  cell  growth,  apoptosis,  angiogenesis,  and  tumour  invasion,  has  allowed  the 
 development of new targeted therapies in this field (61). 
 The  inhibition  of  the  angiogenesis  pathway  represents  an  attractive  strategy  in  the  treatment  of  tumours  with 
 rich  vascularisation,  such  as  GEP-NETs.  Thus,  from  preclinical  studies,  two  therapeutic  strategies  directed 
 against  angiogenesis  have  been  developed:  monoclonal  antibodies  directed  against  VEGF  (bevacizumab)  and 
 small  tyrosine  kinase  inhibitory  molecules  directed  against  mediators  involved  in  the  pathway  (sunitinib, 
 sorafenib, pazopanib, and vatalanib). 
 The  PI3/AKT/mTOR  pathway  plays  a  fundamental  role  in  the  carcinogenesis  of  multiple  neoplasms  by 
 participating  in  multiple  processes  as  proliferation,  growth,  and  cell  survival.  Preclinical  studies  have  shown 
 that  PTEN,  one  of  the  inhibitory  phosphatases  of  the  AKT/PI3K/mTOR  pathway,  is  inactive  in  most 
 pancreatic  NETs  and  may  represent  an  interesting  therapeutic  target  in  these  neoplasms.  mTOR  is  a 
 serine-threonine  kinase  involved  in  PI3K-AKT  signalling  pathway,  an  intracellular  signalling  pathway,  which 
 integrates  the  signalling  of  multiple  stimuli  such  as  growth  factors,  and  is  involved  in  the  process  of 
 angiogenesis  by  regulating  the  translation  and  activity  of  hypoxia-inducible  factor  (HIF1-A)  which  is  related 
 to  the  expression  of  VEGF  in  situations  of  cellular  hypoxia.  In  the  clinic,  two  drugs  directed  against  this 
 pathway have been developed: temsirolimus and everolimus. 
 Therapy  with  somatostatin  analogues  (SST),  marked  with  radioactive  elements  [radiometabolic  therapy 
 (RMT)],  has  been  used  for  the  treatment  of  patients  with  NET  in  the  last  decades.  It  is  linked  to  different 
 radionuclides  such  as  111In  which  provides  a  low  response  rate,  and  90Y  and  177Lu  which  due  to  their 
 emission  of  β  particles  were  more  suitable  for  therapeutic  use,  with  177Lu-octreotate  being  the 
 radiopharmaceutical 
 of 
 choice. 
 Another 
 radiopharmaceutical 
 used 
 for 
 NET 
 therapy 
 is 
 metaiodobenzylguanidine  (MIBG),  and  treatment  with  MIBG  is  indicated  in  patients  with  tumours  that  are 
 resistant  to  surgery  or  radiofrequency  ablation.  With  MIBG,  there  are  similar  results  to  those  obtained  with 
 the  administration  of  subcutaneous  octreotide  and  α-interferon  without  the  need  for  frequent  injections, 
 decreasing  the  expense  per  patient  and  increasing  their  well-being.  To  date,  there  is  no  data  from  controlled 
 trials  with  radiometabolic  therapy  (RMT)  versus  placebo  or  other  therapies  to  evaluate  the  benefits  of  this 
 therapy in terms of progression-free survival or overall survival. 
 Other options include anti-HER drugs, IGFR inhibitors, and histone deacetylase inhibitors. 
 During  the  last  decade,  new  active  drugs  have  been  studied  in  advanced  and/or  refractory  endocrine  tumours 
 due  to  a  better  knowledge  of  the  biology  of  these  neoplasms.  However,  following  first  line  therapy  with 
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 somatostatin  analogues,  there  is  no  clear  information  to  date  indicating  a  preferred  treatment  sequence,  and 
 therefore,  the  treatment  approach  should  be  individualised  based  on  the  characteristics  of  each  NET  patient. 
 In  conclusion,  there  is  a  need  for  novel  therapies  and  immunotherapy  that  may  lead  to  more  effective 
 personalised interventions. 
 3. 
 T  RIAL  RATIONALE 
 Endocrine  tumours  from  different  origins  (thyroid,  lung,  pancreas  and  digestive  tract,  adrenal  gland  and 
 paraganglia)  are  characterised  by  being  remarkably  vascular  and  expressing  several  growth  factors  including 
 vascular  endothelial  growth  factor  (VEGF),  platelet-derived  growth  factor  (PDGF),  insulin-like  growth 
 factor  1  (IGF-1),  basic  fibroblast  growth  factor  (BFGF),  and  transforming  growth  factor  (TGF)-α  and  -β.  In 
 addition,  the  expression  of  several  receptors  of  these  growth  factors  and  ligands  has  been  described, 
 including  VEGF  receptors  (VEGFR)-2  and  -3,  IGF  receptors  (IGFR),  and  PDGF  receptors  (PDGFR).  The 
 (over)  expression  of  some  of  these  factors  has  been  linked  to  poor  prognosis  and  decreased  progression-free 
 survival  (PFS),  as  well  as  to  tumour  growth,  aggressiveness,  and  disease  extent  in  patients  with  endocrine 
 tumours.  Several  targeted  agents  have  been  studied  in  the  treatment  of  advanced  endocrine  tumours  including 
 antiangiogenic  compounds  (such  as  bevacizumab),  inhibitors  of  multiple  receptors  with  kinase  activity  (such 
 as  cabozantinib,  sunitinib,  sorafenib,  lenvatinib,  and  vandetanib),  and  inhibitors  of  intracellular  downstream 
 effector  proteins  such  as  the  mammalian  target  of  rapamycin  (MTOR)  (e.g,  everolimus).  The  overexpression 
 of  c-MET  pathway  has  been  described  as  one  of  the  most  important  mechanism  of  resistance  to 
 antiangiogenic therapies in many cancer types including endocrine tumours. 
 It  has  been  tested  in  several  endocrine  tumour  types  with  promising  results  (62,63)  and  is  currently  on  phase 
 III  for  differentiated  thyroid  cancer  and  neuroendocrine  tumours  of  the  digestive  system  (NCT03690388, 
 NCT03375320). 
 The  activity  of  immune  checkpoint  inhibitors  in  endocrine  cancers  has  been  limited  by  their  tumour  biology, 
 mostly  low  grade  with  low  tumour  mutational  burden  and  low  percentage  of  alterations  in  DNA  repair  genes. 
 However,  activity  in  high  grade  tumours  such  as  MSI  adrenocortical  carcinomas  or  anaplastic  thyroid 
 cancers  has  been  described  with  promising  results.  In  addition  to  that,  there  is  robust  evidence  supporting  the 
 existence  of  cumulative  mutations  that  are  leading  to  more  aggressive  behaviour  of  endocrine  tumours  as 
 these tumours are becoming refractory to subsequent systemic treatments. 
 The rationale for the combination of cabozantinib and atezolizumab in endocrine tumours are as follows: 
 1.  Cabozantinib  has  shown  promising  activity,  in  several  endocrine  tumour  types,  including  thyroid 
 cancer,  neuroendocrine  tumours,  as  well  as  pheochromocytoma  and  paragangliomas  (62-64). 
 Cabozantinib  increased  PFS  on  progressive  medullary  thyroid  cancer  and  refractory  differentiated 
 thyroid  cancer  patients  with  a  manageable  toxicity  profile  (62-63).  Preliminary  results  in  10 
 pheochromocytoma patients showed an ORR of 40% and a clinical benefit rate of 90% (64). 
 2.  The  efficacy  of  anti-PD-1/PD-L1  treatments  (as  atezolizumab)  in  monotherapy  seems  to  be  limited 
 to  high  grade  tumours  such  as  anaplastic  thyroid  cancers  and  MSI  adrenocortical  carcinomas. 
 However,  in  most  well-differentiated  endocrine  neoplasms,  including  thyroid  and  neuroendocrine 
 tumours,  the  immune  system  plays  a  crucial  role  in  the  control  of  tumour  growth  without  systemic 
 therapies  which  allows  the  inclusion  of  active  surveillance  strategies  in  all  treatment  guidelines. 
 Recent  data  showed  potential  higher  activity,  measured  by  ORR,  of  anti-PD1  monotherapy  in 
 well-differentiated  neuroendocrine  tumours  of  the  lung  than  in  gastroenteropancreatic  origins 
 (NTC03167853)(65). 
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 3.  The  combination  of  cabozantinib  and  atezolizumab  may  be  active  in  endocrine  tumours  by 
 overcoming  the  resistance  to  prior  antiangiogenic  drugs  and  sensitising  the  tumours  to 
 immunotherapy through the combination of multikinase inhibitors and anti-PD-L1 therapy (66-67). 
 4. 
 3.1. 
 R  ATIONALE  FOR  DOSE 
 Results  from  the  phase  1b  COSMIC-021  study  of  cabozantinib  in  combination  with  atezolizumab  in  patients 
 with  previously  untreated  advanced  renal  cell  carcinoma  (RCC)  were  presented  at  the  European  Society  for 
 Medical  Oncology  (ESMO)  2018  Congress  in  Munich  (68).  This  dose-escalation  study  primarily  looked  at 
 the  safety  of  cabozantinib  +  atezolizumab  combination  in  untreated  advanced  RCC  patients  to  determine  the 
 best  dose  to  use  in  future  clinical  trials.  The  combination  showed  encouraging  clinical  activity  in  this  group 
 of  patients,  and  the  best  dose  of  cabozantinib  was  found  to  be  40  mg  in  combination  with  the  standard  dose 
 of  atezolizumab  (1200  mg/every  3  weeks)  (68).  Dosing  selected  for  this  trial  is  based  in  the  aforementioned 
 study. 
 4. 
 H  YPOTHESIS  AND  O  BJECTIVES 
 4.1. 
 S  TUDY  H  YPOTHESIS 
 The  main  hypothesis  is  that  the  administration  of  cabozantinib  plus  atezolizumab  will  improve  the 
 probability  of  expected  objective  response  rate  in  advanced  and  refractory  tumours  of  the  endocrine  system. 
 This study will be considered positive if the main hypothesis is achieved in at least one cohort of patients. 
 4.2. 
 S  TUDY  O  BJECTIVES 
 Primary objective: 
 ●  To assess the efficacy of cabozantinib plus atezolizumab by means of radiological objective response 
 rate (ORR) as per RECIST V1.1, in advanced endocrine tumours. 
 Secondary objectives: 
 ●  To evaluate the safety profile of cabozantinib and atezolizumab combination, according to 
 NCI-CTCAE V5.0. 
 ●  Duration of response (DoR) as per RECIST V1.1. 
 ●  Progression-free survival (PFS): median PFS as per RECIST V1.1. 
 ●  Overall Survival (OS): median OS as per RECIST V1.1. 
 ●  Tumour biomarkers: translational substudy (optional). 
 ●  Quality of Life (QoL). 
 Study endpoints for these objectives are described in section 10.2 of this protocol. 
 5. 
 S  TUDY  D  ESIGN 
 5.1. 
 O  VERALL  S  TUDY  D  ESIGN 
 This  is  an  open  labelled,  single  arm,  multicohort  phase  II  multicentre  clinical  trial  of  cabozantinib  plus 
 atezolizumab in advanced and refractory tumours from the endocrine system. 
 The  dose  scheme  includes  the  initial  dose  of  cabozantinib  40  mg  qd  +  atezolizumab  (1200  mg)  intravenously 
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 administered  every  21  days  (one  cycle).  Dose  adjustment  of  cabozantinib  is  allowed  as  per  the  PI  criteria  but 
 dose  reductions  of  atezolizumab  are  not  expected.  Additional  information  on  the  treatment,  modifications, 
 and dose delays is available in section 7 of this protocol. 
 The  CABATEN  trial  will  include  patients  with  advanced  and  refractory  tumours  of  endocrine  system 
 (additional  details  on  the  eligibility  criteria  of  the  study  are  found  in  section  6  of  this  protocol)  and  patients 
 would be allocated to six different cohorts according to the following tumour types: 
 ●  Cohort  1:  Well-differentiated  neuroendocrine  tumours  of  the  lung  and  thymus  (WHO  grades  1  and  2, 
 typical  and  atypical  carcinoids)  after  progression  to  somatostatin  analogs,  targeted  agents,  PRRT, 
 and/or chemotherapy. 
 ●  Cohort  2:  Anaplastic  thyroid  cancer  in  first-line  or  after  progression  to  chemotherapy  or 
 investigational drugs. 
 ●  Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane. 
 ●  Cohort  4:  Pheochromocytoma  and  paraganglioma  after  progression  to  peptide  receptor  radionuclide 
 therapy  (PRRT)  if  indicated,  prior  chemotherapy  and  biological  therapy,  such  as  somatostatin 
 analogs, are allowed. 
 ●  Cohort  5:  Well-differentiated  neuroendocrine  tumours  of  digestive  system  (WHO  grades  1  and  2) 
 after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy. 
 ●  Cohort  6:  Grade  3  neuroendocrine  neoplasm  (WHO  grade  3,  including  NET  and  NEC  G3)  of  any 
 origin, excluding small cell lung cancer, after progression to chemotherapy or targeted agents/PRRT. 
 The  design  includes  screening  phase,  treatment  phase  (including  medical  consultation  and  drug 
 administration  Q3w  ±  3  days),  disease  progression  follow  up  by  RECIST  1.1  every  12  weeks  ±  2w  (disease 
 progression  assessments  may  be  performed  every  Q8w  ±  2w  if  required  by  local  standard  clinical  practice  or 
 by  investigator  criteria,  as  long  as  the  frequency  of  the  assessments  is  maintained),  translational  research 
 with biopsies and blood samples and long term follow-up. 
 Study  treatment  will  begin  as  soon  as  possible  after  signing  the  informed  consent  (as  per  section  5.2  of  this 
 protocol) and inclusion will be completed as per section 5.3 of this protocol. 
 The  first  administration  of  cabozantinib  will  be  carried  out  after  the  infusion  of  the  first  atezolizumab  cycle, 
 the  patient  will  take  the  treatment  in  the  presence  of  a  member  of  the  Site  staff  who  will  advise  the  patient  on 
 the  correct  intake  of  the  treatment  (according  to  the  indications  of  the  section  7.1  of  this  protocol),  discuss 
 with  the  patient  the  process  of  completing  the  patient  diary,  and  address  the  doubts  that  the  patient  may  have 
 at  the  time.  In  addition,  patient  must  bring  all  medication  bottle(s)  (including  empty  ones)  to  each  visit  ,  for 
 IMP adherence and compliance traceability purposes. 
 After  the  first  supervised  administration,  cabozantinib  will  be  self-administered  by  patients  daily  according 
 to  the  indications  of  the  Investigator  staff  and  as  indicated  in  section  7  of  this  protocol.  Treatment  with 
 cabozantinib  will  be  continuous  until  the  progression  of  the  disease  and/or  unacceptable  toxicity,  among 
 others.  Patients  will  attend  follow-up  visits  with  the  study  doctor  every  3  weeks  for  clinical  assessment, 
 laboratory  tests,  laboratory  determinations  should  be  made  within  72  hours  prior  to  the  date  of  administration 
 of  atezolizumab,  in  order  to  assess  the  relevance  of  administration  of  a  new  cycle  (modifications,  delays, 
 etc.),  according  to  what  is  specified  in  sections  7.1.2  and  7.2.2.  Additionally,  the  study  doctor  may  request 
 patients  to  come  to  the  centre  more  frequently  in  case  of  toxicity  or  discomfort  of  the  patient.  Additional 
 information about the study's determinations is found in section 8 of this protocol. 
 Treatment  and  study  determinations  will  be  the  same  for  all  the  patients,  regardless  of  the  cohort  in  which  the 
 patients are included. 
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 This  is  a  study  with  Simon's  two-stage  design;  it  requires  that  an  event  is  observed  in  the  first  nine  patients 
 before  continuing  to  the  second  stage  where  there  is  a  possible  inclusion  of  15  additional  patients  (up  to  a 
 maximum of 24 patients per cohort). 
 In  addition,  an  optional  biomarker  study  with  tumour  and  blood  samples  will  be  performed  (if  it  is  feasible 
 for the Sponsor), and it is detailed in the corresponding biological samples manual. 
 5.2. 
 P  ATIENT  S  CREENING 
 Once  all  regulatory  and  sponsor  requirements  are  completed  confirming  that  the  study  is  fully  active  in  the 
 corresponding site, ICFs can be offered to potential patients. 
 Screening  slots  will  be  assigned  centrally  by  MFAR  Clinical  Research,  and  it  is  important  to  confirm  slot 
 availability  before  giving  an  ICF  to  any  patient.  Informed  consent  will  be  obtained  prior  to  the  start  of  the 
 specified  screening  window.  Procedures  conducted  as  part  of  the  subject’s  routine  clinical  management  (e.g., 
 blood  count  determinations  and  imaging  studies  such  as  bone  scans)  prior  to  signing  of  ICF  may  be  used  for 
 screening  or  for  defining  baseline  data,  provided  these  procedures  are  conducted  as  specified  in  the  protocol. 
 Once  ICFs  are  signed,  a  trial  screening  number  will  be  assigned  to  each  patient  after  registering  at  Electronic 
 Data  Capture  (EDC)  platform.  Each  site  will  receive  access  to  the  EDC  platform  to  register  each  screened 
 case because as per GCP guidelines, it is mandatory to register every patient who signs a consent form. 
 Furthermore,  within  the  Investigator  Site  File  (ISF),  a  Patient  Identification  List  will  be  included  in  order  to 
 identify  patients  according  to  local  normal  practice.  This  document  will  allow  for  immediate  and 
 unequivocal  identification  of  patients  participating  in  this  clinical  trial.  This  document  will  always  be  stored 
 under  Investigator  staff  custody  at  the  site.  The  screening  number  will  identify  patients  throughout  the 
 screening  period  while  the  procedures  that  are  needed  to  confirm  patients’  suitability  for  the  trial  protocol, 
 such as clinical laboratory tests, imaging, and others are performed. 
 Screening  determinations  include  ICF  signature,  eligibility  assessments,  tumour  characteristics,  ECG, 
 clinical  evaluation  (AE,  PE,  ECOG,  VS,  BMI,  and  symptom  control),  laboratory  determinations  [FBE, 
 Biochemistry,  liver  panel  test  function,  pancreatic  enzymes,  serology,  urinalysis,  pregnancy  test,  concomitant 
 medication,  biological  samples  (optional  tumour  sample  and  blood  samples  for  biomarkers)],  and  CT  Scan  / 
 MRI. Additional information about screening procedures can be found in section 8 of this protocol. 
 5.3. 
 P  ATIENT  I  NCLUSION  AND  C  OHORT  A  SSIGNMENT 
 After  confirming  that  a  patient  fulfils  all  the  eligibility  criteria  of  the  study  (section  6  “Eligibility  Criteria), 
 site  staff  will  initiate  the  electronic  case  report  form  (eCRF)  registration  procedure.  Once  registration  has 
 been  completed,  the  site  staff  will  receive  the  “Inclusion  confirmation  communication”,  and  study  treatment 
 can be initiated as per section 7. 
 5.4. 
 P  ATIENT  T  REATMENT 
 All  the  subjects  will  be  treated  with  the  combination  until  disease  progression,  unacceptable  toxicity,  or 
 patient consent withdrawal (whichever occurs first) according to section 7 of this protocol. 
 ●  Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously. 
 ●  Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle). 
 5.5. 
 P  ATIENT  F  OLLOW  UP  A  FTER  T  REATMENT 
 5.5.1.  End of treatment without progression 
 Patients  ending  treatment  without  progression  should  remain  in  the  study,  and  should  be  followed  up 
 according  to  RECIST  1.1  every  12  weeks  (±  2w)  until  progression  or  death.  Follow  up  assessments  may  be 
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 performed  q8w  ±  2w  if  required  by  local  standard  clinical  practice  or  by  investigator  criteria,  as  long  as  the 
 frequency of assessments is maintained. Please see section 8.1 of this protocol. 
 5.5.2.  End of treatment due to progression 
 Information  on  subsequent  treatments  should  include  the  list  of  post-treatment  therapies,  administered  drugs, 
 the  date  of  initiation  and  discontinuation  of  each  drug,  and  the  date  of  subsequent  progression.  All  data  will 
 be recorded in the medical record and in the eCRF as per section 8.1 of this protocol. 
 5.6. 
 T  RANSLATIONAL  R  ESEARCH 
 ●  Optional  substudy  involving  tissue  biopsies  will  be  performed  with  samples  obtained  before 
 treatment, for identification of predictive biomarkers. 
 ●  Blood  samples:  Analysis  of  somatic  alterations  in  tumours  including  proteomics,  transcriptomics, 
 and  metabolics  i.e.  metabolic  pathways  of  insulin  growth  factor,  among  others.  No  germinal  line 
 determinations  will  be  performed.  The  levels  of  IGF-1  in  serum  (others  biomarkers  may  be  analysed) 
 will  be  measured  using  the  blood  samples  collected  from  the  patients  at  the  different  time-points, 
 according  to  table  2  “Schedule  of  assessments”.  The  evolution  of  biomarkers  will  be  evaluated 
 individually and for the different groups of patients. 
 Information  regarding  biological  samples  collection,  management,  and  shipments  are  provided  in  the 
 biological sample manual. 
 5.7. 
 S  TUDY  C  ALENDAR 
 Date first patient enrolled:  08/10/2020 
 Estimated date last patient enrolled:  3Q 2022 
 Estimated date last patient completed:  3Q 2023 
 Estimated End of Study:  1Q 2024 
 6. 
 E  LIGIBILITY  C  RITERIA 
 6.1. 
 I  NCLUSION  C  RITERIA 
 Patients eligible for inclusion in this study must meet all the following criteria: 
 1.  Male or female subjects ≥ 18 years old. 
 2.  Willingness  to  participate  in  the  study  by  signing  ICF  approved  by  the  trial  Central  Ethic  Committee 
 (CEIm). 
 3.  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 4.  Measurable disease per RECIST 1.1 as determined by the investigator. 
 5.  Patients  with  advanced  and  progressive  neuroendocrine  tumors  histopathologically  confirmed  (as  per 
 local pathology report), meeting one of the following (according to WHO 2010 classification): 
 a.  Cohort  1:  Well-differentiated  neuroendocrine  tumours  of  the  lung  and  thymus  (WHO  grade  1 
 and  2,  typical  and  atypical  carcinoids)  after  progression  to  somatostatin  analogs,  targeted 
 agents, PRRT, and/or chemotherapy. 
 b.  Cohort  2:  Advanced  anaplastic  thyroid  cancer  in  first-line  or  after  progression  to 
 chemotherapy  or  investigational  drugs,  that  underwent  prior  primary  tumor  surgical 
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 resection  or  not.  In  patients  that  primary  tumor  has  not  been  resected,  the  risk  of 
 aerodigestive  compression  or  bleeding  should  be  ruled  out  to  ensure  no  interference  with  the 
 administration  of  the  investigational  product  and  undesirable  potential  side  effects  related  to 
 the route of administration. 
 c.  Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane. 
 d.  Cohort  4:  Pheochromocytoma  and  paraganglioma  after  progression  to  peptide  receptor 
 radionuclide  therapy  (PRRT)  if  indicated.  Prior  chemotherapy  and  biological  therapy,  such 
 as somatostatin analogs, are allowed. 
 e.  Cohort  5:  Well-differentiated  neuroendocrine  tumours  of  digestive  system  (WHO  grade  1 
 and  2)  after  progression  to  somatostatin  analogs,  targeted  agents,  PRRT,  and/or 
 chemotherapy. 
 f. 
 Cohort  6:  Grade  3  neuroendocrine  neoplasm  (WHO  grade  3,  including  NET  and  NEC  G3)  of 
 any  origin,  excluding  small  cell  lung  cancer,  after  progression  to  chemotherapy  or  targeted 
 agents/PRRT. 
 Note :  Patients  will  be  eligible  for  inclusion  after  progression  to  one  of  the  lines 
 aforementioned, without limit in the number of treatment lines. 
 6.  Recovery  from  toxicity  related  to  any  prior  treatments  to  ≤  Grade  1,  unless  the  AE(s)  are  clinically 
 non-significant and/or stable on supportive therapy. 
 7.  Ability to swallow tablets. 
 8.  Adequate normal organ and marrow function as defined below: 
 a.  Haemoglobin ≥ 9.0 g/dL. 
 b.  Absolute neutrophil count (ANC)  >  1500 per mm  3  . 
 c.  Platelet count ≥ 100,000 per mm  3  . 
 d.  Serum  bilirubin  ≤  1.5X  institutional  upper  limit  of  normal  (ULN)  unless  liver  metastases  are 
 present,  in  which  case  it  must  be  ≤  2X  ULN.  This  will  not  apply  to  patients  with  confirmed 
 Gilbert’s  syndrome  (persistent  or  recurrent  hyperbilirubinemia  that  is  predominantly 
 unconjugated  in  the  absence  of  haemolysis  or  hepatic  pathology);  however,  they  will  be 
 allowed only in consultation with their physician. 
 e.  AST  (SGOT)/ALT  (SGPT)  ≤  2.5X  institutional  upper  limit  of  normal  unless  liver  metastases 
 are present, in which case it must be ≤ 3X ULN. 
 f. 
 Measured  creatinine  clearance  (CL)  >  40  mL/min  or  Calculated  creatinine  CL  >  40  mL/min 
 by  the  Cockcroft-Gault  formula  (Cockcroft  and  Gault  1976)  or  by  24-hour  urine  collection 
 for the determination of creatinine clearance: 
 Males: 
 Creatinine CL (mL/min)      = 
 Weight (kg) × (140 – Age) 
 72 x serum creatinine (mg/dL) 
 Females: 
 Creatinine CL (mL/min)     = 
 Weight (kg) × (140 – Age)  ×0.85 
 72 x serum creatinine (mg/dL) 
 9.  Female  subjects  of  childbearing  potential  (not  surgically  sterile  or  at  least  2  years  postmenopausal) 
 must  provide  a  negative  urine  pregnancy  test  at  Screening,  and  use  a  medically  accepted  double 
 barrier  method  of  contraception  from  their  inclusion  in  the  study  and  until  5  months  after  the  last 
 dose  of  study  treatment  (i.e  condom  with  spermicide  +  IUD  or  cervical  caps).  (see  section  9.6.1  of 
 this protocol) . 
 10.  Males  should  agree  to  abstain  from  sexual  intercourse  with  a  female  partner  or  agree  to  use  double 
 barrier  method  of  contraception  (i.e.  a  condom  with  spermicide,  in  addition  to  having  their  female 
 partner  use  some  contraceptive  measures  such  as  intrauterine  device,  or  cervical  caps),  for  the 
 duration  of  the  study  and  for  4  months  after  participation  in  the  study  (see  section  7.4.1  of  this 
 protocol). 
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 11.  Willingness  and  ability  of  patients  to  comply  with  the  protocol  for  the  duration  of  the  study  including 
 undergoing  treatment  as  well  as  availability  for  scheduled  visits  and  examinations  including  follow 
 up. 
 6.2. 
 E  XCLUSION  C  RITERIA 
 Patients that meet any of the following criteria will be excluded from the study: 
 1.  Prior  treatment  with  cabozantinib  or  any  immune  checkpoint  inhibitor  therapy  (e.g,  CTLA4,  PD-1, 
 or PD-L1 targeting agent). 
 2.  Receipt  of  any  type  of  small  molecule  kinase  inhibitor  (including  investigational  kinase  inhibitor) 
 within  2  weeks  or  5  half-lives  of  the  agent,  whichever  is  longer.  Patients  should  have  been  out  of 
 mitotane for at least 4 weeks. 
 3.  Receipt  of  any  type  of  anticancer  antibody  (including  investigational  antibody)  or  systemic 
 chemotherapy within 2 weeks before starting treatment. 
 4.  Current  or  prior  use  of  immunosuppressive  medication  within  2  weeks  before  the  first  dose  of 
 cabozantinib  and  atezolizumab,  with  the  exceptions  of  intranasal  and  inhaled  corticosteroids  or 
 systemic  corticosteroids  at  physiological  doses,  which  are  not  to  exceed  10  mg/day  of  prednisone,  or 
 an equivalent corticosteroid. 
 5.  Active or prior documented autoimmune disease within the past 2 years 
 N ote:  Subjects  with  vitiligo,  Grave's  disease,  or  psoriasis  not  requiring  systemic  treatment  (within  the 
 past 2 years) are not excluded. 
 6.  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis). 
 7.  History of allogeneic organ transplant. 
 8.  Subjects  having  a  diagnosis  of  immunodeficiency  or  receiving  systemic  steroid  therapy  or  any  other 
 form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment. 
 9.  Receipt  of  radiation  therapy  for  bone  metastasis  within  2  weeks  or  any  other  radiation  therapy  within 
 4  weeks  before  inclusion.  Subjects  with  clinically  relevant  ongoing  complications  from  prior 
 radiation  therapy  that  have  not  completely  resolved  are  not  eligible  (e.g,  radiation  esophagitis  or 
 other inflammation of the viscera). 
 10.  Known  brain  metastases  or  cranial  epidural  disease  unless  adequately  treated  with  radiotherapy 
 and/or  surgery  (including  radiosurgery)  and  stable  for  at  least  4  weeks  before  inclusion.  Eligible 
 subjects  must  be  neurologically  asymptomatic  and  without  corticosteroid  treatment  at  the  time  of 
 study treatment. 
 11.  Concomitant  anticoagulation  with  oral  anticoagulants  (e.g,  warfarin,  direct  thrombin  and  factor  Xa 
 inhibitors) or platelet inhibitors (e.g, clopidogrel), except for the following allowed anticoagulants: 
 ●  Low-dose  aspirin  for  cardioprotection  (per  local  applicable  guidelines)  and  low-dose  low 
 molecular weight heparins (LMWH). 
 ●  Anticoagulation  with  therapeutic  doses  of  LMWH  in  subjects  without  known  brain 
 metastases  and  who  are  on  a  stable  dose  of  LMWH  for  at  least  6  weeks  before  inclusion  and 
 who  have  had  no  clinically  significant  hemorrhagic  complications  from  the  anticoagulation 
 regimen or the tumour. 
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 12.  The  subject  has  uncontrolled,  significant  intercurrent  or  recent  illness  including,  but  not  limited  to, 
 the following conditions: 
 a.  Cardiovascular disorders: 
 i. 
 Class  3  or  4  congestive  heart  failure  as  defined  by  the  New  York  Heart  Association, 
 unstable angina pectoris, and serious cardiac arrhythmias 
 ii. 
 Uncontrolled  hypertension  defined  as  sustained  blood  press  >  150  mm  hg  systolic  or 
 > 100 mm hg diastolic despite optimal antihypertensive treatment 
 iii. 
 Stroke  (including  transient  ischemic  attack  [TIA]),  myocardial  infarction,  other 
 ischemic  event,  or  thromboembolic  event  (e.g,  deep  venous  thrombosis  [DVT]  and 
 pulmonary  embolism)  within  6  months  before  inclusion.  Subjects  with  a  more  recent 
 diagnosis  of  DVT  are  allowed  if  stable,  asymptomatic,  and  treated  with  LMWH  for 
 at least 6 weeks before study treatment 
 b.  Gastrointestinal  disorders  (e.g,  malabsorption  syndrome  or  gastric  outlet  obstruction) 
 including those associated with a high risk of perforation or fistula formulation: 
 i. 
 Tumours  invading  the  GI  tract,  active  peptic  ulcer  disease,  inflammatory  bowel 
 disease,  ulcerative  colitis,  diverticulitis,  cholecystitis,  symptomatic  cholangitis  or 
 appendicitis,  acute  pancreatitis  or  acute  obstruction  of  the  pancreatic  or  biliary  duct, 
 or gastric outlet obstruction 
 ii. 
 Abdominal  fistula,  GI  perforation,  bowel  obstruction,  or  intra-abdominal  abscess 
 within  6  months  before  inclusion.  Note:  complete  healing  of  an  intra-abdominal 
 abscess must be confirmed prior to start of the treatment 
 c.  Clinically  significant  hematemesis  or  hemoptysis  of  >  0.5  teaspoon  (>  2.5  ml)  of  red  blood 
 or history of other significant bleeding within 3 months before treatment 
 d.  Cavitating pulmonary lesion(s) or known endobronchial disease manifestation 
 e.  Lesions invading major pulmonary blood vessels 
 f. 
 Other clinically significant disorders such as: 
 i. 
 Active 
 infection 
 requiring 
 systemic 
 treatment, 
 infection 
 with 
 human 
 immunodeficiency  virus  or  acquired  immunodeficiency  syndrome-related  illness,  or 
 chronic hepatitis B or C infection 
 ii. 
 Serious non-healing wound/ulcer/bone fracture 
 iii. 
 Malabsorption syndrome 
 iv. 
 Moderate to severe hepatic impairment (child-pugh B or C) 
 v. 
 Requirement for hemodialysis or peritoneal dialysis 
 vi. 
 Uncontrolled diabetes mellitus 
 vii. 
 History of solid organ transplantation 
 13.  Major  surgery  (e.g,  GI  surgery  and  removal  or  biopsy  of  brain  metastasis)  within  8  weeks  before 
 inclusion.  Complete  wound  healing  from  major  surgery  must  have  occurred  4  weeks  before  study 
 treatment  and  from  minor  surgery  (e.g,  simple  excision,  tooth  extraction)  at  least  10  days  before 
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 study  treatment.  Subjects  with  clinically  relevant  ongoing  complications  from  prior  surgery  are  not 
 eligible. 
 14.  Corrected  QT  interval  calculated  by  the  Fridericia  formula  (QTcf)  >  500  ms  within  28  days  before 
 study treatment 
 Note :  if  a  single  ECG  shows  a  QTCf  with  an  absolute  value  >  500  ms,  two  additional  EGGs  at 
 intervals  of  approximately  3  min  must  be  performed  within  30  min  after  the  initial  ECG,  and  the 
 average of these 3 consecutive results for qtcf will be used to determine eligibility. 
 15.  Pregnant or lactating females. 
 16.  Inability to swallow tablets. 
 17.  Previously identified allergy or hypersensitivity to components of the study treatment formulations 
 18.  Diagnosis  of  another  malignancy  within  3  years  before  study  treatment,  except  for  superficial  skin 
 cancers, or localised, low grade tumours deemed cured and not treated with systemic therapy. 
 6.3. 
 P  ATIENT  W  ITHDRAWAL  F  ROM  THE  T  RIAL 
 Patient  is,  at  any  time,  free  to  withdraw  from  study  (investigational  product  and  study  assessments),  without 
 prejudice to further treatment (withdrawal of consent). 
 Subjects  that  choose  to  withdraw  early  from  the  study  will  be  voluntarily  surveyed  for  reasons  for 
 withdrawal,  including  information  of  possible  presence  of  any  adverse  events.  If  possible,  he/she  will  be  seen 
 and assessed by an investigator. 
 Adverse  events  will  be  followed  up  and  all  study  material  (if  any)  should  be  returned  by  the  patient.  The 
 investigator  may  also,  at  his/her  discretion,  withdraw  the  subject  from  participating  in  this  study  at  any  time, 
 or the sponsor may discontinue the study. Withdrawn patients will not be replaced. 
 If patient withdraws consent, he/she will be specifically asked if he/she is withdrawing consent to: 
 ●  To further participation in the study including any further follow up (e.g., survival calls). 
 ●  The use of her data generated from the study. 
 ●  The use of any samples. 
 Reasons for early withdrawal from the study should be documented in the eCRF and patient's records as: 
 ○  Study closed/terminated. 
 ○  Subject lost to follow-up. 
 ○  Investigator’s decision. 
 ○  Subject withdrew consent. 
 ○  Participation in another clinical trial. 
 ○  Major protocol violations that invalidates patient’s data. 
 ○  Death. 
 Date  of  withdrawal  from  the  study,  with  reason  for  withdrawal,  will  be  recorded  on  the  eCRF  and  patient's 
 records.  In  the  case  of  death,  a  death  certificate  should  be  obtained  if  possible,  with  the  cause  of  death 
 evaluated and documented. 
 6.4. 
 P  REMATURE  T  ERMINATION  OF  THE  T  RIAL 
 The  clinical  trial  may  be  terminated  prematurely  or  suspended  at  the  request  of  Health  Authorities  or  if  new 
 safety  or  efficacy  information  leads  to  an  unfavourable  risk  benefit  judgment  for  any  IMP.  The  Sponsor  may 
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 discontinue  the  trial  if  it  becomes  unjustifiable  for  medical  or  ethical  reasons,  poor  enrolment,  or  the 
 discontinuation  of  clinical  development  of  the  IMP  or  withdrawal  of  the  IMP  from  the  market  for  safety 
 reasons. 
 Health  Authorities  and  Independent  Ethics  Committees  (IECs)/Institutional  Review  Boards  (IRBs)  will  be 
 informed about the discontinuation of the trial in accordance with applicable regulations. 
 6.5. 
 D  EFINITION  OF  E  ND  OF  T  RIAL 
 ‘Last  patient  last  visit’,  as  defined  in  this  protocol,  is  12  months  after  the  enrolment  of  last  patient.  Subjects 
 may  continue  to  receive  IMPs  after  the  cut-off  because  treatment  cannot  be  discontinued  for  ethical  reasons, 
 but  in  such  cases,  Sponsor  agrees  to  continue  with  cabozantinib  supply  to  sites  to  cover  patient  treatment 
 until  it's  finalisation  and  atezolizumab  for  a  maximum  of  6  months  after  the  end  of  the  study  (LPLV).  For 
 these  6  additional  months  (since  LPLV),  the  principal  investigators  must  inform  on  any  suspicion  on  adverse 
 events/special  situations  in  patients  receiving  atezolizumab’s,  to  the  marketing  authorisation  holder,  Roche’s 
 Pharmacovigilance  Department  ( madrid.drug_safety@roche.com ,  Tel.  +34  91.324.8183).  Those  events 
 reported  in  patients  receiving  cabozantinib  the  marketing  authorisation  holder:  Ipsen  Pharmacovigilance 
 Department ( pharmacovigilance.spain@ip sen.com), Tel.  +34 93.685.81.00. 
 7. 
 T  REATMENT  OF  S  UBJECTS 
 7.1. 
 C  ABOZANTINIB 
 7.1.1.  Cabozantinib presentation and administration 
 Pharmaceutical  form  and  route  of  administration:  Cabozantinib  is  formulated  as  two  distinct  drug 
 product  types  for  oral  administration:  capsules  and  tablets.  For  this  trial,  tablets  containing  cabozantinib  20 
 mg and 40 mg will be supplied. 
 Strength :  Tablet  strengths  are  20  and  40  mg  (FBE  weight).  They  are  formulated  from  a  wet  granulation 
 process  that  consists  of  mixing  cabozantinib  malate  salt  and  excipients  together;  the  granulation  is 
 subsequently  further  blended  and  then  compressed  into  tablets  and  film-coated.  Tablets  are  distinguished  by 
 shape. 
 Presentation:  Commercial  medication  labeled  for  clinical  trial,  containing  cabozantinib  20  mg  or  40  mg  in 
 HDPE  bottle  with  a  polypropylene  child-resistant  closure  and  three  silica  gel  desiccant  canisters.  Each  bottle 
 contains 30 film-coated tablets. 
 Administration instructions 
 Cabozantinib  tablets  are  meant  to  be  taken  orally  only  and  not  to  be  opened  or  crushed  for  dissolving  in 
 liquid  or  administered  through  other  routes  including  percutaneous  endoscopic  gastrostomy  (PEG)  tubes. 
 Cabozantinib  tablets  should  not  be  administered  to  subjects  who  do  not  have  adequate  swallowing  capacity. 
 Cabozantinib  is  meant  to  be  taken  without  food  (subjects  should  not  eat  for  at  least  2  h  before  and  at  least  1  h 
 after  taking  cabozantinib)  with  a  full  glass  (at  least  8  ounces  or  240  mL)  of  water.  If  a  dose  is  missed,  the 
 missed dose should not be taken less than 12 h before the next dose. 
 Important dosage information: 
 ●  Stop  treatment  with  cabozantinib  at  least  28  days  prior  to  scheduled  surgery,  including  dental 
 surgery. 
 ●  Do not substitute cabozantinib tablets with cabozantinib capsules. 
 ●  Do  not  administer  cabozantinib  with  food.  Administer  at  least  1  hour  before  or  at  least  2  hours  after 
 eating. 
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 ●  Patients should swallow cabozantinib tablets whole. Do not crush cabozantinib tablets. 
 ●  Patients do not take a missed dose within 12 hours of the next dose. 
 ●  Modify  the  dose  for  certain  patients  with  hepatic  impairment  and  for  patients  taking  drugs  known  to 
 strongly induce or inhibit CYP450. 
 7.1.2.  Dose modifications 
 The allowed dosing schemes of this trial are: 
 ●  Level 0 (starting dose): cabozantinib 40 mg qd + atezolizumab 1200 mg iv every 21 days (one cycle) 
 ●  Level -1: cabozantinib 20 mg qd + atezolizumab 1200 mg iv every 21 days (one cycle) 
 If  cabozantinib  is  temporarily  or  definitively  interrupted  for  its  toxicity,  atezolizumab  will  be  continued, 
 unless  the  toxicity  of  cabozantinib  prevents  the  administration  of  atezolizumab  or  increases  the  risk  of 
 atezolizumab  toxicity.  In  this  case,  both  treatments  will  be  interrupted  until  toxicity  resolution  (or  NCI 
 CTCAE grade 1) or definitively. 
 If  one  of  the  two  drugs  is  discontinued  or  interrupted  due  to  toxicity,  the  administration  of  the  other  drug 
 should continue according to the protocol schedule. 
 All  dose  reductions  and  interruptions  (including  any  missed  doses),  and  the  reasons  for  the 
 reductions/interruptions are to be recorded in the eCRF and patient record. 
 As  previously  mentioned,  cabozantinib  dose  reduction  to  20  mg  qd  is  allowed.  Once  reduced,  dose 
 re-escalation  of  cabozantinib  is  allowed  in  the  opinion  of  the  Principal  Investigator,  taking  into  account 
 clinical benefit, type and degree of toxicity that produced the dose reduction. 
 Cabozantinib should be withheld for: 
 ●  Intolerable Grade 2 adverse reactions 
 ●  Grade 3 or 4 adverse reactions 
 ●  Osteonecrosis of the jaw 
 Upon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse reaction, reduce 
 the dose as follows: 
 ●  If previously receiving 40 mg daily dose, resume treatment at 20 mg daily. 
 ●  If previously receiving 20 mg daily dose, resume at 20 mg if tolerated, otherwise, discontinue 
 cabozantinib. 
 Permanently discontinue cabozantinib for any of the following: 
 ●  Severe hemorrhage 
 ●  Development of gastrointestinal (GI) perforation or unmanageable fistula 
 ●  Serious thromboembolic event (e.g., myocardial infarction, cerebral infarction) 
 ●  Hypertensive crisis or severe hypertension despite optimal medical management 
 ●  Nephrotic syndrome 
 ●  Reversible posterior leukoencephalopathy syndrome 
 7.1.3.  Cabozantinib Special warnings and precautions for use 
 1)  Hepatic effects 
 Abnormalities  of  liver  function  tests  (increases  in  alanine  aminotransferase  [ALT],  aspartate 
 aminotransferase  [AST]  and  bilirubin)  have  been  frequently  observed  in  patients  treated  with  cabozantinib.  It 
 is  recommended  to  perform  liver  function  tests  (ALT,  AST  and  bilirubin)  before  initiation  of  cabozantinib 
 treatment  and  to  monitor  closely  during  treatment.  For  patients  with  worsening  of  liver  function  tests 
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 considered  related  to  cabozantinib  treatment  (i.e.  where  no  alternative  cause  is  evident),  the  dose 
 modification  advice  in  section  7.1.2).  Cabozantinib  is  eliminated  mainly  via  the  hepatic  route.  Closer 
 monitoring  of  the  overall  safety  is  recommended  in  patients  with  mild  or  moderate  hepatic  impairment  (see 
 also  section  7.1.2).  A  higher  relative  proportion  of  patients  with  moderate  hepatic  impairment  (Child-Pugh 
 B)  developed  6  hepatic  encephalopathy  with  cabozantinib  treatment.  Cabozantinib  is  not  recommended  for 
 use  in  patients  with  severe  hepatic  impairment  (Child-Pugh  C)  as  cabozantinib  has  not  been  studied  in  this 
 population and exposure might be increased in these patients. 
 2)  Hepatic encephalopathy 
 In  the  HCC  study  (CELESTIAL),  hepatic  encephalopathy  was  reported  more  frequently  in  the  cabozantinib 
 than  the  placebo  arm.  Cabozantinib  has  been  associated  with  diarrhoea,  vomiting,  decreased  appetite  and 
 electrolyte  abnormalities.  In  HCC  patients  with  compromised  livers,  these  non-hepatic  effects  may  be 
 precipitating  factors  for  the  development  of  hepatic  encephalopathy.  Patients  should  be  monitored  for  signs 
 and symptoms of hepatic encephalopathy. 
 3)  Perforations and Fistulas 
 Fistulas,  including  fatal  cases,  occurred  in  1%  of  cabozantinib-treated  patients.  Gastrointestinal  (GI) 
 perforations, including fatal cases, occurred in 1% of cabozantinib-treated patients. 
 Monitor  patients  for  signs  and  symptoms  of  fistulas  and  perforations,  including  abscess  and  sepsis. 
 Discontinue  cabozantinib  in  patients  who  experience  a  fistula  which  cannot  be  appropriately  managed  or  a 
 GI perforation. 
 4)  Gastrointestinal (GI) disorders 
 Diarrhoea,  nausea/vomiting,  decreased  appetite,  and  stomatitis/oral  pain  were  some  of  the  most  commonly 
 reported  GI  adverse  reactions.  Prompt  medical  management,  including  supportive  care  with  antiemetics, 
 antidiarrheals,  or  antacids,  should  be  instituted  to  prevent  dehydration,  electrolyte  imbalances  and  weight 
 loss.  Dose  interruption  or  reduction,  or  permanent  discontinuation  of  cabozantinib  should  be  considered  in 
 case of persistent or recurrent significant GI adverse reactions. 
 Diarrhea  occurred  in  63%  of  patients  treated  with  cabozantinib.  Grade  3  diarrhea  occurred  in  11%  of  patients 
 treated with cabozantinib. 
 Withhold  cabozantinib  until  improvement  to  Grade  1  and  resume  cabozantinib  at  a  reduced  dose  for 
 intolerable  Grade  2  diarrhea,  Grade  3  diarrhea  that  cannot  be  managed  with  standard  anti  diarrhea  treatments, 
 or Grade 4 diarrhea. 
 5)  Thrombotic Events 
 Cabozantinib  increased  the  risk  of  thrombotic  events.  Venous  thromboembolism  occurred  in  7%  (including 
 4%  pulmonary  embolism)  and  arterial  thromboembolism  occurred  in  2%  of  cabozantinib-treated  patients. 
 Fatal thrombotic events occurred in cabozantinib-treated patients. 
 Discontinue  cabozantinib  in  patients  who  develop  an  acute  myocardial  infarction  or  serious  arterial  or  venous 
 thromboembolic events that require medical intervention 
 6)  Hemorrhage 
 Severe  and  fatal  hemorrhages  occurred  with  cabozantinib.  The  incidence  of  Grade  3  to  5  hemorrhagic  events 
 was  5%  in  cabozantinib-treated  patients.  Discontinue  cabozantinib  for  Grade  3  or  4  hemorrhage.  Do  not 
 administer  cabozantinib  to  patients  who  have  a  recent  history  of  hemorrhage,  including  hemoptysis, 
 hematemesis, or melena. 
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 7)  Thrombocytopenia 
 In  the  HCC  study  (CELESTIAL),  thrombocytopenia  and  decreased  platelets  were  reported.  Platelet  levels 
 should  be  monitored  during  cabozantinib  treatment  and  the  dose  modified  according  to  the  severity  of  the 
 thrombocytopenia (see section 7.1.2). 
 8)  Wound Complications 
 Wound  complications  have  been  reported  with  cabozantinib.  Stop  cabozantinib  at  least  28  days  prior  to 
 scheduled  surgery.  Resume  cabozantinib  after  surgery  based  on  clinical  judgment  of  adequate  wound 
 healing.  Withhold  cabozantinib  in  patients  with  dehiscence  or  wound  healing  complications  requiring 
 medical intervention. 
 9)  Hypertension and Hypertensive Crisis 
 Cabozantinib  can  cause  hypertension,  including  hypertensive  crisis.  Hypertension  was  reported  in  36%  (17% 
 Grade 3 and <1% Grade 4) of cabozantinib treated patients. 
 Do  not  initiate  cabozantinib  in  patients  with  uncontrolled  hypertension.  Monitor  blood  pressure  regularly 
 during  cabozantinib  treatment.  Withhold  cabozantinib  for  hypertension  that  is  not  adequately  controlled  with 
 medical  management;  when  controlled,  resume  cabozantinib  at  a  reduced  dose.  Discontinue  cabozantinib  for 
 severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis. 
 10)  Palmar-Plantar Erythrodysesthesia 
 Palmar-plantar  erythrodysesthesia  (PPE)  occurred  in  44%  of  patients  treated  with  cabozantinib.  Grade  3  PPE 
 occurred in 13% of patients treated with cabozantinib. 
 Withhold  cabozantinib  until  improvement  to  Grade  1  and  resume  cabozantinib  at  a  reduced  dose  for 
 intolerable Grade 2 PPE or Grade 3 PPE. 
 11)  Proteinuria 
 Proteinuria  was  observed  in  7%  of  patients  receiving  cabozantinib.  Monitor  urine  protein  regularly  during 
 cabozantinib treatment. Discontinue cabozantinib in patients who develop nephrotic syndrome. 
 12)  Reversible Posterior Leukoencephalopathy Syndrome 
 Reversible  Posterior  Leukoencephalopathy  Syndrome  (RPLS),  a  syndrome  of  subcortical  vasogenic  edema 
 diagnosed  by  characteristic  finding  on  MRI,  can  occur  with  cabozantinib.  Perform  an  evaluation  for  RPLS  in 
 any  patient  presenting  with  seizures,  headache,  visual  disturbances,  confusion  or  altered  mental  function. 
 Discontinue cabozantinib in patients who develop RPLS. 
 13)  Prolongation of QT interval 
 Cabozantinib  should  be  used  with  caution  in  patients  with  a  history  of  QT  interval  prolongation,  patients  who 
 are  taking  antiarrhythmics,  or  patients  with  relevant  pre-existing  cardiac  disease,  bradycardia,  or  electrolyte 
 disturbances.  When  using  cabozantinib,  periodic  monitoring  with  ontreatment  ECGs  and  electrolytes  (serum 
 calcium, potassium, and magnesium) should be considered. 
 14)  Biochemical laboratory test abnormalities 
 Cabozantinib  has  been  associated  with  an  increased  incidence  of  electrolyte  abnormalities  (including  hypo- 
 and  hyperkalemia,  hypomagnesaemia,  hypocalcaemia,  hyponatremia).  It  is  recommended  to  monitor 
 biochemical  parameters  during  cabozantinib  treatment  and  to  institute  appropriate  replacement  therapy 
 according  to  standard  clinical  practice  if  required.  Cases  of  hepatic  encephalopathy  in  HCC  patients  can  be 
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 attributed  to  the  development  of  electrolyte  disturbances.  Dose  interruption  or  reduction,  or  permanent 
 discontinuation  of  cabozantinib  should  be  considered  in  case  of  persistent  or  recurrent  significant 
 abnormalities (see section 7.1.2). 
 15)  Osteonecrosis of the Jaw 
 Osteonecrosis  of  the  jaw  (ONJ)  occurred  in  <1%  of  patients  treated  with  cabozantinib.  ONJ  can  manifest  as 
 jaw  pain,  osteomyelitis,  osteitis,  bone  erosion,  tooth  or  periodontal  infection,  toothache,  gingival  ulceration 
 or  erosion,  persistent  jaw  pain  or  slow  healing  of  the  mouth  or  jaw  after  dental  surgery.  Perform  an  oral 
 examination  prior  to  initiation  of  cabozantinib  and  periodically  during  cabozantinib.  Advise  patients 
 regarding  good  oral  hygiene  practices.  Withhold  cabozantinib  for  at  least  28  days  prior  to  scheduled  dental 
 surgery  or  invasive  dental  procedures,  if  possible.  Withhold  cabozantinib  for  development  of  ONJ  until 
 complete resolution. 
 16)  Embryo-Fetal Toxicity 
 Based  on  data  from  animal  studies  and  its  mechanism  of  action,  cabozantinib  can  cause  fetal  harm  when 
 administered  to  a  pregnant  woman.  Cabozantinib  administration  to  pregnant  animals  during  organogenesis 
 resulted  in  embryolethality  at  exposures  below  those  occurring  clinically  at  the  recommended  dose,  and  in 
 increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. 
 Advise  pregnant  women  of  the  potential  risk  to  a  fetus.  Advise  females  of  reproductive  potential  to  use 
 effective contraception during treatment with cabozantinib and for 4 months after the last dose. 
 7.2. 
 A  TEZOLIZUMAB 
 7.2.1.  Atezolizumab presentation and administration 
 Pharmaceutical  form  and  route  of  administration:  Preservative-free  clear  liquid  solution  for  intravenous 
 administration. 
 Strength : 60 mg/mL glass vials of 20-mL, nominal atezolizumab  amount per vial, 1200 mg. 
 Presentation:  Glass vials of 20-mL, commercial medication  labeled for clinical trial. 
 Administration instructions: 
 Atezolizumab  is  for  intravenous  use.  The  infusions  must  not  be  administered  as  an  intravenous  push  or  bolus. 
 The  initial  dose  of  Atezolizumab  must  be  administered  over  60  minutes.  If  the  first  infusion  is  well  tolerated, 
 all subsequent infusions may be administered over 30 minutes. 
 Atezolizumab  will  be  administered  in  IV  infusion  bags  containing  0.9%  sodium  chloride  (NaCl)  and  infusion 
 lines  equipped  with  0.2  or  0.22  m  in-line  filters.  The  IV  bag  may  be  constructed  of  polyvinyl  chloride, 
 polyolefin,  polyethylene,  or  polypropylene,  the  IV  infusion  line  may  be  constructed  of  polyvinyl  chloride, 
 polyethylene,  polybutadiene,  or  polyurethane  and  the  0.2  or  0.22  m  in-line  filter  may  be  constructed  of 
 polyethersulfone  or  polysulfone.  The  use  of  administration  supplies  composed  of  materials  other  than  those 
 listed  should  be  avoided  if  possible.  Atezolizumab  can  be  diluted  to  concentrations  between  3.2  mg/mL  and 
 16.8 mg/mL in IV bags containing 0.9% NaCl. 
 Atezolizumab  must  be  prepared/diluted  under  appropriate  aseptic  conditions  as  it  does  not  contain 
 antimicrobial  preservatives.  The  prepared  solution  for  infusion  should  be  used  immediately  to  limit  microbial 
 growth  in  case  of  potential  accidental  contamination.  If  not  used  immediately,  in-use  storage  time  and 
 conditions  prior  to  use  are  the  responsibility  of  the  user.  For  flat  or  fixed  dosing  (1200  mg  for  this  clinical 
 trial)  in  IV  infusion  bags,  the  dose  solution  may  be  stored  at  2°C–8°C  (36°F  –  46°F)  for  24  hours  or  at 
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 ambient  temperature  ≤  25°C  (77°F)  for  8  hours.  This  time  includes  storage  and  time  for  administration  for 
 infusion. Do not shake or freeze infusion bags containing the dose solution. 
 7.2.2.  Atezolizumab dose modifications 
 There  will  be  no  dose  reduction  for  atezolizumab  in  this  study .  Patients  may  temporarily  suspend  study 
 treatment  if  they  experience  toxicity  that  is  considered  to  be  related  to  study  drug  and  requires  a  dose  to  be 
 held.  If  atezolizumab  is  held  because  of  related  adverse  events  for  42  days  beyond  when  the  dose  would  have 
 been  given,  then  the  patient  will  be  discontinued  from  atezolizumab  and  will  be  followed  for  safety  and 
 efficacy  as  specified  in  section  8.  Please  see  Section  7.2.3  for  guidelines  for  the  management  of  infusion 
 related reactions. 
 Dose interruption of atezolizumab 
 Any  toxicity  observed  during  the  study  treatment  phase  could  be  managed  by  interruption  of  the  dose  of  the 
 study  treatment  if  deemed  appropriate  by  the  Investigator.  Repeated  dose  interruptions  are  allowed  as 
 required,  for  a  maximum  of  42  days  on  each  occasion.  If  the  interruption  is  any  longer  than  this,  the 
 Coordinating  Investigator  must  be  informed  and  treatment  restart  should  be  discussed  between  the  Sponsor 
 study  team  and  the  investigator.  If  in  the  judgment  of  the  investigator,  the  patient  is  likely  to  derive  clinical 
 benefit  from  resuming  atezolizumab  after  a  hold  of  42  days,  the  treatment  may  be  restarted  with  the  approval 
 of the Coordinating Investigator. 
 If  patients  must  be  tapered  off  steroids  used  to  treat  adverse  events,  study  treatment  may  be  held  for  42  days. 
 The  acceptable  length  of  interruption  will  depend  on  agreement  between  the  investigator  and  the 
 Coordinating Investigator. 
 Study  treatment  must  be  interrupted  until  the  patient  recovers  completely  or  the  toxicity  reverts  to  the 
 National  Cancer  Institute  Common  Terminology  Criteria  for  Adverse  Events  (NCI  CTCAE  version  5.0) 
 grade 1 or less. 
 Treatment  with  atezolizumab  must  be  temporarily  or  permanently  interrupted  if  any  NCI  CTCAE  grade  3  or 
 4  adverse  event  occurs  which  the  Investigator  considers  to  be  related  to  the  administration  of  atezolizumab. 
 Dose  interruptions  for  reason(s)  other  than  toxicity,  such  as  surgical  procedures,  may  be  allowed.  The 
 acceptable  length  of  interruption  will  depend  on  agreement  between  the  investigator  and  the  Coordinating 
 Investigator. 
 If  atezolizumab  is  temporarily  or  definitively  interrupted  for  its  toxicity,  cabozantinib  will  be  continued, 
 unless  the  toxicity  of  atezolizumab  prevents  the  administration  of  cabozantinib  or  increase  the  risk  of 
 cabozantinib  toxicity.  In  this  case,  both  treatments  will  be  interrupted  until  toxicity  resolution  (or  NCI 
 CTCAE grade 1) or definitively. 
 If  one  of  the  two  drugs  is  discontinued  or  interrupted  due  to  toxicity,  the  administration  of  the  other  drug 
 should continue according to the protocol schedule. 
 All  dose  reductions  and  interruptions  (including  any  missed  doses),  and  the  reasons  for  the 
 reductions/interruptions  are  to  be  recorded  in  the  eCRF  and  patient  record.  An  occurrence  of  auto immune 
 disease  will  be  declared  in  this  study  as  a  serious  adverse  event  (SAE)  at  any  time  during  atezolizumab 
 treatment and at any time after the treatment has been stopped. 
 7.2.3.  Atezolizumab  Special warnings and precautions  for use 
 In  order  to  improve  the  traceability  of  biological  medicinal  products,  the  trade  name  and  the  batch  number  of 
 the administered product should be clearly recorded (or stated) in the patient file. 
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 Most  immune-mediated  adverse  reactions  that  occurs  during  treatment  with  atezolizumab  are  reversible  with 
 the  interruptions  of  atezolizumab  and  initiation  of  corticosteroids  and/or  supportive  care.  Immune-mediated 
 adverse  reactions  affecting  more  than  one  body  system  have  been  observed.  Immune-mediated  adverse 
 reactions with atezolizumab may occur after the last dose of atezolizumab. 
 For  suspected  immune-mediated  adverse  reactions,  thorough  evaluation  to  confirm  aetiology  or  exclude 
 other  causes  should  be  performed.  Based  on  the  severity  of  the  adverse  reaction,  atezolizumab  should  be 
 withheld  and  corticosteroids  administered.  Upon  improvement  to  Grade  ≤  1,  corticosteroid  should  be  tapered 
 over  ≥  1  month.  Based  on  limited  data  from  clinical  studies  in  patients  whose  immune-mediated  adverse 
 reactions  could  not  be  controlled  with  systemic  corticosteroid  use,  the  administration  of  other  systemic 
 immunosuppressants may be considered. 
 Atezolizumab  must  be  permanently  discontinued  for  any  Grade  3  immune-mediated  adverse  reaction  that 
 recurs  and  for  any  Grade  4  immune-mediated  adverse  reactions,  except  for  endocrinopathies  that  are 
 controlled with replacement hormones. 
 1) 
 Pulmonary events 
 Cases  of  pulmonary  events,  including  dyspnea,  cough,  fatigue,  pulmonary  infiltrates  and  pneumonitis,  have 
 been  observed  in  clinical  trials  with  atezolizumab.  Patients  should  be  monitored  for  pulmonary  signs  and 
 symptoms. 
 2) 
 Hepatic events 
 Immune-mediated  hepatitis  has  been  associated  with  the  administration  of  atezolizumab.  Patients  eligible  for 
 study  treatment  must  have  adequate  liver  function,  as  manifested  by  measurements  of  total  bilirubin  and 
 hepatic  transaminases;  liver  function  will  be  monitored  throughout  study  treatment.  Management  guidelines 
 for hepatic events are provided in Appendix 1. 
 3) 
 Gastrointestinal events 
 Immune-mediated  colitis  has  been  associated  with  the  administration  of  atezolizumab.  All  events  of  diarrhea 
 or  colitis  should  be  thoroughly  evaluated  for  other  common  etiologies.  For  events  of  significant  duration  or 
 or  magnitude  or  associated  with  signs  of  systemic  inflammation  or  acute-phase  reactants  (e.g.,  increased(e.g., 
 increased  C-reactive  protein,  platelet  count,  or  bandemia):  Perform  sigmoidoscopy  (or  colonoscopy,  if 
 appropriate)  with  colonic  biopsy,  with  three  to  five  specimens  for  standard  paraffin  block  to  check  for 
 inflammation  and  lymphocytic  infiltrates  to  confirm  colitis  diagnosis.  More  information  provided  in 
 Appendix 1. 
 4) 
 Endocrine events 
 Thyroid  disorders,  adrenal  insufficiency,  diabetes  mellitus,  and  pituitary  disorders  have  been  associated  with 
 the administration of atezolizumab. 
 Patients  with  unexplained  symptoms  such  as  headache,  fatigue,  myalgias,  impotence,  constipation,  or  mental 
 status  changes  should  be  investigated  for  the  presence  of  thyroid,  pituitary,  or  adrenal  endocrinopathies.  The 
 patient should be referred to an endocrinologist if an endocrinopathy is suspected. 
 Thyroid-stimulating  hormone  (TSH)  and  free  triiodothyronine  (T3)  and  thyroxine  (T4)  levels  should  be 
 measured  to  determine  whether  thyroid  abnormalities  are  present.  Pituitary  hormone  levels  and  function  tests 
 (e.g.,  TSH,  growth  hormone,  luteinizing  hormone,  follicle-stimulating  hormone,  testosterone,  prolactin, 
 adrenocorticotropic  hormone  [ACTH]  levels,  and  ACTH  stimulation  test)  and  magnetic  resonance  imaging 
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 (MRI)  of  the  brain  (with  detailed  pituitary  sections)  may  help  to  differentiate  primary  pituitary  insufficiency 
 from primary adrenal insufficiency. More information provided in Appendix 1. 
 5) 
 Ocular events 
 An  ophthalmologist  should  evaluate  visual  complaints  (e.g.,  uveitis,  retinal  events).  More  information 
 provided in Appendix 1. 
 6) 
 Immune-Mediated Myocarditis 
 Immune-mediated  myocarditis  has  been  associated  with  the  administration  of  atezolizumab  and  should  be 
 suspected  in  any  patient  presenting  with  signs  or  symptoms  suggestive  of  myocarditis,  including,  but  not 
 limited  to,  laboratory  (e.g.,  B-type  Natriuretic  Peptide])  or  cardiac  imaging  abnormalities,  dyspnea,  chest 
 pain,  palpitations,  fatigue,  decreased  exercise  tolerance,  or  syncope.  Myocarditis  may  also  be  a  clinical 
 manifestation of myositis and should be managed accordingly. 
 Immune-mediated  myocarditis  needs  to  be  distinguished  from  myocarditis  resulting  from  infection 
 (commonly  viral,  e.g..,  in  a  patient  who  reports  a  recent  history  of  gastrointestinal  illness),  ischemic  events, 
 underlying arrhythmias, exacerbation of pre-existing cardiac conditions, or progression of malignancy. 
 All  patients  with  possible  myocarditis  should  be  urgently  evaluated  by  performing  cardiac  enzyme 
 assessment,  an  ECG,  a  chest  X  Ray,  an  echocardiogram,  and  a  cardiac  MRI  as  appropriate  per  institutional 
 guidelines.  A  cardiologist  should  be  consulted.  An  endomyocardial  biopsy  may  be  considered  to  enable  a 
 definitive  diagnosis  and  appropriate  treatment,  if  clinically  indicated.  Patients  with  signs  and  symptoms  of 
 myocarditis,  in  the  absence  of  an  identified  alternate  etiology,  should  be  treated  according  to  the  guidelines  in 
 Appendix 1. 
 7) 
 Infusion-Related Reactions and Cytokine-Release Syndrome 
 No  premedication  is  indicated  for  the  administration  of  Cycle  1  of  atezolizumab.  However,  patients  who 
 experience  an  infusion-related  reaction  (IRR)  or  cytokine-release  syndrome  (CRS)  with  atezolizumab  may 
 receive  premedication  with  antihistamines,  antipyretics,  and/or  analgesics  (e.g.,  acetaminophen)  for 
 subsequent 
 infusions.  Metamizole  (dipyrone)  is  prohibited  in  treating  atezolizumab-associated 
 infusion-related reactions, due to IRRs because of its potential for causing agranulocytosis. 
 IRRs  are  known  to  occur  with  the  administration  of  monoclonal  antibodies  and  have  been  reported  with 
 atezolizumab.  These  reactions,  which  are  thought  to  be  due  to  release  of  cytokines  and/or  other  chemical 
 mediators,  occur  within  24  hours  of  atezolizumab  administration  and  are  generally  mild  to  moderate  in 
 severity. 
 CRS  is  defined  as  a  supraphysiologic  response  following  administration  of  any  immune  therapy  that  results 
 in  activation  or  engagement  of  endogenous  or  infused  T  cells  and/or  other  immune  effector  cells.  Symptoms 
 can  be  progressive,  always  include  fever  at  the  onset,  and  may  include  hypotension,  capillary  leak  (hypoxia), 
 and  end  -organ  dysfunction  (Lee  et  al.  2019).  CRS  has  been  well  documented  with  chimeric  antigen  receptor 
 T-cell  therapies  and  bispecific  T-cell  engager  antibody  therapies  but  has  also  been  reported  with 
 immunotherapies  that  target  PD-L1  or  PD-1  (Rotz  et  al.  2017;  Adashek  and  Feldman  2019),  including 
 atezolizumab. 
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 There  may  be  significant  overlap  in  signs  and  symptoms  of  IRRs  and  CRS,  and  in  recognition  of  the 
 challenges  in  clinically  distinguishing  between  the  two,  consolidated  guidelines  for  the  medical  management 
 of IRRs during Cycle 1 and CRS are provided in Appendix 1. 
 Severe  COVID-19  appears  to  be  associated  with  a  cytokine-release  syndrome  (CRS)  involving  the 
 inflammatory  cytokines  interleukin  (IL)-6,  IL-10,  IL-2,  and  interferon-(Merad  and  Martin  2020).  If  a  patient 
 develops  suspected  CRS  during  the  study,  a  differential  diagnosis  should  include  COVID-19,  which  should 
 be  confirmed  or  refuted  through  assessment  of  exposure  history,  appropriate  laboratory  testing,  and  clinical 
 or  radiologic  evaluations  per  investigator  judgment.  If  a  diagnosis  of  COVID-19  is  confirmed,  the  disease 
 should be managed as per local or institutional guidelines. 
 8) 
 Pancreatic Events 
 Symptoms  of  abdominal  pain  associated  with  elevations  of  amylase  and  lipase,  suggestive  of  pancreatitis, 
 have  been  associated  with  the  administration  of  atezolizumab.  The  differential  diagnosis  of  acute  abdominal 
 pain  should  include  pancreatitis.  Appropriate  work-up  should  include  an  evaluation  for  ductal  obstruction,  as 
 well  as  serum  amylase  and  lipase  tests.  Management  guidelines  for  pancreatic  events,  including  pancreatitis, 
 are provided in Appendix 1. 
 9) 
 Dermatologic Events 
 Treatment-emergent  rash  has  been  associated  with  atezolizumab.  The  majority  of  cases  of  rash  were  mild  in 
 severity  and  self-limited,  with  or  without  pruritus.  Although  uncommon,  cases  of  severe  cutaneous  adverse 
 reactions  such  as  Stevens-Johnson  syndrome  and  toxic  epidermal  necrolysis  have  been  reported  with 
 atezolizumab.  A  dermatologist  should  evaluate  persistent  and/or  severe  rash  or  pruritus.  A  biopsy  should  be 
 considered  unless  contraindicated.  Management  guidelines  for  dermatologic  events  are  provided  in  Appendix 
 1. 
 10) 
 Neurologic Disorders 
 Myasthenia  gravis  and  Guillain-Barré  syndrome  have  been  observed  with  single-agent  atezolizumab. 
 Patients  may  present  with  signs  and  symptoms  of  sensory  and/or  motor  neuropathy.  Diagnostic  work-up  is 
 essential  for  an  accurate  characterization  to  differentiate  between  alternative  etiologies.  Management 
 guidelines for neurologic disorders are provided in Appendix 1. 
 11) 
 Immune-Mediated Meningoencephalitis 
 Immune-mediated  meningoencephalitis  is  an  identified  risk  associated  with  the  administration  of 
 atezolizumab.  Immune-mediated  meningoencephalitis  should  be  suspected  in  any  patient  presenting  with 
 signs  or  symptoms  suggestive  of  meningitis  or  encephalitis,  including,  but  not  limited  to,  headache,  neck 
 pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of consciousness. 
 Encephalopathy  from  metabolic  or  electrolyte  imbalances  needs  to  be  distinguished  from  potential 
 meningoencephalitis  resulting  from  infection  (bacterial,  viral,  or  fungal)  or  progression  of  malignancy,  or 
 secondary  to  a  paraneoplastic  process.  All  patients  being  considered  for  meningoencephalitis  should  be 
 urgently  evaluated  with  a  CT  scan  and/or  MRI  scan  of  the  brain  to  evaluate  for  metastasis,  inflammation,  or 
 edema.  If  deemed  safe  by  the  treating  physician,  a  lumbar  puncture  should  be  performed  and  a  neurologist 
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 should be consulted. 
 Patients  with  signs  and  symptoms  of  meningoencephalitis,  in  the  absence  of  an  identified  alternate  etiology, 
 should be treated according to the guidelines in Appendix 1 
 12) 
 Renal Events 
 Immune-mediated  nephritis  has  been  associated  with  the  administration  of  atezolizumab.  Eligible  patients 
 must  have  adequate  renal  function,  and  renal.  Renal  function,  including  serum  creatinine,  should  be 
 monitored  throughout  study  treatment.  Patients  with  abnormal  renal  function  should  be  evaluated  and  treated 
 for  other  more  common  etiologies  (including  prerenal  and  postrenal  causes,  and  concomitant  medications 
 such  as  non-steroidal  anti-inflammatory  drugs).  Refer  the  patient  to  a  renal  specialist  if  clinically  indicated.  A 
 renal biopsy may be required to enable a definitive diagnosis and appropriate treatment. 
 Patients  with  signs  and  symptoms  of  nephritis,  in  the  absence  of  an  identified  alternate  etiology,  should  be 
 treated according to the guidelines in Appendix 1. 
 13) 
 Immune-Mediated Myositis 
 Immune-mediated  myositis  has  been  associated  with  the  administration  of  atezolizumab.  Myositis  or 
 inflammatory  myopathies  are  a  group  of  disorders  sharing  the  common  feature  of  inflammatory  muscle 
 injury;  dermatomyositis  and  polymyositis  are  among  the  most  common  disorders.  Initial  diagnosis  is  based 
 on  clinical  (muscle  weakness,  muscle  pain,  skin  rash  in  dermatomyositis),  biochemical  (serum  creatine 
 kinase  increase),  and  imaging  (electromyography/MRI)  features,  and  is  confirmed  with  a  muscle  biopsy. 
 Patients  with  possible  myositis  should  be  referred  to  a  rheumatologist  or  neurologist.  Patients  with  possible 
 myositis should be monitored for signs of myocarditis. More information provided in Appendix 1. 
 14) 
 Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
 Immune-mediated  reactions  may  involve  any  organ  system  and  may  lead  to  hemophagocytic 
 lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). 
 Clinical  and  laboratory  features  of  severe  CRS  overlap  with  HLH,  and  HLH  should  be  considered  when  CRS 
 presentation is atypical or prolonged. 
 Patients  with  suspected  HLH  should  be  diagnosed  according  to  published  criteria  by  McClain  and  Eckstein 
 (2014). A patient should be classified as having HLH if five of the following eight criteria are met: 
 ●  Fever ≥ 38.5°C 
 ●  Splenomegaly 
 ●  Peripheral blood cytopenia consisting of at least two of the following: 
 ○  Hemoglobin <90 g/L (9 g/dL) (<100 g/L [10 g/dL] for infants <4 weeks old) 
 ○  Platelet count <100  10  9  /L (100,000/μL) 
 ○  ANC  1.0 <10  9  /L (1000/μL) 
 ● 
 Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen <1.5 g/L (150 mg/dL) 
 ●  Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 ●  Low or absent natural killer cell activity 
 ●  Ferritin  >500 mg/L (500 ng/mL) 
 ●  Soluble  interleukin  2  (IL-2)  receptor  (soluble  CD25)  elevated  ≥2  standard  deviations  above 
 age-adjusted laboratory-specific norms 
 Patients  with  suspected  MAS  should  be  diagnosed  according  to  published  criteria  for  systemic  juvenile 
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 idiopathic  arthritis  by  Ravelli  et  al.  (2016).  A  febrile  patient  should  be  classified  as  having  MAS  if  the 
 following criteria are met: 
 ●  Ferritin >684 mg/L (684 ng/mL) 
 ●  At least two of the following: 
 ○  Platelet count ≤181  10  9  /L (181,000/μL) 
 ○  AST ≥48 U/L 
 ○  Triglycerides ≥1.761 mmol/L (156 mg/dL) 
 ○  Fibrinogen ≤3.6 g/L (360 mg/dL) 
 More information provided in Appendix 1. 
 15) 
 Severe Cutaneous Adverse Reactions (SCARs) 
 SCARs  are  a  heterogeneous  group  of  immunologically  mediated  drug  eruptions.  Although  rare,  these  events 
 are  potentially  fatal,  and  mainly  constituted  by  erythema  multiforme,  acute  generalised  exanthematous 
 pustulosis,  Stevens-Johnson  syndrome  (SJS),  Toxic  Epidermal  Necrolysis  (TEN)  and  drug  rash  with 
 eosinophilia  and  systemic  symptoms  (DRESS).  As  per  epidemiology  data,  the  incidence  of  SJS  and  TEN 
 ranges from 0.8 to 5.3 and 1.2 to 6 per million person-years respectively. 
 The following recommendations should be followed: 
 ●  For  suspected  SCARs  the  patients  should  be  referred  to  a  dermatologist  for  further  diagnosis  and 
 management 
 ●  Atezolizumab should be withheld for patients with suspected SJS or TEN 
 ●  Atezolizumab should be permanently withdrawn for any grade confirmed SJS or TEN 
 ●  Caution  should  be  used  when  considering  the  use  of  atezolizumab  in  a  patient  who  has  previously 
 experienced  a  severe  or  life-threatening  skin  adverse  reaction  on  prior  treatment  with  other 
 immune-stimulatory anticancer agents. 
 7.3. 
 C  ONCOMITANT  M  EDICATIONS 
 Full  and  updated  information  regarding  potential  drug  interactions  and  effects  of  food  are  available  in  the  IBs 
 (69,70)  and  SmPC  of  cabozantinib  (71)  and  atezolizumab  (72)  allocated  at  investigator  site  file.  However, 
 general information regarding permitted/prohibited concomitant treatment is detailed below. 
 All  medications  (prescriptions  or  over-the-counter  medications)  on-going  at  the  start  of  the  trial  or  initiated 
 during  the  study  or  until  30  days  from  the  end  of  the  last  protocol  treatment  and  different  from  the  study 
 medication will be documented. 
 All  concomitant  medications  taken  by  the  subject  during  the  trial,  starting  from  the  date  of  signing  the 
 informed  consent,  will  be  recorded.  The  indication,  dose,  frequency,  and  dates  of  treatment  will  be  recorded 
 in the patient’s medical records and in the appropriate section of the eCRF. 
 The  patient  must  notify  the  investigational  site  about  any  new  medications  he/she  takes  after  the  start  of  the 
 study  drug.  All  medications  (other  than  the  study  drug)  and  significant  non-drug  therapies  (including 
 physical  therapy,  herbal/natural  medications,  and  blood  transfusions)  administered  during  the  study  must  be 
 listed  on  the  Concomitant  Medications  or  the  Surgical  and  Medical  Procedures  eCRF.  Patients  taking 
 concomitant  medications  should  maintain  the  same  dose  and  dose  schedule  throughout  the  study  if  medically 
 feasible. 
 Caution  should  be  used  regarding  the  use  of  herbal  medications  as  there  may  be  yet  unknown  interactions 
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 with  study  treatment.  Discontinuation  of  the  use  of  herbal  medications  prior  to  study  enrolment  is 
 encouraged. 
 Any  medications  that  are  considered  necessary  to  protect  subject’s  welfare  and  will  not  interfere  with  the  trial 
 medication may be given at the Investigator’s discretion. 
 Rescue  medications  may  be  administered  to  address  anticipated  adverse  reactions  or  anticipated  emergency 
 situations. 
 7.3.1.  Allowed concomitant treatment 
 ●  Antiemetics  and  antidiarrheal  medications  are  allowed  prophylactically  according  to  standard 
 clinical practice if clinically indicated. 
 ●  Granulocyte  colony‑stimulating  factors  (G-CSF  or  GM-CSF)  are  allowed  if  used  per  clinical 
 guidelines (eg, ASCO or ESMO guidelines). 
 ●  Bisphosphonates  can  be  used  per  standard  of  care  if  the  benefit  outweighs  the  risk  per  the 
 Investigator’s discretion. 
 Note:  osteonecrosis  of  the  jaw  has  been  reported  in  subjects  using  bisphosphonates.  Oral 
 examinations  are  recommended  at  screening  to  determine  eligibility  and  periodically  during  the 
 study.  In  addition,  subjects  should  be  advised  regarding  oral  hygiene  practice  and  to  quickly  report 
 symptoms  to  the  Investigator.  Frequent  monitoring  for  potentially  overlapping  toxicities  with  study 
 treatment is recommended. 
 ●  Transfusions and hormone replacement should be utilized as indicated by standard clinical practice. 
 ●  Inhaled,  intranasal,  intra-articular,  or  topical  corticosteroids  are  allowed  if  minimal  systemic 
 absorption.  Systemic  corticosteroids  are  allowed  for  control  of  infusion  reactions  or  irAEs  and  must 
 be  tapered  over  ≥  1  month  to  a  dose  level  ≤  10  mg/day  of  prednisone  equivalent  before  next 
 atezolizumab  administration.  Prophylactic  steroid  treatment  for  subjects  with  contrast  allergies  prior 
 to tumor imaging is allowed. 
 ●  Individualized  anticoagulation  therapy  with  heparin  is  allowed  if  it  can  be  provided  safely  and 
 effectively under the following circumstances: 
 ○  Low  dose  LMWH  for  prophylactic  use  are  allowed  if  clinically  indicated  and  the  benefit 
 outweighs the risk per the investigator’s discretion. 
 ○  Therapeutic  doses  of  LMWH  after  first  dose  of  study  treatment  are  allowed  if  clinically 
 indicated  (eg,  for  the  treatment  of  DVT),  and  the  benefit  outweighs  the  risk  per  the 
 investigator’s  discretion.  For  management  of  thromboembolic  complications  while  on  study, 
 refer to Section 7.1.2 and 7.1.3 
 ○  Accepted  clinical  guidelines  regarding  appropriate  management  while  receiving 
 anticoagulation  therapy  with  heparins  must  be  followed.  This  includes,  but  is  not  limited  to, 
 subject  education  regarding  potential  adverse  drug  reactions,  monitoring  laboratory 
 parameters, dose adjustments (eg, due to kidney dysfunction, platelet decrease). 
 ○  For restrictions on oral anticoagulants see Section 7.3.3. 
 Additional  information  on  potential  drug  interactions  with  cabozantinib,  atezolizumab  are  summarized  in 
 Section 7.4.1 and 7.4.2 respectively 
 7.3.2.  Prohibited concomitant treatment 
 The following therapies are  prohibited  until study  treatment has been permanently discontinued: 
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 ●  Any investigational agent or investigational medical device. 
 ●  Therapeutic  doses  of  oral  anticoagulants  (eg,  warfarin  or  other  coumarin-related  agents,  direct 
 thrombin  or  direct  FXa  inhibitors,  or  antiplatelet  agents  such  as  clopidogrel,  or  chronic  use  of  aspirin 
 above low dose levels for cardioprotection per local applicable guidelines). 
 ●  Any  non-protocol  systemic  anticancer  treatment  (eg,  chemotherapy,  immunotherapy,  radionuclides, 
 drugs or herbal products used specifically for the treatment of the cancer under investigation). 
 ●  Concomitant  use  of  denosumab  with  atezolizumab  is  prohibited  due  to  a  potential  for  increased  risk 
 of infections. 
 ●  Immunosuppressive  agents  including  immunosuppressive  doses  of  systemic  corticosteroids  with 
 exceptions as stated in Section 7.2.3 and 7.3.1. 
 The  following  therapies  should  be  avoided  until  study  treatment  has  been  permanently  discontinued  or  until 
 otherwise specified: 
 ●  Local  anticancer  treatment  including  palliative  radiation,  ablation,  embolization,  or  surgery  with 
 impact  on  tumor  lesions  should  not  be  performed  until  radiographic  progression  per  RECIST  1.1  has 
 been  established.  If  clinically  unavoidable  the  investigator  should  consult  the  Sponsor  prior  to  the 
 procedure for safety guidance. 
 ●  Erythropoietic  stimulating  agents  (eg,  epoetin  alfa  and  darbepoetin  alfa)  should  not  be  used  based  on 
 a  report  of  increased  risk  of  tumor  recurrence/progression  associated  with  erythropoietin  (Wright  et 
 al 2007). 
 ●  Concomitant  medications  that  are  known  to  prolong  the  QTc  interval  should  be  avoided  in  subjects 
 until  they  have  permanently  discontinued  cabozantinib  or  sorafenib  treatment  (refer  to 
 http://www.qtdrugs.org  for a list of drugs which have  the potential to prolong the QTc interval). 
 ●  Live  vaccines  are  prohibited  while  on  study  and  until  5  months  after  last  atezolizumab  dose  (eg, 
 intranasal  influenza,  measles,  mumps,  rubella,  oral  polio,  Bacillus  Calmette-Guérin,  yellow  fever, 
 varicella,  and  TY21a  typhoid  vaccines).  The  use  of  inactivated  (killed)  vaccines  for  the  prevention  of 
 infectious disease requires Sponsor approval. 
 ●  Chronic  co-administration  of  cabozantinib  or  sorafenib  with  strong  inducers  of  the  CYP3A4  family 
 (eg,  phenytoin,  carbamazepine,  rifampin,  rifabutin,  rifapentine,  phenobarbital,  and  St.  John’s  Wort) 
 may  significantly  decrease  concentrations  of  these  study  drugs  and  should  be  avoided.  Selection  of 
 alternate  concomitant  medications  with  no  or  minimal  CYP3A4  enzyme  induction  potential  is 
 recommended. 
 ●  Caution  must  be  used  when  discontinuing  treatment  with  a  strong  CYP3A4  inducer  in  a  subject  who 
 has  been  concurrently  receiving  a  stable  dose  of  cabozantinib  or  sorafenib,  as  this  could  significantly 
 increase the exposure to these study drugs. 
 ●  Co-administration  of  cabozantinib  with  strong  inhibitors  of  the  CYP3A4  family  (eg,  boceprevir, 
 conivaptan,  posaconazole,  ketoconazole,  itraconazole,  clarithromycin,  atazanavir,  indinavir, 
 nefazodone,  nelfinavir,  saquinavir,  ritonavir,  lopinavir,  telaprevir,  telithromycin,  and  voriconazole) 
 may  increase  concentrations  of  study  drug  and  should  be  avoided.  Grapefruit,  star  fruit,  and  Seville 
 oranges may also increase plasma concentrations of these study drugs and should be avoided. 
 Additional  information  on  potential  drug  interactions  with  cabozantinib,  atezolizumab  are  summarized  in 
 Section 7.4.1 and 7.4.2 respectively 
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 7.4 
 P  OTENTIAL  D  RUG  I  NTERACTIONS 
 7.4.1 
 Potential Drug Interactions with Cabozantinib 
 Cytochrome  P450:  Data  from  a  clinical  drug  interaction  study  (Study  XL184‑008)  show  that  clinically 
 relevant  steady‑state  concentrations  of  cabozantinib  appear  to  have  no  marked  effect  on  the  area  under  the 
 plasma  concentration-vs-time  curve  (AUC)  of  co‑administered  rosiglitazone,  a  CYP2C8  substrate. 
 Therefore,  cabozantinib  is  not  anticipated  to  markedly  inhibit  CYP2C8  in  the  clinic,  and  by  inference,  is  not 
 anticipated  to  markedly  inhibit  other  CYP450  isozymes  that  have  lower  [I]/Ki  values  compared  with 
 CYP2C8  (ie,  CYP2C9,  CYP2C19,  CYP2D6,  CYP1A2,  and  CYP3A4).  In  vitro  data  indicate  that 
 cabozantinib  is  unlikely  to  induce  CYP  enzymes,  except  for  possible  induction  of  CYP1A1  at  high 
 cabozantinib concentrations (30 μM). 
 Cabozantinib  is  a  CYP3A4  substrate  and  a  weak  substrate  for  CYP2C9  (but  not  a  CYP2D6,  CYP2C8, 
 CYP2C19,  CYP2B6,  or  CYP1A2  substrate),  based  on  data  from  in  vitro  studies.  Results  from  a  clinical 
 pharmacology  study,  XL184‑006,  showed  that  concurrent  administration  of  cabozantinib  with  the  strong 
 CYP3A4  inducer,  rifampin,  resulted  in  an  approximately  77%  reduction  in  cabozantinib  exposure  (AUC 
 values)  after  a  single  dose  of  cabozantinib  in  healthy  volunteers.  Chronic  co-administration  of  cabozantinib 
 with  strong  inducers  of  the  CYP3A4  family  (eg,  phenytoin,  carbamazepine,  rifampin,  rifabutin,  rifapentine, 
 phenobarbital,  and  St.  John’s  Wort)  may  significantly  decrease  cabozantinib  concentrations.  The  chronic  use 
 of  strong  CYP3A4  inducers  should  be  avoided.  Other  drugs  that  induce  CYP3A4  should  be  used  with 
 caution  because  these  drugs  have  the  potential  to  decrease  exposure  (ie,  AUC)  to  cabozantinib.  Selection  of 
 alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended. 
 Results  from  a  clinical  pharmacology  study,  XL184‑007,  showed  that  concurrent  administration  of 
 cabozantinib  with  the  strong  CYP3A4  inhibitor,  ketoconazole,  resulted  in  a  38%  increase  in  the  cabozantinib 
 exposure  (AUC  values)  after  a  single  dose  of  cabozantinib  in  healthy  volunteers.  Co-administration  of 
 cabozantinib  with  strong  inhibitors  of  the  CYP3A4  family  (eg,  boceprevir,  conivaptan,  posaconazole, 
 ketoconazole,  itraconazole,  clarithromycin,  atazanavir,  indinavir,  nefazodone,  nelfinavir,  saquinavir, 
 ritonavir,  lopinavir,  telaprevir,  telithromycin,  and  voriconazole)  may  increase  cabozantinib  concentrations. 
 Grapefruit,  star  fruit  and  Seville  oranges  may  also  increase  plasma  concentrations  of  cabozantinib  and  should 
 be  avoided.  Strong  CYP3A4  inhibitors  should  be  avoided  and  other  drugs  that  inhibit  CYP3A4  should  be 
 used  with  caution  because  these  drugs  have  the  potential  to  increase  exposure  (ie,  AUC)  to  cabozantinib. 
 Selection  of  alternate  concomitant  medications  with  no  or  minimal  CYP3A4  enzyme  inhibition  potential  is 
 recommended. 
 Please  refer  to  the  drug  interaction  tables  at  the  following  website  for  lists  of  substrates,  inducers,  and 
 inhibitors of selected CYP450 isozyme pathways: 
 https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions 
 Other  Interactions:  Food  may  increase  exposure  levels  of  cabozantinib  by  57%,  fasting  recommendations 
 should  be  followed.  In  vitro  data  suggest  that  cabozantinib  is  unlikely  to  be  a  substrate  for  P‑glycoprotein, 
 but  has  the  potential  to  inhibit  the  P-glycoprotein  transport  activity  (IC50=7.0  μM)  at  high  concentrations. 
 Subject  should  be  cautioned  regarding  taking  substrates  of  P-glycoprotein  (eg,  fexofenadine,  aliskiren, 
 ambrisentan,  dabigatran  etexilate,  digoxin,  colchicine,  maraviroc,  posaconazole,  ranolazine,  saxagliptin, 
 sitagliptin,  talinolol,  tolvaptan).  Therefore,  subjects  are  cautioned  regarding  taking  drugs  containing  a 
 P-glycoprotein  substrate.  In  addition,  cabozantinib  was  shown  to  be  a  substrate  of  drug  transporter  multidrug 
 resistance-associated  protein  2  (MRP2)  in  an  in  vitro  assay.  Administration  of  MRP2  inhibitors  may  result  in 
 increases  in  cabozantinib  plasma  concentrations.  Therefore,  concomitant  use  of  MRP2  inhibitors  (eg, 
 cyclosporine,  efavirenz,  emtricitabine)  should  be  approached  with  caution.  Additional  details  related  to  these 
 overall conclusions can be found in the investigator brochure. 
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 Administration  of  the  proton  pump  inhibitor  (PPI)  esomeprazole  resulted  in  no  clinically-relevant  effect  on 
 cabozantinib  plasma  PK  in  healthy  volunteers.  Therefore,  concomitant  use  of  gastric  pH  modifying  agents 
 (ie, PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects administered cabozantinib. 
 The  effect  of  cabozantinib  on  the  pharmacokinetics  on  contraceptive  steroids  has  not  been  investigated.  Since 
 it  cannot  be  guaranteed  that  there  are  no  changes  on  the  contraceptive  effect,  it  is  recommended  to  use  an 
 additional contraceptive method, such as a barrier method. 
 From  in  vitro  data,  cannabinoids  have  been  shown  to  be  CYP3A4  inhibitors.  Investigators  should  be  mindful 
 that  an  increase  in  cabozantinib  exposure  with  cannabinoid  use  could  potentially  exist  although  it  seems 
 unlikely. 
 Additional  details  regarding  potential  drug  interactions  with  cabozantinib  can  be  found  in  the  Investigator’s 
 Brochure. 
 7.4.2 
 Potential Drug Interactions with Atezolizumab 
 Cytochrome  P450  enzymes,  as  well  as  conjugation/glucuronidation  reactions,  are  not  involved  in  the 
 metabolism  of  atezolizumab.  No  drug  interaction  studies  for  atezolizumab  have  been  conducted.  There  are 
 no  known  interactions  with  other  medicinal  products  or  other  form  of  interactions.  For  additional  details  refer 
 to the local prescribing information and the atezolizumab Investigator’s Brochure. 
 7.5. 
 T  REATMENT  C  OMPLIANCE 
 Study  drug  compliance  will  be  assessed  by  the  Investigator  and/or  study  personnel  at  each  patient’s  visit,  and 
 it  will  be  captured  in  the  patient’s  records  as  part  of  source  documentation  at  each  patient’s  visit. 
 Corresponding drug administration information will be reported also in the eCRF. 
 The  investigator  or  designee  must  maintain  an  accurate  record  of  the  shipment  and  the  dispensing  of  study 
 treatments  in  the  IWRS  system  designed  for  this  trial  (access  to  IWRS  system  will  be  created  by  study 
 monitors during site initiation visit, or can be requested by email to:  investigacion@mfar.net ). 
 Compliance  with  the  IMP  schema  is  critical  for  patients  and  trial  outcomes,  and  any  deviation  from  the  IMP 
 schema  may  jeopardise  trial  results  or  may  affect  patient  safety;  for  these  reasons,  non-compliance  may  be 
 considered  a  protocol  deviation.  When  an  investigational  product  is  dispensed  in  a  clinical  trial,  the 
 investigator  or  a  person  designated  by  the  investigator  will  ensure  high  level  of  compliance  with  the 
 investigational product administration procedures. 
 All  the  stages  from  IMP  will  be  documented  in  the  corresponding  forms  to  guarantee  traceability  during  the 
 procedure. 
 For  this  trial,  IMP  compliance  will  be  assessed  by  reviewing  the  consistency  of  information  in  the  IWRS,  the 
 eCRF, patient records, nurse sheets, and in the pharmacy source documentation. 
 At  study  close-out,  and  as  appropriate  during  the  study,  the  investigator  will  return  all  used  and  unused  study 
 treatment,  packaging,  and  drug  labels  to  the  Sponsor,  designated  monitor,  or  to  the  Sponsor’s  address 
 provided in the Investigator Site File at each site. 
 Upon  approval  by  the  Sponsor’s  delegate  and  after  accountability  has  been  confirmed  by  the  Sponsor  or 
 designated monitor, the study drug supply will be destroyed at Sponsor’s vendor, as appropriate. 
 7.6. 
 S  TUDY  D  RUG  S  UPPLY , L  ABELLING , D  ISPENSING  AND  H  ANDLING 
 7.6.1.  Study Drug Supply 
 The  Sponsor  will  supply  cabozantinib  and  atezolizumab  The  Investigator  or  responsible  site  personnel  must 
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 instruct  the  clinical  site  staff  as  per  protocol.  Study  drug(s)  will  be  managed  by  authorised  site  personnel 
 only.  All  dosages  prescribed  to  the  patient  and  all  dose  changes  during  the  study  must  be  recorded  on  the 
 patient’s record and the eCRF. 
 7.6.2.  Study drug labelling 
 Study  drug  will  be  open  labelled.  Medication  labels  will  be  created  in  the  local  language  and  will  comply 
 with  the  legal  requirements  of  each  participating  country,  including  storage  conditions  for  the  drugs,  batch 
 number  and  expiration  date,  among  others.  The  patient  number  should  be  hand-written  by  the  investigator  or 
 its staff at the drug delivery time. 
 7.6.3.  Study drug storage 
 Study  treatments  must  be  received  by  designated  personnel  at  the  study  site,  handled  and  stored  safely  and 
 properly,  and  kept  in  a  secured  location  to  which  only  the  Investigator  and  designated  site  personnel  have 
 access. 
 Upon  receipt,  the  study  drugs  should  be  stored  according  to  the  instructions  specified  on  the  drug  labels  and 
 Investigator’s  Brochure  of  cabozantinib  and  atezolizumab.  Study  drug  is  to  be  stored  in  a  secure  locked  area 
 while  under  the  responsibility  of  the  Investigator.  Receipt  and  dispensing  of  study  medication  must  be 
 recorded by an authorised person at the Investigator’s site. 
 Records  of  drug  formulation,  batch  number,  and  number  of  blisters/bottles  dispensed  must  be  recorded  in  the 
 IWRS system of this trial and in pharmacy source records. 
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 8. 
 S  TUDY  A  SSESSMENTS 
 8.1. 
 S  CHEDULE  FOR  TESTS  AND  DETERMINATIONS 
 Study  assessments  should  be  performed  following  the  indications  of  this  schedule  of  determinations  and 
 when clinically indicated according treating clinician (i.e: more frequent determinations in case of toxicities). 
 Table 2. Schedule for test and determinations throughout the study period 
 Screening 
 C1 
 C2 
 C3 
 C4 
 C5 
 C6 
 C7 to PD 
 EOT 
 Up 
 to 
 EOS 
 Week 
 -4 To -1 
 0 
 Q3w ±3 days unless dosing 
 needs to be held for toxicity 
 reasons 
 Q3w ±3 days unless 
 dosing needs to be held 
 for toxicity reasons 
 Day 
 -28 To -1 
 1  a 
 Q21 Days ±3 days unless dosing 
 needs to be held for toxicity 
 reasons 
 Q21 Days ±3 days unless 
 dosing needs to be held 
 for toxicity reasons 
 Informed Consent 
 Informed Consent  b 
 X 
 Consent  and  Collection  of  Specimens  for 
 Future Biomedical Research 
 X 
 Study Procedures 
 Medical History 
 X 
 Physical Exam (Full) 
 X 
 Targeted 
 Physical 
 Exam 
 (Based 
 On 
 Symptoms) 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Vital Signs  c 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 ECG  d 
 X 
 As clinically indicated 
 X 
 Prior and Concomitant Medications 
 <-------------------------------------------------------------------------> 
 Demography, 
 Including 
 Baseline 
 Characteristics And Tobacco Use 
 X 
 Eligibility Criteria 
 X 
 Laboratory Assessments 
 Clinical Chemistry  e 
 X 
 X  f 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Hematology  e 
 X 
 X  f 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 TSH  g  (Reflex Free T3 Or Free T4  h  ) 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Hepatitis B, C and HIV  i 
 X 
 Urinalysis 
 X 
 X 
 Tumor markers  q 
 X 
 q12w ± 2w until objective disease progression or death (whichever occurs first). 
 Pregnancy Test  j 
 X 
 If clinically indicated 
 Monitoring 
 ECOG Performance Status 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 QoL (EQ-5D-5L, EORTC QLQ-C30)  p 
 X 
 X 
 X 
 X 
 q6w 
 X 
 AE/SAE/AESI Assessment  k 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 Post-treatment Follow-up  l 
 X 
 IMPs Administration 
 Cabozantinib  m 
 X 
 (p.o. daily, until PD or unacceptable toxicity) 
 Atezolizumab  m 
 X 
 (IV. q3w, 21 days ±3 days  until PD or unacceptable toxicity) 
 Biological samples collection 
 Tumor Biopsy (Archival, If Available) 
 X 
 Processed blood samples  n 
 X 
 X 
 X 
 Efficacy Evaluations 
 Tumor  evaluation  (CT  scan  or  MRI) 
 (RECIST 1.1)  o 
 X 
 q12w ± 2w until objective disease progression/death (whichever comes first). 
 X 
 Note:  all  assessments  on  treatment  days  are  to  be  performed  prior  to  atezolizumab  infusion,  unless  otherwise  indicated.  C:  cycle;  ECG: 
 electrocardiogram;  IM:  intramuscular;  LFT:  liver  function  test;  QxW:  every x weeks;  T3:   triiodothyronine;  T4:   thyroxine;  TSH: 
 thyroid-stimulating hormone. EOT: end of treatment, EOS: end of study. 
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 a) 
 Every effort should be made to minimise the time between inclusion and start of treatment. (i.e.  within 1 day of inclusion) 
 b) 
 Informed  consent  of  study  procedures  may  be  obtained  prior  to  the  28-day  screening  window.  If  laboratory  or  imaging 
 procedures  were  performed  for  different  reasons  prior  to  signing  consent,  these  can  be  used  for  the  screening  purposes  with 
 the  consent  of  the  patient.  However,  all  screening  laboratory  and  imaging  results  must  have  been  obtained  within  28  days 
 of inclusion. 
 c) 
 Body weight is to be recorded at each visit along with vital signs. 
 d) 
 Any clinically significant abnormalities detected require triplicate ECG results. 
 e) 
 Complete  blood  count  that  includes  total  white  blood  cell  count  with  leukocyte  formula,  haemoglobin,  and  platelet  count. 
 The  analytical  studies  may  be  performed  up  to  72  hours  before  the  scheduled  visits  in  order  to  have  the  results  at  the  time 
 of  the  patient’s  visit.  Biochemistry  tests  include  albumin,  alkaline  phosphatase,  lactate  dehydrogenase  (LDH),  calcium, 
 magnesium,  phosphorus,  sodium,  potassium,  creatinine,  creatine  kinase,  direct  bilirubin,  indirect  bilirubin,  total  bilirubin, 
 total  protein,  urea,  uric  acid,  amylase,  lipase,  and  glucose  tests.  Liver  test  panel  function  include  alanine  transaminase 
 (ALT),  aspartate  transaminase  (AST),  alkaline  phosphatase  (ALP),  and  gamma-glutamyl  transpeptidase  (GGT)  tests.  Tests 
 for pancreatic enzymes include lipase and amylase. 
 f) 
 If  clinical  chemistry  screening  and  haematology  assessments  are  performed  within  14  days  prior  to  day  1  (first  infusion 
 day), they do not need to be repeated at day 1. 
 g) 
 If TSH is measured within 14 days prior to C1D1 (first infusion day), it does not need to be repeated at day 1. 
 h) 
 Free  T3  or  free  T4  will  only  be  measured  if  TSH  is  abnormal  or  if  there  is  clinical  suspicion  of  an  AE  related  to  the 
 endocrine system. 
 i) 
 Serology including HIV, hepatitis B (HBsAg and anti-HBc), and hepatitis C virus (HCV). 
 j) 
 Women  of  childbearing  potential  are  required  to  have  a  pregnancy  test  within  72  hours  prior  to  the  first  dose  of  the  study 
 drug,  and  every  3  cycles  (9  weeks)  thereafter  (if  clinically  indicated).  Latest  pregnancy  results  (maximum  9  weeks  old) 
 must  be  available  and  reviewed  by  the  treating  physician  or  investigator  prior  to  commencing  a  new  cycle  of  infusion.  A 
 urine or serum pregnancy test is acceptable. 
 k) 
 For  AEs/SAEs  reported  during  screening,  additional  information  such  as  medical  history  and  concomitant  medications  may 
 be needed. 
 l) 
 Post-treatment  follow  up:  all  patients  will  be  followed  up  according  to  RECIST  1.1  every  12  weeks  (+/-14  days)  up  to 
 disease  progression  or  death  (whichever  occurs  first),  regardless  of  the  reason  for  ending  the  treatment.  Follow  up 
 assessments  may  be  performed  q8w  ±  2w  if  required  by  local  standard  clinical  practice  or  by  investigator  criteria,  as  long 
 as  the  frequency  of  assessments  is  maintained.  Neuroendocrine  markers  are  to  be  analysed  according  to  local  practice.  The 
 follow-up  period  according  to  this  protocol  is  12  months  considering  last  patient  inclusion.  Information  on  subsequent 
 treatments  should  include  the  list  of  post-treatment  therapies,  the  drugs  administered,  and  the  date  of  initiation  and 
 discontinuation of each drug. All the data will be recorded in the medical record and in the eCRF. 
 m)  The  initial  dose  of  atezolizumab  will  be  administered  before  cabozantinib  and  must  be  administered  over  60  minutes.  If  the 
 first  infusion  is  well  tolerated,  all  subsequent  infusions  may  be  administered  over  30  minutes.  For  the  rest  of  the  cycles, 
 cabozantinib  will  be  self-administered  by  the  patients  daily  and  as  per  principal  investigator  indications.  Results  for  LTFs, 
 electrolytes,  and  creatinine  must  be  available  before  commencing  an  infusion  (within  3  days)  and  reviewed  by  the  treating 
 physician or investigator prior to dosing. 
 n) 
 Biomarker  study:  Collection  of  the  most  recent  archived  tumour-biopsy  sections.  Processed  blood  samples  at  baseline,  day 
 1  of  cycle  2  (D1C2),  at  EOT/progression.  Blood  samples  should  be  obtained  in  all  patients  at  the  time  of  EOT  (even  by 
 toxicity  without  progressing)  and  samples  are  to  be  stored  at  site  at  -80  ºC  and  are  to  be  sent  at  the  end  of  study  (1  dry  ice 
 shipment per site). 
 o) 
 CT  Scan  or  MRI  is  to  be  performed  at  baseline  and  q12w  ±  2w  until  the  objective  disease  progression  or  death  (whichever 
 comes  first).  Image  assessments  by  CT  scan  or  MRI  may  be  performed  q8w  ±  2w  if  required  by  local  standard  clinical 
 practice  or  by  investigator  criteria,  as  long  as  the  frequency  of  assessments  is  maintained.  The  schedule  of  q12w  ±  2  week 
 (q8w  ±  2w  when  applicable)  must  be  followed  regardless  of  any  delays  in  dosing,  in  case  of  suspected  pseudo-progression; 
 treatment  should  be  continued  until  progression  of  disease  is  confirmed  from  the  imaging  results.  RECIST  assessments  will 
 be  performed  on  images  from  CT  scans  (preferred)  or  MRI,  each  preferably  with  IV  contrast  of  the  neck,  chest,  abdomen 
 (including  liver  and  adrenal  glands),  and  pelvis.  Pelvic  imaging  is  recommended  only  when  primary  or  metastatic  disease 
 in  the  pelvic  region  is  likely.  Additional  anatomy  should  be  imaged  based  on  signs  and  symptoms  of  individual  patients  at 
 baseline  and  follow-up.  Baseline  assessments  should  be  performed  no  more  than  28  days  before  the  date  of  inclusion  and, 
 ideally, should be performed as close as possible to and prior to the start of treatment. 
 p) 
 EQ-5D-5L  and  EORTC  QLQ-C30  Questionnaires  (appendix  2  and  3)  will  be  done  prior  to  the  start  of  treatment  (at 
 screening) and every 2 cycles (q6w, 42 days) thereafter until PD. 
 q) 
 Tumor  markers  should  be  analyzed  at  screening  and  every  12  weeks  ±  2  weeks  to  determine  the  non-radiological  response. 
 The  markers  to  collect  are  NSE  in  tumors  from  cohort  1,  CGA  in  tumors  from  cohort  5,  cortisol  in  functionant  tumors  from 
 cohort  3,  metanephrines  and  adrenaline  in  functionant  tumors  from  cohort  4.  Norepinephrine,  5-HIAA  and  CEA  may  be 
 collected when considered. 
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 8.2. 
 C  LINICAL  E  VALUATION , L  ABORATORY  T  ESTS  AND  F  OLLOW -  UP 
 Study procedures and timing are summarised in the Schedule for test and determinations (section 8.1). 
 ●  All  immediate  safety  concerns  must  be  discussed  with  the  Sponsor  immediately  upon  occurrence  or 
 awareness to determine if the participant should continue or discontinue treatment. 
 ●  Adherence to the study design requirements is essential and required for study conduct. 
 ●  All  screening  evaluations  must  be  completed  and  reviewed  to  confirm  that  potential  participants 
 meet  all  eligibility  criteria  before  inclusion.  The  investigator  will  maintain  a  patient  log  to  record  the 
 details  of  all  participants  screened  and  to  confirm  eligibility  or  record  reasons  for  screening  failure, 
 as  applicable.  Patient  log  will  remain  at  the  site  at  all  time  and  will  be  available  for  monitoring  and 
 audit purposes. 
 8.2.1.  Before treatment start 
 Informed Consent 
 For  this  study  a  single  informed  consent  has  been  generated  that  includes  the  general  information  of  the 
 clinical  trial  and  a  section  for  the  collection  of  samples  for  future  research.  The  investigator  or  qualified 
 designee  must  obtain  documented  consent  from  each  potential  subject  or  each  subject’s  legally  acceptable 
 representative  prior  to  participating  in  a  clinical  trial  or  Future  Biomedical  Research.  The  informed  consent 
 will adhere to EC requirements, applicable laws and regulations. 
 The following recommendations should be considered for informed consent procedure: 
 ●  Consent  must  be  documented  by  the  subject’s  dated  signature  or  by  the  subject’s  legally  acceptable 
 representative  dated  signature  on  a  consent  form  along  with  the  dated  signature  of  the  person 
 conducting the consent discussion. 
 ●  All  fields  aimed  at  collecting  information  of  the  patient  and  investigator  performing  the  informed 
 consent  procedure  should  be  completed.  Any  finding  on  signed  consent  forms  could  be  considered  as 
 GCP breach. 
 ●  A  copy  of  the  signed  and  dated  consent  form  should  be  given  to  the  subject  before  participation  in 
 the  trial.  The  initial  informed  consent  form,  any  subsequent  revised  written  informed  consent  form, 
 and  any  written  information  provided  to  the  subject  must  receive  the  EC  approval  or  favourable 
 opinion in advance of use. 
 ●  The  subject  or  his/her  legally  acceptable  representative  should  be  informed  in  a  timely  manner  if  new 
 information  becomes  available  that  may  be  relevant  to  the  subject’s  willingness  to  continue 
 participation  in  the  trial.  The  communication  of  this  information  will  be  provided  and  documented 
 through  a  revised  consent  form  or  addendum  to  the  original  consent  form  that  captures  the  subject’s 
 dated signature or by the subject’s legally acceptable representative dated signature. 
 ●  Consent and Collection of Specimens for Future Biomedical Research: 
 ○  In  accordance  with  Annex  VIIIA  -  Guide  for  the  elaboration  of  patient  information  sheet  and 
 informed  consent  of  the  AEMPS,  taking  into  account  that  Future  Biomedical  Research  will 
 be  offered  to  all  patients,  the  information  related  to  this  part  of  the  study  will  be  included  in  a 
 section  of  the  general  informed  consent  form.  In  this  section,  participation  implications  will 
 be  clearly  explained,  detailing  the  risk  and  benefit,  answering  all  of  patient’s  questions,  and 
 obtaining written informed consent before collection of biological samples. 
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 ○  The  patient  may  accept  or  NOT  to  participate  in  this  optional  collection  of  biological 
 samples  by  marking  the  corresponding  box  YES/NO  in  the  section  of  informed  consent.  Site 
 staff  obtaining  the  informed  consent  must  verify  that  the  patient  has  correctly  completed  all 
 the sections including their willingness to participate or not in the collection of samples. 
 ●  The  Principal  Investigator  or  the  designee  should  clearly  indicate  in  patient  records  that  the  patient 
 has  signed  the  informed  consent  stating  his  willingness  to  participate  in  the  GETNE  T-1914  - 
 CABATEN Study indicating the level of acceptance, clinical part +/- sample collection. 
 Medical History 
 ●  A  medical  history  will  be  obtained  by  the  investigator  or  qualified  designee.  Medical  history  will 
 include  all  active  conditions,  any  diagnosed  condition  that  are  considered  to  be  clinically  significant 
 by  the  Investigator,  and/or  relevant  medical  history  taking  into  consideration  the  eligibility  criteria 
 (section 6.1 and 6.2). 
 ●  Any autoimmune disorders, regardless of the onset date, should be recorded. 
 Physical Exam 
 ●  Full  Physical  Exam:  The  investigator  or  clinical  designee  will  perform  a  full  physical  exam  during 
 the screening period. Clinically significant abnormal findings should be recorded as medical history. 
 ●  Targeted  Physical  Exam  (prior  treatment  administration):  Additional  physical  exams  (targeted) 
 should  be  performed  based  on  investigator  criteria  as  specified  in  the  Trial  Flow  Chart-Section  8.1, 
 considering  the  disease  under  study,  patients’  symptoms,  and  prior  physical  exams.  After  the  first 
 dose of trial treatment, new clinically significant abnormal findings should be recorded as AEs. 
 Vital Signs 
 ●  The  investigator  or  qualified  designee  will  take  vital  signs  as  specified  in  the  Trial  Flow 
 Chart-Section 8.1. 
 ●  Vital  signs  should  include  temperature,  pulse,  respiratory  rate,  weight  and  blood  pressure.  Body 
 weight  is  to  be  recorded  at  each  visit  along  with  vital  signs,  but  height  will  be  measured  at  screening 
 only. 
 12-Lead Electrocardiogram (ECG) 
 A  standard  12-lead  ECG  will  be  performed  at  baseline  and  at  the  end  of  the  treatment  visit  using  local 
 standard  procedure.  Any  clinically  significant  abnormalities  detected  require  triplicate  ECG  results  and 
 should  be  recorded  as  medical  history  or  adverse  event,  and  monitored  if  needed.  No  new  ECGs  will  be 
 performed unless clinically indicated. 
 Prior and concomitant medications review 
 ●  Prior Medications: 
 The  investigator  or  qualified  designee  will  review  prior  medication  use  including  any 
 protocol-specified  washout  requirement,  and  record  prior  medication  taken  by  the  subject  within  4 
 weeks of first dose of the study treatment. 
 ●  Concomitant Medications: 
 ○  The investigator or qualified designee will record the medication, if any, taken by the subject 
 during the trial from the time of signing the informed consent form until the Safety 
 Follow-up Visit. 
 ○  All medications related to reportable SAEs should be recorded 
 . 
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 Demography, Including Baseline Characteristics And Tobacco Use 
 ●  Date of birth (month/year of birth) or age at informed consent, race, and sex. 
 ●  Smoking  history:  never  smoke  (≤  100  cigarettes/life  time),  former  smoker  (≥  1  year),  smoker, 
 unknown) 
 ●  Tobacco use: pack/year and cigarettes/day. 
 Eligibility Criteria 
 All  inclusion  and  exclusion  criteria  will  be  reviewed  by  the  investigator  or  qualified  designee  to  ensure  that 
 each subject qualifies for the trial. More details on criteria for patients’ eligibility are in section 6.1 and 6.2. 
 Laboratory Assessments 
 The  summary  of  the  procedures  required  is  summarised  in  Table  2  and  flow  chart  (Section  8.1  and  the 
 corresponding  footnotes).  Laboratory  tests  for  screening  should  be  performed  within  7  days  prior  to  study 
 enrolment.  If  performed  <  14  days  prior  to  the  first  dose  of  trial  therapy,  the  screening  laboratory  tests  will 
 serve  as  cycle  1  day  1  laboratory  tests.  If  not,  laboratory  tests  will  need  to  be  performed  again  on  day  1  of 
 cycle  1.  Laboratory  determinations  include  full  clinical  chemistry  panel  (including  albumin,  alkaline 
 phosphatase,  LDH,  calcium,  magnesium,  phosphorus,  sodium,  potassium,  creatinine,  creatine  kinase,  direct 
 bilirubin,  indirect  bilirubin,  total  bilirubin,  total  protein,  urea,  uric  acid,  amylase,  lipase,  glucose,  ALT,  AST, 
 ALP,  GGT),  hematological  counts  (total  white  blood  cell  count  with  leukocyte  formula,  haemoglobin,  and 
 platelet  count),  TSH  hormone  levels,  serology  (HIV,  HBV,  and  HCV),  urianalysis  and  tumor  markers  (NSE 
 in  tumors  from  cohort  1,  CGA  in  tumors  from  cohort  5,  cortisol  in  functionant  tumors  from  cohort  3, 
 metanephrines  and,  adrenaline  in  functionant  tumors  from  cohort  4.  Norepinephrine,  5-HIAA  and  CEA  may 
 be collected when considered). 
 Pregnancy test 
 A serum pregnancy test must be performed at screening (at the local laboratory) within ≤ 72 hours before the 
 first dose of study treatment (if clinically indicated). 
 Eastern Cooperative Oncology Group (ECOG) Performance Status 
 The  investigator  or  qualified  designee  will  assess  ECOG  performance  status  at  screening,  prior  to  the 
 administration  of  each  dose  of  trial  treatment  and  as  specified  in  the  Table  of  Schedule  of  Assessments  (Table 
 2). It is  important to collect ECOG Status in patient’s  record and eCRF. 
 Biological samples collection 
 Tumour Biopsy (Archival, If Available) 
 ●  If available, it is mandatory that archival tumour tissue samples are analysed in this trial. 
 ●  Either  pre-existing  archived  or  newly-obtained  (fresh  tissue)  biopsy  specimens  from  either  primary 
 or metastatic tumour, whichever is the most recent. 
 ●  Tumour tissue specimen submitted in FFPE block is acceptable. 
 Processed blood samples: 
 ●  Serum and plasma samples to be collected at baseline, D1C2, and at progression. 
 ●  Blood  samples  are  to  be  stored  at  site  at  -80ºC,  and  are  to  be  sent  at  the  end  of  study  (1  dry  ice 
 shipment per site). 
 Tumour Imaging 
 The  site  study  team  must  review  pre-trial  images  to  confirm  that  the  subject  has  at  least  one  target  lesion  (i.e. 
 meets measurability requirements) as per RECIST 1.1. 
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 RECIST  assessments  will  be  performed  on  images  from  CT  scans  (preferred)  or  MRI,  each  preferably  with 
 IV  contrast  of  the  neck,  chest,  abdomen  (including  liver  and  adrenal  glands),  and  pelvis.  Pelvic  imaging  is 
 recommended  only  when  primary  or  metastatic  disease  in  the  pelvic  region  is  likely.  Patients  with  known 
 baseline  brain  lesions  are  not  eligible  for  this  study,  but  brain  CT  scan  or  MRI  is  neither  required  at  baseline 
 nor  in  the  follow-up  in  the  absence  of  neurological  signs  or  symptoms.  Additional  anatomical  imaging 
 should be carried out based on signs and symptoms of individual patients at baseline and follow-up. 
 Baseline  assessments  should  be  performed  no  more  than  28  days  before  the  date  of  inclusion  and,  ideally, 
 should be performed as close as possible to and prior to the start of treatment. 
 Quality of life (QoL) 
 The  QoL  measured  by  the  self  administered  questionnaires  EQ-5D-5L  and  EORTC  QLQ-C30(appendix  2 
 and  3)  will  be  performed  at  screening,  no  more  than  28  days  before  the  date  of  inclusion  and,  ideally,  should 
 be performed as close as possible to the start of treatment. 
 8.2.2.  Assessment during treatment 
 Physical Exam 
 ●  Targeted  Physical  Exam  (prior  treatment  administration):  Additional  physical  exams  (targeted) 
 should  be  performed  based  on  investigator  criteria  as  specified  in  the  Trial  Flow  Chart  (Section  8.1), 
 considering  the  disease  under  study,  patient  symptoms,  and  prior  physical  exams.  After  the  first  dose 
 of trial treatment, new clinically significant abnormal findings should be recorded as AEs. 
 Vital Signs 
 ●  The  investigator  or  qualified  designee  will  take  vital  signs  as  specified  in  the  Trial  Flow  Chart 
 (Section 8.1). 
 ●  Vital  signs  should  include  temperature,  pulse,  respiratory  rate,  weight,  and  blood  pressure.  Body 
 weight  is  to  be  recorded  at  each  visit  along  with  vital  signs;  however,  height  will  be  measured  at 
 screening only. 
 Laboratory Assessments 
 The  summary  of  the  procedures  required  is  summarised  in  Section  8.1  and  the  corresponding  footnotes.  It  is 
 recommended  that  laboratory  tests  be  performed  <  3  days  prior  to  the  next  dose  of  trial  therapy  in  order  to 
 have  the  results  to  decide  on  the  continuity  of  study  treatment  (dose  modifications  and  delays,  among  other 
 relevant clinical decisions). 
 Laboratory  determinations  include  full  clinical  chemistry  panel  (including  albumin,  alkaline  phosphatase, 
 LDH,  calcium,  magnesium,  phosphorus,  sodium,  potassium,  creatinine,  creatine  kinase,  direct  bilirubin, 
 indirect  bilirubin,  total  bilirubin,  total  protein,  urea,  uric  acid,  amylase,  lipase,  glucose,  ALT,  AST,  ALP, 
 GGT),  hematological  counts  (total  white  blood  cell  count  with  leukocyte  formula,  haemoglobin,  and  platelet 
 count), TSH hormone levels, and tumor markers. 
 Tumor  markers  should  be  analyzed  at  screening  and  every  12  weeks  ±  2  weeks  until  PD  or  death  (whichever 
 occurs  first)  to  determine  the  non-radiological  response.  The  markers  to  collect  are  NSE  in  tumors  from 
 cohort  1,  CGA  in  tumors  from  cohort  5,  cortisol  in  functionant  tumors  from  cohort  3,  metanephrines  and, 
 adrenaline  in  functionant  tumors  from  cohort  4.  Norepinephrine,  5-HIAA  and  CEA  may  be  collected  when 
 considered. 
 Eastern Cooperative Oncology Group (ECOG) Performance Status 
 The  investigator  or  qualified  designee  will  assess  ECOG  performance  status  prior  to  the  administration  of 
 each  dose  of  atezolizumab  as  specified  in  the  Table  of  Schedule  of  Assessments  (Table  2).  It  is  important  to 
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 collect ECOG Status in patient’s record and eCRF. 
 Adverse Event (AE)/Serious Adverse Events (SAE) assessment 
 ●  The  investigator  or  qualified  designee  will  assess  each  subject  to  evaluate  for  potential  new  or 
 worsening AEs as specified in the Trial Flow Chart, and subsequently if clinically indicated. 
 ●  Adverse  events  will  be  graded  and  recorded  throughout  the  trial  and  during  the  follow-up  period 
 according  to  NCI  CTCAE  Version  5.0.  Toxicities  will  be  characterised  in  terms  of  seriousness, 
 causality, toxicity grading, and action taken with regard to trial treatment. 
 ●  All  AEs  of  unknown  etiology  associated  with  study  treatment  exposure  should  be  evaluated  to 
 determine  if  it  is  possibly  an  ECI  of  a  potentially  immunologic  etiology  (termed  immune-related 
 adverse events, or irAEs). 
 Tumour Imaging 
 ●  q12w  ±  2w  until  the  objective  disease  progression  or  death  (whichever  comes  first).  Image 
 assessments  by  CT  scan  or  MRI  may  be  performed  q8w  ±  2w  if  required  by  local  standard  clinical 
 practice or by investigator criteria, as long as the frequency of assessments is maintained. 
 Biological samples collection 
 Processed blood samples: 
 ●  Serum and plasma samples to be collected at D1C2. 
 ●  Blood  samples  are  to  be  stored  at  site  at  -80  ºC  and  are  to  be  sent  at  the  end  of  study  (1  dry  ice 
 shipment per site). 
 Pregnancy test 
 Women  of  childbearing  potential  are  required  to  have  a  pregnancy  test  within  72  hours  prior  to  the  first  dose 
 of  the  study  drug,  and  every  3  cycles  (9  weeks)  thereafter  (if  clinically  indicated).  Latest  pregnancy  results 
 (maximum  9  weeks  old)  must  be  available  and  reviewed  by  the  treating  physician  or  investigator  prior  to 
 commencing a new cycle of infusion. A urine or serum pregnancy test is acceptable. 
 Quality of life 
 The  questionnaires  EQ-5D-5L  and  EORTC  QLQ-C30  will  be  fulfilled  every  two  cycles  by  the  patient  during 
 the  visit,  before  the  knowledgement  of  tumor  assessment  and  before  the  administration  of  each  dose  of 
 atezolizumab as specified in the Table of Schedule of Assessments (Table 2). 
 8.2.3.  End of treatment Visit 
 Physical Exam 
 ●  Targeted  Physical  Exam  (prior  treatment  administration):  Additional  physical  exams  (targeted) 
 should  be  performed  based  on  investigator  criteria  as  specified  in  the  Trial  Flow  Chart-Section  8.1, 
 considering  the  disease  under  study,  patient  symptoms,  and  prior  physical  exams.  After  the  first  dose 
 of trial treatment, new clinically significant abnormal findings should be recorded as AEs. 
 Vital Signs 
 ●  The  investigator  or  qualified  designee  will  take  vital  signs  as  specified  in  the  Trial  Flow 
 Chart-Section 8.1. 
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 ●  Vital  signs  should  include  temperature,  pulse,  respiratory  rate,  weight,  and  blood  pressure.  Body 
 weight  is  to  be  recorded  at  each  visit  along  with  vital  signs;  however,  height  will  be  measured  at 
 screening only. 
 12-Lead Electrocardiogram (ECG) 
 A  standard  12-lead  ECG  will  be  performed  at  baseline  and  at  end  of  treatment  visit  using  local  standard 
 procedure.  Any  clinically  significant  abnormalities  detected  require  triplicate  ECG  results  and  should  be 
 recorded  as  medical  history  or  adverse  event,  and  monitored  if  needed.  No  new  ECGs  will  be  performed 
 unless clinically indicated. 
 Laboratory Assessments 
 The  summary  of  the  procedures  required  is  summarised  in  Section  8.1  and  in  the  corresponding  footnotes.  It 
 is recommended that laboratory tests be performed < 3 days prior to the EOT visit. 
 Laboratory  determinations  include  full  clinical  chemistry  panel  (including  albumin,  alkaline  phosphatase, 
 LDH,  calcium,  magnesium,  phosphorus,  sodium,  potassium,  creatinine,  creatine  kinase,  direct  bilirubin, 
 indirect  bilirubin,  total  bilirubin,  total  protein,  urea,  uric  acid,  amylase,  lipase,  glucose,  ALT,  AST,  ALP, 
 GGT),  hematological  counts  (total  white  blood  cell  count  with  leukocyte  formula,  haemoglobin,  and  platelet 
 count),  TSH  hormone  levels,  and  tumor  markers  (NSE  in  tumors  from  cohort  1,  CGA  in  tumors  from  cohort 
 5,  cortisol  in  functionant  tumors  from  cohort  3,  metanephrines  and,  adrenaline  in  functionant  tumors  from 
 cohort 4. Norepinephrine, 5-HIAA and CEA may be collected when considered). 
 Eastern Cooperative Oncology Group (ECOG) Performance Status 
 The  investigator  or  qualified  designee  will  assess  ECOG  performance  status.  It  is  important  to  record 
 ECOG Status in patient’s record and eCRF. 
 Adverse Event (AE)/Serious Adverse Events (SAE) assessment 
 ●  The  investigator  or  qualified  designee  will  assess  each  subject  to  evaluate  for  potential  new  or 
 worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. 
 ●  Adverse  events  will  be  graded  and  recorded  throughout  the  trial  and  during  the  follow-up  period 
 according  to  NCI  CTCAE  Version  5.0.  Toxicities  will  be  characterised  in  terms  of  seriousness, 
 causality, toxicity grading, and action taken with regards to trial treatment. 
 ●  All  AEs  of  unknown  etiology  associated  with  study  treatment  exposure  should  be  evaluated  to 
 determine  if  it  is  possibly  an  ECI  of  a  potentially  immunologic  etiology  (termed  immune-related 
 adverse events, or irAEs). 
 Biological samples collection 
 Processed blood samples: 
 ●  Serum and plasma samples to be collected at progression. 
 ●  Blood  samples  are  to  be  stored  at  site  at  -80  ºC  and  are  to  be  sent  at  the  end  of  the  study  (1  dry  ice 
 shipment per site). 
 Quality of life 
 The  QoL  EQ-5D-5L,  EORTC  QLQ-C30  questionnaires  (appendix  2  and  3)  will  be  fulfilled  by  the  patient 
 during the EOT visit. 
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 8.2.4.  Post-treatment (Follow-up) 
 8.2.4.1.  Progression Free Survival follow-up 
 After  the  end  of  the  treatment  visit,  clinical  procedures  and  assessment  will  be  performed  as  previously 
 explained  and  reflected  in  the  summary  table  2  (section  8.1),  all  patients  will  be  followed  by  RECIST  1.1 
 every  12  weeks  (+/-14  days)  up  to  disease  progression  or  death  (whichever  occurs  first),  independently  of  the 
 reason  for  ending  the  treatment.  Follow  up  assessments  may  be  performed  every  8  weeks  (±  14  days)  if 
 required  by  local  standard  clinical  practice  or  by  investigator  criteria,  as  long  as  the  frequency  of  assessments 
 is  maintained.  The  follow-up  period  according  to  this  protocol  is  12  months  considering  last  patient 
 inclusion. 
 8.2.4.2.  Overall Survival (Long term follow-up) 
 Follow-up  after  disease  progression  will  be  carried  out  according  to  local  practice.  The  follow-up  period 
 according  to  this  protocol  is  12  months  considering  last  patient  inclusion.  Information  on  subsequent 
 treatments  should  include  the  list  of  post-treatment  therapies,  the  drugs  administered,  the  date  of 
 initiation/discontinuation  of  each  drug  and  date  of  progression.  All  the  data  will  be  recorded  in  the  medical 
 record and in the eCRF. 
 Survival  information  may  be  obtained  through  telephone  contact  with  the  patient,  patient’s  family  or  by 
 contact  with  the  patient’s  current  physician.  Survival  data  will  be  collected  up  to  the  time  of  the  final  overall 
 survival  (OS)  analysis,  and  at  this  point,  Investigators  will  be  notified  that  no  further  data  collection  for  the 
 study is required. 
 The  status  of  ongoing,  withdrawn  (from  the  study),  and  lost  to  follow-up  patients  at  the  time  of  an  OS 
 analysis  should  be  obtained  by  the  site  personnel  by  checking  the  patient’s  notes  and  hospital  records, 
 contacting the patient’s general clinician, and checking publicly available death registries. 
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 9. 
 A  SSESSMENT  OF  S  AFETY 
 Sites  should  record  all  adverse  events  both  in  patient’s  medical  record  and  in  eCRF  according  to  the  National 
 Cancer  Institute  Common  Terminology  Criteria  for  Adverse  Events  (NCI-CTCAE)  version  5.0,  following  the 
 Table  of  assessment  (Table  2,  Section  8.1).  For  patients  who  are  still  on  treatment  at  the  end  of  trial,  and  for 
 the  additional  6  months  with  provision  of  both  investigational  products,  any  suspicion  on  adverse 
 events/special  situation  should  be  reported  to  sponsor.  Those  events  reported  in  patients  receiving 
 atezolizumab 
 the 
 marketing 
 authorisation 
 holder: 
 Roche’s 
 Pharmacovigilance 
 Department 
 ( madrid.drug_safety@roche.com ,  Tel.  +34  91.324.8183).  Those  events  reported  in  patients  receiving 
 cabozantinib 
 the 
 marketing 
 authorisation 
 holder: 
 Ipsen’s 
 Pharmacovigilance 
 Department 
 (pharmacovigilance.spain@ipsen.com, Tel. +34 93.685.81.00). 
 9.1. 
 S  AFETY  P  ARAMETERS 
 Safety parameters are AE, SAE, AESI, pregnancy, medication error, overdose, drug abuse and drug misuse. 
 Additional safety information could be derived from ECG, lab test, pregnancy test, or vital sign exam. 
 9.2. 
 A  DVERSE  AND  S  ERIOUS  A  DVERSE  E  VENTS 
 9.2.1.  Definitions 
 Definitions regarding safety and pharmacovigilance to be applied in this study are defined below. 
 9.2.1.1. Adverse Event (AE) 
 An  AE  is  any  untoward  medical  occurrence  in  a  patient  or  clinical  investigation  subject  administered  a 
 medicinal  product  and  that  does  not  necessarily  have  a  causal  relationship  with  this  treatment.  An  AE  can 
 therefore  be  the  development  of  a  new  medical  condition,  or  the  deterioration  of  a  pre-existing  medical 
 condition.  This  includes  any  unfavorable  and  unintended  sign  (e.g.  tachycardia,  enlarged  liver),  symptom 
 (e.g.  nausea,  chest  pain)  or  the  abnormal  results  of  an  investigation  (e.g.  laboratory  findings, 
 electrocardiogram)  temporally  associated  with  the  use  of  a  medicinal  product,  whether  or  not  considered 
 related. 
 This  requirement  includes  specific  events  or  symptoms  associated  with  cancer  progression  or  general  clinical 
 deterioration  to  ensure  potential  toxicities  are  not  overlooked.  Radiographic  progression  without  associated 
 clinical  sequelae  is  not  considered  an  AE;  terms  such  as  ‘disease  progression’  should  be  avoided. 
 Pre-existing  medical  conditions  that  worsen  during  a  study  will  be  recorded  as  AEs.  Abnormal  laboratory 
 values,  ECG  findings,  or  vital  signs  are  to  be  recorded  as  AEs  if  they  meet  the  criteria  described  in  Section 
 9.3. 
 All  untoward  events  that  occur  after  informed  consent  through  30  days  (100  days  for  SAEs  and  AESIs)  after 
 the  date  of  the  decision  to  permanently  discontinue  study  treatment  (defined  as  the  later  of  the  date  of  the 
 decision  to  discontinue  all  study  treatment  or  the  date  of  the  last  dose  of  any  study  treatment)  are  to  be 
 recorded by the investigational site. 
 At  each  scheduled  and  unscheduled  visit,  AEs  are  to  be  identified  and  assessed  based  upon  study  procedures, 
 routine and symptom-directed clinical investigations, and subject query/report. 
 Assessment  of  the  relationship  of  the  AEs  to  study  treatment  by  the  investigator  will  be  based  on  the 
 following two definitions: 
 ●  Not  Related:  An  event  is  assessed  as  not  related  to  study  treatment  if  it  is  attributable  to  another 
 cause and/or there is no evidence to support a causal relationship. 
 ●  Related:  An  event  is  assessed  as  related  to  study  treatment  when  there  is  a  reasonable  possibility  that 
 study  treatment  caused  the  event.  Reasonable  possibility  means  there  is  evidence  to  suggest  a  causal 
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 relationship  between  study  treatment  and  the  event.  This  event  is  called  a  suspected  adverse  reaction. 
 A  suspected  adverse  reaction  implies  a  lesser  degree  of  certainty  about  causality  than  adverse 
 reaction, which means any AE caused by a drug. 
 9.2.1.2. Severity of Events 
 Assessment  of  adverse  events,  safety,  and  toxicity  will  be  performed  according  to  the  National  Cancer 
 Institute  Common  Toxicity  Criteria  (version  5.0)  from  the  time  of  Informed  Consent  for  the  pre-registration 
 phase  until  the  end  of  study.  The  following  definitions  should  be  considered  when  evaluating  the  severity  of 
 oncology events when not present in NCI-CTCAE version 5.0: 
 Severity of Events 
 Grade 
 Definition 
 1 
 Mild adverse event 
 2 
 Moderate adverse event 
 3 
 Severe and undesirable adverse event 
 4 
 Life-threatening or disabling adverse event 
 5 
 Death related to adverse event 
 9.2.1.3.  Laboratory Abnormalities 
 All  laboratory  data  required  by  this  protocol  and  any  other  clinical  investigations  will  be  reviewed.  Any 
 abnormal  value  that  leads  to  a  change  in  subject  management  (eg,  dose  reduction  or  delay  or  requirement  for 
 additional  medication  or  monitoring)  or  that  is  considered  to  be  of  clinical  significance  by  the  Investigator 
 will  be  reported  as  an  AE  or  SAE  as  appropriate,  unless  this  value  is  consistent  with  the  subject’s  present 
 disease state or is consistent with values obtained prior to entry into the study. 
 9.3. 
 S  ERIOUS  A  DVERSE  E  VENT  (SAE) 
 9.3.1.  Definitions 
 The  SAE  definition  and  reporting  requirements  are  in  accordance  with  the  ICH  Guideline  for  Clinical  Safety 
 Data Management: Definitions and Standards for Expedited Reporting, Topic E2A. 
 An SAE is any AE occurring at any dose that: 
 o 
 Results in death. 
 o 
 Is  immediately  life‑threatening  (ie,  in  the  opinion  of  the  investigator,  the  AE  places  the  subject  at 
 immediate  risk  of  death;  it  does  not  include  a  reaction  that,  had  it  occurred  in  a  more  severe 
 form, might have caused death). 
 o 
 Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
 o 
 Results  in  significant  incapacity  or  substantial  disruption  of  the  ability  to  conduct  normal  life 
 functions. 
 o 
 Is a congenital anomaly or birth defect. 
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 o 
 Is  an  important  medical  event  that  may  not  be  immediately  life‑threatening,  result  in  death,  or 
 require  hospitalization,  but  may  be  considered  an  SAE  when,  based  upon  appropriate  medical 
 judgment,  it  jeopardizes  the  subject  or  may  require  medical  or  surgical  intervention  to  prevent 
 one of the outcomes listed above. 
 9.3.2.  SAE Reporting 
 As  soon  as  an  investigator  becomes  aware  of  an  AE  that  meets  the  criteria  for  an  SAE,  the  investigator  will 
 document the SAE to the extent that information is available. 
 SAEs,  regardless  of  causal  relationship,  must  be  reported  to  the  Sponsor  or  designee  within  24  hours  of  the 
 investigator’s  knowledge  of  the  event  by  submitting  the  completed  SAE  report  form  and  any  other  pertinent 
 SAE  information  as  indicated  on  the  SAE  Reporting  form  (or  in  the  SAE  Reporting  form  Completion 
 Guidelines)  and  confirming  the  report  was  received.  Forms  for  reporting  SAEs  and  contact  information  will 
 be provided to the study sites. 
 Reporting Information for safety reports 
 To report initial or follow-up information to Ipsen/Roche, a completed Clinical Study Serious Adverse 
 Event (SAE) report form should be sent to the following within 24 hours of becoming aware of the event: 
 Serious Adverse Events 
 All serious adverse events must be reported by fax within 24 h to MFAR Clinical Research, S.L. 
 by fax (+ 34 93 253 11 68) or e-mail to investigacion@mfar.net 
 SAEs that must be recorded on an SAE Reporting form include the following: 
 ●  All  SAEs  that  occur  after  informed  consent  and  through  100  days  after  the  date  of  the  decision  to 
 permanently  discontinue  study  treatment  (ie,  the  later  of  the  date  of  the  decision  of  the  investigator  to 
 permanently  discontinue  study  treatment  or  the  date  of  the  last  dose  of  any  study  treatment  taken  by 
 the subject) or the date the subject is deemed to be a screen failure. 
 ●  Any  SAEs  assessed  as  related  to  study  treatment  or  study  procedures,  even  if  the  SAE  occurs  more 
 than 100 days after the date of the decision to permanently discontinue study treatment. 
 Note:  If  the  subject  does  not  meet  the  eligibility  criteria  during  screening,  then  SAEs  only  need  to  be 
 reported  from  the  time  the  subject  signs  the  informed  consent  until  the  day  when  the  subject  has  been 
 determined to not be eligible for study participation. 
 SAEs  that  occur  after  the  initiation  of  study  treatment  through  100  days  after  the  date  of  the  decision  to 
 permanently discontinue of study treatment must also be recorded on the CRF page. 
 The  minimum  information  required  for  SAE  reporting  includes  identity  of  Investigator,  site  number,  subject 
 number,  and  an  event  description.  Other  important  information  requiring  timely  reporting  are  the  SAE 
 term(s),  the  reason  why  the  event  is  considered  to  be  serious  (ie,  the  seriousness  criteria),  and  the 
 Investigator’s  assessment  of  the  relationship  of  the  event  to  study  treatment.  Additional  SAE  information 
 including  medications  or  other  therapeutic  measures  used  to  treat  the  event,  action  taken  with  the  study 
 treatment because of the event, and the outcome/resolution of the event will be recorded on the SAE form. 
 In  all  cases,  the  Investigator  should  continue  to  monitor  the  clinical  situation  and  report  all  material  facts 
 relating  to  the  progression  or  outcome  of  the  SAE.  Furthermore,  the  Investigator  may  be  required  to  provide 
 supplementary information as requested by the Sponsor’s Drug Safety personnel or designee. 
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 When reporting SAEs, the following additional points will be noted: 
 ●  When  the  diagnosis  of  an  SAE  is  known  or  suspected,  the  Investigator  will  report  the  diagnosis  or 
 syndrome  as  the  primary  SAE  term,  rather  than  as  signs  or  symptoms.  Signs  and  symptoms  may  then 
 be described in the event description. 
 ●  Death  will  not  be  reported  as  an  SAE,  but  as  an  outcome  of  a  specific  SAE,  unless  the  event 
 preceding  the  death  is  unknown.  Terms  of  “Unexplained  Death”  or  “Death  from  unknown  origin” 
 may  be  used  when  the  cause  is  unknown.  In  these  circumstances  the  cause  of  death  must  be 
 investigated  and  the  diagnosis  amended  when  the  etiology  has  been  identified.  If  an  autopsy  was 
 performed, the autopsy report should be provided. 
 ●  While  most  hospitalizations  necessitate  reporting  of  an  SAE,  some  hospitalizations  do  not  require 
 SAE reporting, as follows: 
 ○  Elective  or  previously  scheduled  surgeries  or  procedures  for  preexisting  conditions  that  have 
 not  worsened  after  initiation  of  treatment  (eg,  a  previously  scheduled  ventral  hernia  repair). 
 SAEs  must,  however,  be  reported  for  any  surgical  or  procedural  complication  resulting  in 
 prolongation of the hospitalization. 
 ○  Prespecified study hospitalizations for observation. 
 ○  Events  that  result  in  hospital  stays  of  fewer  than  24  hours  and  that  do  not  require  admission 
 (eg,  an  emergency  room  visit  for  hematuria  that  results  in  a  diagnosis  of  cystitis  and 
 discharge to home on oral antibiotics). 
 ●  SAEs  must  be  reported  for  any  surgical  or  procedural  complication  resulting  in  prolongation  of  the 
 hospitalization. 
 9.3.2.  SAE Regulatory Reporting 
 The  Sponsor’s  Drug  Safety  group  (or  designee)  will  process  and  evaluate  all  SAEs  and  AESIs  as  the  reports 
 are  received.  For  each  SAE  received,  the  Sponsor  will  make  a  determination  as  to  whether  the  criteria  for 
 expedited reporting to relevant regulatory authorities have been met. 
 The  Sponsor’s  Drug  Safety  group  (or  designee)  will  assess  the  expectedness  of  each  SAE  to  the  study 
 treatment  using  the  current  reference  safety  information  (RSI)  for  each  study  drug.  RSI  for  this  trial  will  be 
 the  last  version  of  study  treatment  Investigator  Brochure.  If  information  on  the  expectedness  has  been  made 
 available  by  the  reporting  investigator,  this  should  be  taken  into  consideration  by  Sponsor.  If  Sponsor 
 disagrees  with  the  investigator’s  expectedness  assessment,  both  the  opinion  of  the  investigator  and  the 
 sponsor should be provided in the report. 
 The  Sponsor  or  its  designee  is  responsible  for  reporting  relevant  SAEs  to  the  relevant  regulatory  authorities, 
 and  participating  investigators,  in  accordance  with  FDA  regulations  (21  Code  of  Federal  Regulations  [CFR] 
 312.32),  ICH  guidelines,  European  Clinical  Trials  Directive  (Directive  2001/20/EC),  and/or  local  regulatory 
 requirements. 
 Reporting  of  SAEs  by  the  Investigator  to  his  or  her  IRB/ECs  will  be  done  in  accordance  with  the  standard 
 operating  procedures  and  policies  of  the  IRB/EC.  Adequate  documentation  must  be  maintained  showing  that 
 the IRB/EC was properly notified. 
 MFAR  Clinical  Research  on  behalf  of  GETNE  will  forward  safety  reports  received  to  both  IPSEN  and 
 ROCHE  within  one  working  day,  following  agreed  procedures  (signed  IPSEN  agreement  and  ROCHE 
 SDEA)  in  order  they  can  fulfill  the  corresponding  legal  requirement  regarding  pharmacovigilance  as  MAH 
 of cabozantinib and atezolizumab respectively. 
 All  adverse  events  will  be  processed  by  MFAR/Ipsen/Roche  according  to  their  relevant  Standard  Operating 
 Procedures.  This  includes  the  follow  up  of  adverse  event  reports  with  the  Investigator  through  MFAR 
 Clinical  Research,  as  required.  If  an  AE  occurs  with  a  “non  Ipsen/Roche  product”,  the  Investigator  should 
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 consider  informing  the  competent  authority  in  the  Member  State  where  the  event  occurred  or  to  the 
 marketing  authorisation  holder  of  the  suspected  medicinal  product,  but  not  to  both  (to  avoid  duplicate 
 reporting). 
 The  Sponsor  through  MFAR  Clinical  Research  ensures  that  the  reporting  requirements  and  timelines  for 
 reporting,  as  defined  in  the  respective  applicable  laws,  are  followed.  A  Development  Safety  Update  Report 
 (DSUR)  will  be  provided  to  the  local  investigators  for  filing  into  the  investigator’s  file.  MFAR  Clinical 
 Research will submit the DSUR to the involved ECs and involved Regulatory Agencies. 
 9.4. 
 A  DVERSE  E  VENTS  OF  S  PECIAL  I  NTEREST 
 Adverse  events  of  special  interest  (AESIs)  consist  of  immune-mediated  AEs  associated  with  ICIs,  cases  of 
 potential DILI, and suspected transmission of an infectious agent by the study treatment (Table 3). 
 AESIs  will  be  reported  to  the  Sponsor  or  designee  using  the  SAE  reporting  form  irrespective  of  whether  the 
 event  is  serious  or  nonserious;  all  AESIs  must  be  reported  within  24  hours  using  the  SAE  process  as 
 described in Section 9.3. 
 Guidance  for  management  of  immune-mediated  AEs  associated  is  provided  in  Investigator’s  Brochure  for 
 atezolizumab. 
 Table 3. Adverse Events of Special Interest 
 Category 
 Event 
 DILI 
 ● 
 Cases of potential Drug-induced Liver Injury (DILI) that include an elevated ALT or AST in 
 combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and based on 
 the following observations: 
 ○ 
 Treatment-emergent ALT or AST > 3 × baseline value in combination with total bilirubin > 2 
 × ULN (of which ≥ 35% is direct bilirubin). 
 ○ 
 Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical jaundice. 
 Other 
 ● 
 Suspected transmission of an infectious agent by the study treatment, as defined below: 
 ○ 
 Any  organism,  virus,  or  infectious  particle  (eg,  prion  protein  transmitting  transmissible 
 spongiform  encephalopathy),  pathogenic  or  non-pathogenic,  is  considered  an  infectious 
 agent.  A  transmission  of  an  infectious  agent  may  be  suspected  from  clinical  symptoms  or 
 laboratory  findings  that  indicate  an  infection  in  a  patient  exposed  to  a  medicinal  product. 
 This term applies only when a contamination of study treatment is suspected. 
 irAE 
 ● 
 Systemic lupus erythematosus 
 irAE 
 ● 
 Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, HLH and 
 MAS 
 irAE 
 ● 
 Nephritis 
 irAE 
 ● 
 Ocular toxicities (eg, uveitis, retinitis) 
 irAE 
 ● 
 ≥ Grade 2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis) 
 irAE 
 ● 
 Vasculitis 
 irAE 
 ● 
 Autoimmune hemolytic anemia 
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 irAE 
 ● 
 Severe  cutaneous  reactions  (e.g.,  Stevens-Johnson  syndrome,  dermatitis  bullous,  toxic  epidermal 
 necrolysis) 
 ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; irAE, immune-related adverse 
 event; ULN, upper limit of normal. 
 9.4.1 
 General Information on Immune-Related Adverse Events 
 The  immune-modulating  properties  of  checkpoint-inhibitors,  such  as  the  anti-PD-L1  antibody  atezolizumab, 
 are  able  to  unbalance  immunologic  tolerance  and  generate  a  subset  of  AEs  (called  irAEs)  with  an 
 autoimmune  inflammatory  pathomechanism.  Immune-related  adverse  events  may  involve  any  organ  or  tissue 
 (Michot  et  al  2016).  Most  irAEs  occur  within  the  first  12  weeks  of  exposure  to  ICIs  but  some  of  them  may 
 appear  with  a  delayed  onset.  Diagnosis  of  irAEs  should  be  based  on  exposure  to  an  ICI  and  a  reasonable 
 immune-based  mechanism  of  the  observed  AE.  Whenever  possible,  histologic  examination  or  other 
 immune-based  diagnostic  evaluations  should  be  used  to  support  the  diagnosis.  Other  etiologic  causes 
 including AEs from tumor progression should be ruled out. 
 The  spectrum  of  irAEs  is  wide  and  can  be  general  or  organ-specific.  Examples  of  general  irAEs  in  subjects 
 treated  with  ICIs  are  fatigue,  fever,  and  chills.  Organ-specific  irAEs  consist  of  dermatitis  (rash,  pruritus, 
 vitiligo,  oral  mucositis,  and  gingivitis),  enterocolitis  (diarrhea  with  abdominal  pain  and  clinical  or 
 radiological  evidence  of  colonic  inflammation),  and  endocrinopathies  (pituitary,  thyroid,  adrenal,  testes). 
 Diagnosis  of  endocrine  dysfunction  is  challenging  with  relatively  nonspecific  symptoms.  Additional 
 laboratory  testing  of  the  endocrine  axes  may  be  helpful:  prolactin  (pituitary-hypothalamic  function),  FT4  and 
 TSH  (pituitary-thyroid  function),  luteinizing  hormone  (LH)  and  follicle-stimulating  hormone  (FSH; 
 pituitary-gonadal function), adrenocorticotropic hormone (ACTH) and cortisol (pituitary-adrenal function). 
 Additional  organ-specific  irAEs  include  hepatitis  (AST/ALT  increases,  hepatomegaly,  periportal  edema, 
 periportal  lymphadenopathy,  lymphocyte  infiltrates  periportal  and  surrounding  primary  biliary  ducts)  and 
 pneumonitis  (acute  interstitial  pneumonia).  Less  frequent  irAEs  include  neurologic  syndromes  (myasthenia 
 gravis,  Guillian-Barré  syndrome,  aseptic  meningitis),  ocular  AEs  (uveitis),  renal  AEs  (interstitial  nephritis), 
 cardiac AEs (myocarditis), muscular AEs (myositis), and pancreatic AEs (lipase increase). 
 9.5. 
 F  OLLOW -U  P  OF  A  DVERSE  E  VENTS 
 Non-serious  AEs  are  to  be  recorded  in  the  CRF  until  30  days  after  the  date  of  the  decision  to  discontinue 
 study  treatment  (the  later  of  the  date  of  the  decision  by  the  investigator  to  permanently  discontinue  study 
 treatment  or  the  date  of  the  last  dose  of  any  study  treatment  taken  by  the  subject).  The  status  of  unrelated 
 SAEs  that  are  ongoing  after  the  date  of  the  decision  to  discontinue  study  treatment  will  be  documented  as  of 
 the 100-day FU-2 visit. 
 All  AESIs  (regardless  of  seriousness)  and  all  related  SAEs  that  are  ongoing  100  days  after  the  date  of  the 
 decision  to  discontinue  study  treatment  (the  later  of  the  date  of  the  decision  by  the  investigator  to 
 permanently  discontinue  study  treatment  or  the  date  of  the  last  dose  of  any  study  treatment  taken  by  the 
 subject),  and  AEs  assessed  as  related  that  led  to  study  treatment  discontinuation  that  are  ongoing  100  days 
 after the date of the decision to discontinue study treatment, are to be followed until either: 
 ●  the AE has resolved 
 ●  the AE has improved to Grade 2 or lower 
 ●  The Investigator determines that the event has become stable or irreversible. 
 Further details on follow-up procedures are summarized in section 8.1 study determinations chart. 
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 9.6. 
 O  THER  S  AFETY  C  ONSIDERATIONS 
 9.6.1.  Pregnancy 
 Use  of  highly  effective  methods  of  contraception  is  very  important  during  the  study  and  for  5  months  after 
 the  last  dose  of  study  treatment.  If  a  subject  becomes  pregnant  during  the  study,  she  will  be  taken  off  study 
 treatment.  She  will  be  followed  through  the  end  of  her  pregnancy  and  the  infant  should  have  follow  up  for  at 
 least  6  months  after  birth.  Furthermore,  male  subjects  are  required  to  use  condoms  in  order  to  avoid 
 transmission  of  study  treatment  in  semen  for  5  months  after  their  last  dose  of  study  treatment.  If  a  female 
 partner  of  a  male  subject  becomes  pregnant  during  the  study,  the  Sponsor  will  ask  the  pregnant  female 
 partner  to  be  followed  through  the  end  of  her  pregnancy  and  for  the  infant  to  be  followed  for  at  least  6 
 months  after  birth.  Both  male  and  female  subjects  should  seek  advice  and  consider  fertility  preservation 
 before receiving study treatment. 
 The  Investigator  must  inform  the  Sponsor  of  the  pregnancy.  Forms  for  reporting  pregnancies  will  be 
 provided  to  the  study  sites  upon  request.  The  outcome  of  a  pregnancy  (for  a  subject  or  for  the  partner  of  a 
 subject)  and  the  medical  condition  of  any  resultant  offspring  must  be  reported  to  the  Sponsor  or  designee. 
 Any  birth  defect  or  congenital  anomaly  must  be  reported  as  an  SAE  and  any  other  untoward  events  occurring 
 during the pregnancy must be reported as AEs or SAEs, as appropriate. 
 Females  should  not  breastfeed  while  receiving  study  treatment  and  for  the  following  periods  after 
 discontinuing study treatment: 
 ●  Combination  cabozantinib  plus  atezolizumab:  at  least  5  months  from  the  last  dose  of 
 atezolizumab or 4 months from the last dose of cabozantinib, whichever is later 
 ●  Single-agent cabozantinib:  at least 4 months from  the last dose of cabozantinib 
 ●  Single-agent atezolizumab:  at least 5 months from  the last dose of atezolizumab 
 9.6.2.  Medication Errors/Overdose/Drug abuse/Drug misuse 
 Medication  error  is  defined  as  accidental  deviation  in  the  administration  of  a  drug  (e.g.  wrong  dose 
 administered,  wrong  dosing  schedule,  incorrect  route  of  administration,  wrong  drug,  expired  drug 
 administered). In some cases, a medication error may be intercepted prior to administration of the drug. 
 Any  study  medication  overdose,  misuse,  abuse,  or  study  medication  error  (excluding  missed  doses)  that 
 results  in  an  AE  or  SAE  requires  reporting  to  the  Sponsor  or  designee  according  to  the  guidance  for  AE  and 
 SAE reporting (Sections 9.1 and 9.2, respectively). 
 In  case  of  overdose,  the  Coordinating  Investigator  or  designee  should  be  contacted  promptly  to  discuss  how 
 to  proceed.  Any  AEs  that  occur  as  a  result  of  an  overdose  have  to  be  treated  according  to  clinical  standard 
 practice. 
 Please  refer  to  the  Investigator’s  Brochure  for  additional  management  recommendations  for  an  overdose  of 
 cabozantinib and/or atezolizumab. 
 In  addition,  all  study  medication  overdose,  misuse,  abuse  or  medication  error,  regardless  of  whether  they 
 result in an adverse event, should be recorded on the Adverse Event CRF 
 9.6.2 Lack of Efficacy or Worsening of study disease: 
 Events  that  are  clearly  consistent  with  the  expected  pattern  of  progression  of  the  underlying  disease  should 
 not  be  recorded  as  adverse  events.  These  data  will  be  captured  as  efficacy  assessment  data  only.  In  most 
 cases,  the  expected  pattern  of  progression  will  be  based  on  RECIST  v1.1  criteria.  In  rare  cases,  the 
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 determination  of  clinical  progression  will  be  based  on  symptomatic  deterioration.  However,  every  effort 
 should  be  made  to  document  progression  through  use  of  objective  criteria.  If  there  is  any  uncertainty  as  to 
 whether an event is due to disease progression, it should be reported as an adverse event. 
 10. 
 S  TATISTICS 
 10.1. 
 S  AMPLE  S  IZE  C  ALCULATION 
 Simon-II  optimal  two-stage  design  was  applied  for  sample  size  estimation.  We  hypothesise  that  the 
 experimental  therapy  will  improve  the  probability  of  expected  objective  response  rate  in  refractory  settings, 
 from  less  than  5  %  in  previous  reports,  to  20  %  in  the  current  study.  With  80  %  of  power  (0.2)  and  unilateral 
 alpha  (0.1),  24  patients  per  cohort  are  needed  to  demonstrate  the  primary  hypothesis.  The  Simon-II  design 
 suggested  the  observation  of  ≥  1  patient  with  objective  response  within  the  first  nine  patients  included  in  the 
 first  stage.  If  ≥  1  out  of  nine  patients  in  each  cohort  achieve  an  objective  radiological  response  in  the  first 
 stage,  the  study  will  continue  to  recruit  15  additional  patients  up  to  24  patients  per  cohort.  If  ≥  3  out  of  a  total 
 of  24  patients  achieve  a  radiological  objective  response  at  the  final  analysis,  the  study  should  be  declared 
 positive.  If  stage  I  is  reached  only  in  one  cohort,  recruitment  will  continue  in  the  successful  cohort  and 
 stopped in the non-effective cohorts. 
 10.2. 
 S  TUDY  E  NDPOINTS 
 10.2.1.  Primary endpoint 
 Overall  Response  Rate  (ORR):  includes  patients  with  partial  (PR)  and  complete  response  (CR)  as  best 
 response according to RECIST v 1.1. 
 10.2.2.  Secondary endpoints 
 ●  Safety  profile  of  cabozantinib  and  atezolizumab:  The  number  of  patients  with  AEs  and  SAEs, 
 changes  in  laboratory  values,  vital  signs,  ECGs,  and  results  of  physician  examinations  graded 
 according  to  the  CTCAE  v  5.0.  This  will  be  analysed  using  descriptive  statistics  techniques  such  as 
 frequency  and  contingency  tables.  The  final  statistical  analysis  of  this  endpoint  is  expected  to  be 
 performed  within  6  months  after  database  closure,  which  is  expected  at  12  months  after  last  patient 
 inclusion. However, interim analysis may be performed when analysing other primary endpoints. 
 ●  Duration  of  response  (DOR)  as  per  RECIST  1.1:  DOR  calculated  as  the  time  from  the  date  of  first 
 documented CR or PR to the first documented progression or death due to underlying cancer. 
 ●  Progression-free  Survival  (PFS):  Median  Progression  free  survival  (mPFS)  is  defined  as  the  time 
 from  the  date  of  inclusion  to  the  date  of  the  first  documented  disease  progression  or  death  due  to  any 
 cause,  whichever  occurs  first.  PFS  will  be  determined  based  on  tumour  assessment  (RECIST  version 
 1.1  criteria).  The  local  Investigator's  assessments  will  be  used  for  analyses.  Patients  who  are  alive 
 and  have  not  progressed  at  the  last  follow-up  will  be  censored  at  the  date  of  the  last  available  image 
 determination  (CT  Scan  or  MRI).  Patient  with  no  additional  image  test  other  than  that  at  baseline 
 will be censored to the day after inclusion. 
 ●  Overall  Survival  (OS) :  Median  Overall  Survival  (mOS)  is  calculated  as  the  time  from  date  of 
 inclusion to date of death due to any cause. 
 ●  Biomarkers:  To be determined according to study results  and Sponsor feasibility. 
 ●  Quality  of  Life  (QoL):  Quality  of  Life  will  be  analyzed  descriptively  by  QoL  questionnaires 
 (EQ-5D-5L, EORTC QLQ-C30, see appendix 2 and 3). 
 10.3. 
 E  FFICACY  A  SSESSMENT 
 Body  CT  scan  or  MRI  will  be  performed  at  baseline  and  every  12  weeks  (±  2  week)  until  progression.  Body 
 CT  scan  or  MRI  may  be  performed  every  8  weeks  (±  2  week)  if  required  by  local  standard  clinical  practice 
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 or  by  investigator  criteria,  as  long  as  the  frequency  of  assessments  is  maintained.  All  target  and  non-target 
 lesions  in  the  initial  evaluation  will  be  measured  according  to  the  aforementioned  timeline,  until  disease 
 progression. Imaging tests will be performed using the same method each time. 
 10.3.1.  Time-point efficacy assessment 
 Table 4. Criteria for disease evaluation for target lesions 
 CR 
 Disappearance  of  all  target  lesions.  Any  pathological  lymph  nodes  (whether  target  or  non-target)  must 
 have reduction in short axis to <10 mm 
 PR 
 At  least  a  30%  decrease  in  the  sum  of  diameters  of  target  lesions,  taking  as  reference  the  baseline  sum 
 diameters. 
 PD 
 At  least  a  20%  increase  in  the  sum  of  diameters  of  target  lesions,  taking  as  reference  the  smallest  sum  on 
 study  (this  includes  the  baseline  sum  if  that  is  the  smallest  on  study).  In  addition  to  the  relative  increase  of 
 20%,  the  sum  must  also  demonstrate  an  absolute  increase  of  at  least  5  mm.  (Note:  the  appearance  of  one 
 or more new lesions is also considered progression). 
 SD 
 Neither  sufficient  shrinkage  to  qualify  for  PR  nor  sufficient  increase  to  qualify  for  PD,  taking  as  reference 
 the smallest sum diameters while on study. 
 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable. 
 Table 5. Criteria for disease evaluation for non-target lesions 
 CR 
 Disappearance  of  all  non-target  lesions  and  normalisation  of  tumour  marker  level.  All  lymph  nodes  must 
 be non-pathological in size (<10 mm short axis). 
 Non-CR/ 
 non-PD 
 Persistence  of  one  or  more  non-target  lesion(s)  and/or  maintenance  of  tumour  marker  level  above  the 
 normal limits. 
 PD 
 Unequivocal  progression  (see  comments  below)  of  existing  non-target  lesions.  (Note:  the  appearance  of 
 one or more new lesions is also considered progression). 
 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable. 
 Table 6. Overall Response Assessment (RECIST 1.1) 
 Target Lesions 
 Non-target Lesions 
 New Lesions 
 Overall Response 
 CR 
 CR 
 No 
 CR 
 CR 
 Non-CR/non-PD 
 No 
 PR 
 CR 
 Not evaluated 
 No 
 PR 
 PR 
 Non-PD or not all evaluated 
 No 
 PR 
 SD 
 Non-PD or not all evaluated 
 No 
 SD 
 Not all evaluated 
 Non-PD 
 No 
 NE 
 PD 
 Any 
 Yes or No 
 PD 
 Any 
 PD 
 Yes or No 
 PD 
 Any 
 Any 
 Yes 
 PD 
 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable. 
 10.4. 
 D  EFINITION  OF  S  TUDY  P  OPULATIONS 
 Data will be analysed in the following populations: 
 1.  Intent-To-Treat (ITT): All patients that has been enrolled in the trial. 
 2.  Evaluable  population  per  protocol  (PP):  All  patients  fulfilling  all  eligibility  criteria  without 
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 any protocol deviation that makes patient invalid for the primary endpoint evaluation. 
 3.  Safety population: All patients receiving at least one dose of treatment. 
 10.5. 
 S  AFETY  A  NALYSIS 
 The  safety  population  (SP)  consists  of  all  enrolled  subjects  who  received  at  least  one  dose  of  study  treatment. 
 Patients  will  be  monitored  for  safety  during  all  the  stages  of  the  study.  All  safety  and  tolerability  assessments 
 will be done at pre-dosing time, unless otherwise specified. 
 Assessment  of  adverse  events,  safety,  and  toxicity  will  be  performed  according  to  the  National  Cancer 
 Institute  Common  Toxicity  Criteria  (version  5.0)  from  the  time  of  Informed  Consent  for  the  pre-registration 
 phase  until  the  end  of  study.  Safety  and  tolerability  of  study  medication  will  be  determined  by  evaluating  the 
 type,  incidence,  frequency,  severity,  seriousness  and  causality  of  adverse  effects.  Physical  examinations,  and 
 laboratory  tests  will  also  be  assessed.  Any  signs  and/or  symptoms  associated  with  the  worsening  of  the 
 existing tumour at baseline (in severity or frequency) during the trial should be reported as adverse event. 
 10.6. 
 S  TATISTICAL  A  NALYSIS 
 For  each  categorical  variable,  the  results  will  be  summarised  by  frequencies  and  percentages.  For  each 
 continuous  variable,  the  results  will  be  summarised  by  descriptive  statistics  such  as  median,  range,  and 
 interquartile  range  or  by  means,  standard  deviations,  and  95  %  confidence  intervals  (CIs).  For  proportions, 
 point  estimates  and  exact  95  %  confidence  intervals  will  be  calculated.  For  time  to  event  endpoints, 
 Kaplan-Meier  estimates  at  selected  time  points  and  corresponding  curves  will  be  presented.  Time  to  event  is 
 derived  relative  to  the  first  study  treatment  administration.  Laboratory  values  will  be  expressed  as  absolute 
 values and in grades (ordinal categorical variables) according to NCI CTCAE v 5.0. 
 Treatment-emergent  AE  (AEs  starting  after  the  administration  of  study  treatment  and  up  to  study  completion) 
 will  be  summarised  by  system  organ  class  and  preferred  term.  Grading  will  be  presented  by  type  and  in 
 tables  showing  the  frequency  and  percentage  of  the  within-patient  worst  grades.  In  addition,  grade  ≥  3  AEs 
 will be summarised separately. Full analysis details will be outlined in the statistical analysis plan (SAP). 
 10.7. 
 S  TATISTICAL  M  ETHODS 
 Analysis  will  be  based  on  observed  data,  and  missing  data  for  drop-outs  are  not  replaced  by  methods  like 
 LOCF (last option carried forward). 
 Continuous  data  will  be  presented  with  the  number  of  observations,  mean  value,  standard  deviation, 
 minimum,  maximum,  and  median.  Categorical  data  will  be  presented  as  counts  and  percentages.  Individual 
 subject data will be listed. 
 Vital  signs,  ECG  parameters,  clinical  laboratory  data  (haematology,  serum  biochemistry,  and  urinalysis)  will 
 be  presented  in  tabular  form.  Values  outside  the  reference  range  will  be  flagged,  and  the  clinically 
 significantly  abnormal  values  will  be  listed  in  tabular  form.  Adverse  events  will  be  tabulated  by  system  organ 
 class and preferred term after medical coding using the according to NCI CTCAE v 5.0. 
 11. 
 D  IRECT  ACCESS  TO  SOURCE  DATA /  DOCUMENTS 
 11.1. 
 S  OURCE  D  ATA  D  EFINITION 
 Source  data  is  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. 
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 The  Investigator  must  keep  a  file  (medical  file  and  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 listed below and should be as complete as possible. 
 ●  Subject’s full name, date of birth, sex, height, and weight 
 ●  Medical history and concomitant diseases 
 ●  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.  Where  possible,  this  information  should  be  printed  by  the  instrument  used  to  perform  the 
 assessment  or  measurement.  Medical  evaluation  of  such  records  will  be  performed  as  necessary;  all 
 evaluations will be documented, signed, and dated by the Investigator. 
 Electronic  subject  files  will  be  printed  whenever  the  Monitor  performs  source  data  verification.  Printouts  will 
 be  signed  and  dated  by  the  Investigator,  countersigned  by  the  Monitor,  and  will  be  secured  in  a  safe  place  at 
 the site. 
 According  to  the  directives  of  the  European  Parliament  95/46  and  Regulation  Regulation  No.  536/2014  of 
 the  European  Parliament  and  of  the  Council  on  clinical  trials  on  medicinal  products  for  human  use,  the 
 information  obtained  in  the  course  of  the  clinical  trial  may  only  be  used  by  the  Sponsor  of  clinical  trial  to 
 evaluate the results in compliance with the directive mentioned. 
 11.2. 
 S  TUDY  O  VERSIGHT  AND  S  TUDY  M  ONITORING 
 During  the  study,  according  to  monitoring  plan,  a  monitor  from  MFAR  Clinical  Research  or  a  representative 
 will have regular contact with the investigational site, for the following: 
 ●  Provide information and support to the investigator(s) 
 ●  Confirm that facilities remain acceptable 
 ●  Confirm  that  the  investigational  team  is  adhering  to  the  protocol,  data  are  being  accurately 
 recorded  in  the  case  report  forms,  and  that  investigational  product  accountability  checks  are 
 being performed 
 ●  Perform  source  data  verification.  This  includes  a  comparison  of  the  data  in  the  case  report  forms 
 with  the  patient’s  medical  records  at  the  hospital  or  practice,  and  other  records  relevant  to  the 
 study. This will require direct access to all original records for each patient (e.g., clinic charts). 
 ●  Record and report any protocol deviations not previously sent to MFAR Clinical Research. 
 ●  Confirm  that  AEs  and  SAEs  have  been  properly  documented  on  eCRFs,  all  SAEs  have  been 
 forwarded  to  MFAR  Clinical  Research,  and  all  the  SAEs  that  met  criteria  for  reporting  have  been 
 forwarded to the IRB 
 The  monitor  will  be  available  between  visits  if  the  investigator(s)  or  other  staff  members  need  information  or 
 advice. 
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 12. 
 R  EGULATORY 
 12.1. 
 A  UDITS  AND  I  NSPECTIONS 
 Authorised  representatives  of  Sponsor,  a  regulatory  authority,  an  Independent  Ethics  Committee  or  an 
 Institutional  Review  Board  may  visit  the  site  to  perform  audits  or  inspections,  including  source  data 
 verification.  The  purpose  of  a  Sponsor  audit  or  inspection  is  to  systematically  and  independently  examine  all 
 study-related  activities  and  documents  to  determine  whether  these  activities  were  conducted,  and  data  were 
 recorded,  analysed,  and  accurately  reported  according  to  the  protocol,  Good  Clinical  Practice  guidelines  of 
 the  International  Conference  on  Harmonisation,  and  any  applicable  regulatory  requirements.  The  investigator 
 should  contact  the  Sponsor  through  MFAR  immediately  if  contacted  by  a  regulatory  agency  about  an 
 inspection. 
 12.2. 
 I  NDEPENDENT  E  THICAL  C  OMMITTEE  (IEC)  OR  I  NSTITUTIONAL  R  EVIEW  B  OARD  (IRB) R  EVIEW 
 Prior  to  the  commencement  of  the  trial  at  a  given  site,  this  clinical  trial  protocol  will  be  submitted  together 
 with  its  associated  documents  to  the  Central  IEC  for  its  approval,  which  will  be  filed  in  the  Investigator  Site 
 File. A copy will be filed in the Sponsor Trial Master File. 
 The  IEC  will  be  asked  to  document  the  date  of  the  meeting  at  which  the  favourable  opinion  or  approval  was 
 given,  with  the  members  and  voting  members  present.  Written  evidence  of  favourable  opinion  or  approval 
 that  clearly  identifies  the  trial,  the  clinical  trial  protocol  and  the  version,  the  Subject  Information  and 
 Informed Consent Form, should be provided. 
 Amendments  to  this  clinical  trial  protocol  will  also  be  submitted  to  the  concerned  IEC  or  IRB,  before 
 implementation  of  substantial  changes.  Relevant  safety  information  will  be  submitted  to  the  IEC  during  the 
 course of the trial, in accordance with national regulations and requirements. 
 Initial  IEC  positive  vote,  and  all  materials  approved  by  the  IEC  for  this  study  including  the  patient  consent 
 form and recruitment materials must be maintained by the Investigator and made available for inspection. 
 12.3. 
 E  THICAL  C  ONDUCT  OF  THE  S  TUDY 
 The  study  will  be  performed  in  accordance  with  ethical  principles  that  have  their  origin  in  the  Declaration  of 
 Helsinki,  and  are  consistent  with  ICH/Good  Clinical  Practice  and  applicable  regulatory  requirements 
 including: 
 ●  Oviedo  Convention,  of  4  April  1997  on  Human  Rights  and  Biomedicine,  ratified  in  BOE  in  October 
 1999. 
 ●  The  rules  for  the  adequate  protection  of  personal  data,  in  accordance  with  Law  3/2018  Protection  of 
 Personal Data and guarantee of digital rights. 
 ●  The  rights  and  obligations  concerning  clinical  information  and  documentation,  in  accordance  with 
 Law 41/2002 of 14 November, a basic regulatory patient autonomy. 
 ●  Royal  Decree  1090/2015,  of  4  December,  regulating  clinical  trials  with  medicinal  products,  Ethics 
 Committees for Investigation with medicinal products and the Spanish Clinical Studies Registry. 
 ●  Law 14/2007 of 3 July, on Biomedical Research. 
 12.4. 
 W  RITTEN  I  NFORMED  C  ONSENT 
 The  Principal  Investigator(s)  at  each  centre  will  ensure  that  the  patient  is  given  full  and  adequate  oral  and 
 written  information  about  the  nature,  purpose,  possible  risk,  and  benefit  of  the  study.  Patients  must  also  be 
 notified  that  they  are  free  to  discontinue  from  the  study  at  any  time.  The  patient  should  be  given  the 
 opportunity  to  ask  questions  and  allowed  time  to  consider  the  information  provided.  The  patient’s  signed  and 
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 dated informed consent must be obtained before conducting any study procedures. 
 The  Principal  Investigator(s)  will  retain  the  original  signed  ICF  and  this  form  will  be  made  available  for 
 reviewing  during  monitoring  visits.  A  copy  of  the  signed  ICF  will  be  provided  to  the  patient.  The  Principal 
 Investigator will document the informed consent procedure in the patient medical records. 
 12.5. 
 I  NSURANCE 
 An  insurance  policy  in  accordance  with  spanish  regulatory  requirements  will  be  contracted  so  all  patients  in 
 this  clinical  study  will  be  protected  with  a  policy  that  will  meet  the  conditions  stipulated  by  the  RD 
 1090/2015. 
 13. 
 Q  UALITY  C  ONTROL  AND  Q  UALITY  A  SSURANCE 
 To  ensure  compliance  with  Good  Clinical  Practices  and  all  applicable  regulatory  requirements,  the  Sponsor 
 may conduct a quality assurance audit. 
 14. 
 D  ATA  H  ANDLING  AND  R  ECORD  K  EEPING 
 The  data  will  be  recorded  using  the  Electronic  Data  Capture  software  property  of  MFAR  S.L.,  which  is 
 developed  and  maintained  with  strict  observance  of  the  regulatory  standards  for  Clinical  EDC  systems,  with 
 special observance of the guidelines specified at: 
 ●  CPMP/ICH/135/95. ICH E6. Note for Guidance on Good Clinical Practice. 
 ●  Good  Clinical  Data  Management  Practice,  Version  4,  Society  for  Clinical  Data  Management 
 (SCDM), October 2005. 
 ●  EMEA.  Reflection  on  expectations  for  electronic  source  documents  used  in  clinical  trials.  London, 
 17 October 2007. 
 ●  Directive  9  Guidance  for  Industry.  Part  11,  Electronic  Records;  Electronic  Signatures  –  Scope  and 
 Application (August 2003). 
 ●  FDA. Guidance for Industry. Computerised Systems Used in Clinical Investigations (May 2007). 
 ●  FDA.  Guidance  for  Industry.  Part  11,  Electronic  Records;  Electronic  Signatures  –  Scope  and 
 Application (August 2003) 
 ●  Organic Law 3/2018, of December 5, Protection of Personal Data and  guarantee of digital rights 
 The  EDC  database  is  hosted  at  data  server  located  at  the  Data  Centre  maintained  by  Claranet  SAU  located  at 
 “ Calle  Juan  Gris,  10-18,  08014  Barcelona ” .  The  physical  access  to  the  Data  Centre  is  restricted  to  authorised 
 Claranet personnel, and the logical access to the database is restricted to named MFAR personnel. 
 All  the  EDC  users  are  uniquely  identified  by  name,  all  the  access  to  the  software  are  made  through  a  secure, 
 encrypted connection and all the activities are logged and audited. 
 All  the  EDC  forms  are  designed  according  to  the  eCRF  defined  by  the  study  protocol,  and  are  validated 
 according to the DVP (Data Validation Plan). 
 14.1. 
 I  NSPECTION  OF  R  ECORDS 
 The  Sponsor  will  be  allowed  to  conduct  site  visits  to  the  investigation  facilities  for  the  purpose  of  monitoring 
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 any  aspect  of  the  study.  The  Investigator  agrees  to  allow  the  monitor  to  inspect  the  drug  storage  area,  drug 
 stocks,  drug  accountability  records,  subject  charts  and  study  source  documents,  and  other  records  relating  to 
 study conduct. 
 14.2. 
 R  ETENTION  OF  R  ECORDS 
 Upon  initiation  of  the  trial,  the  Investigator  will  be  provided  with  an  Investigator  Site  File  containing  all 
 necessary  trial  documents,  which  will  be  completed  throughout  the  trial  and  updated  as  necessary.  The  file 
 must  be  available  for  review  by  the  Monitor  during  Sponsor  audits,  and  for  inspection  by  Health  Authorities 
 during  and  after  the  trial.  Moreover,  the  file  must  be  safely  archived  for  at  least  25  years  (as  per  local 
 requirements)  after  the  end  of  the  trial.  The  documents  to  be  archived  include  the  Subject  Identification  List 
 and  the  signed  subject  Informed  Consent  Forms.  If  archiving  the  Investigator  Site  File  is  no  longer  possible 
 at the site, the Investigator must notify the Sponsor/designee. 
 All  original  subject  files  (medical  records)  must  be  stored  at  the  site  (hospital,  research  institution,  or 
 practice)  for  the  longest  possible  time  permitted  by  the  applicable  regulations,  and/or  as  per  ICH  GCP 
 guidelines,  whichever  is  longer  (In  Spain  25  years).  In  any  case,  the  Investigator  should  ensure  that  no 
 destruction of medical records is performed without the written approval of the Sponsor. 
 15. 
 P  UBLICATION  P  OLICY 
 As  stated  in  article  42  of  RD  1090/2015  of  clinical  trials,  the  Sponsor  is  obliged  to  publish  both  positive  and 
 negative  results  of  the  authorised  clinical  trials  in  scientific  journals,  and  inform  the  Ethical  Committee  of 
 Clinical Research that approved the study. 
 After  completion  of  the  trial,  the  clinical  publication  will  be  carried  out  by  the  Sponsor  in  collaboration  with 
 the  Coordinating  Investigator  and  Principal  Investigators.  The  order  of  authors  will  strictly  depend  on  the 
 Sponsor  Publication  Policy,  the  contribution  to  the  clinical  trial  and  number  of  eligible  patients  included  by 
 the  Investigators.  Coordinating  investigator,  will  be  first  or  last  authors,  and  the  number  of  the  rest  of  the 
 authors will depend on the above rule and the requirements of the congresses and/or journals. 
 The  first  publication  will  include  the  results  of  the  analysis  of  the  primary  endpoints  and  will  include  data 
 from  all  trial  sites  that  provided  valuable  data.  The  Investigator  will  inform  the  Sponsor  in  advance  about  any 
 plans  to  publish  or  present  data  from  the  trial.  Any  publications  and  presentations  of  the  results  (abstracts  in 
 journals  or  newspapers,  oral  presentations,  etc.),  either  in  whole  or  in  part,  by  Investigators  or  their 
 representatives will require written authorisation by the Sponsor before submission. 
 The  anonymity  of  the  source  subjects  of  the  data  and  biological  samples  will  be  maintained  at  all  times.  The 
 results  or  conclusions  of  the  study  will  be  communicated  primarily  in  scientific  publications  before  being 
 released  to  the  non-health  public.  No  study  outcome  will  be  reported  prematurely  or  in  a  sensationalistic  way. 
 Participating  investigators  should  not  publish  any  patient  data  that  is  directly  related  to  the  study  objectives 
 until the trial report is published. 
 The  trial  will  be  registered  in  the  Spanish  Registry  of  Clinical  Studies  (REEC  -  Registro  Español  de  Estudios 
 Clínicos ) and  Clinical trials.gov  before enrolling the first patient. 
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 APPENDICES 
 Appendix 1. Management of Atezolizumab-specific Adverse Events 
 A)  Management Guidelines for Pulmonary Events, Including Pneumonitis 
 Event 
 Management 
 Pulmonary event, Grade 1 
 ● 
 Continue atezolizumab and monitor closely. 
 ● 
 Re-evaluate on serial imaging. 
 ● 
 Consider patient referral to pulmonary specialist. 
 ● 
 For Grade 1 pneumonitis, consider withholding atezolizumab 
 Pulmonary event, Grade 2 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer  patient  to  pulmonary  and  infectious  disease  specialists 
 and consider bronchoscopy or BAL. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone or equivalent. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 ● 
 For  recurrent  events  or  events  with  no  improvement  after 
 48–72 hours of corticosteroids, treat as a Grade 3 or 4 event. 
 Pulmonary event, Grade 3 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Bronchoscopy or BAL is recommended. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day IV methylprednisone. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over  ≥  1 month. 
 BAL = bronchoscopic alveolar lavage. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of 
 the  extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
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 B)  Management Guidelines for Hepatic Events 
 Event 
 Management 
 In patients without HCC 
 Hepatic event, 
 Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Monitor  LFTs  until  values  resolve  to  within  normal  limits  or 
 to baseline values. 
 Hepatic event, 
 Grade 2 
 All events: 
 ● 
 Monitor LFTs more frequently until return to baseline values. 
 Events of  5 days’ duration: 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer  patient  to  GI  specialist  for  evaluation  and  confirmatory 
 biopsy. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Hepatic event, 
 Grade 3 or 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Consider  patient  referral  to  gastrointestinal  specialist  for 
 evaluation  and  liver  biopsy  to  establish  etiology  of  hepatic 
 injury. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over 1-month. 
 In patients with HCC 
 AST/ALT is within normal 
 limits at baseline and 
 increases to  3ULN to 
 10ULN 
 or 
 AST/ALT is ULN to 3ULN 
 at baseline and increases to 
 5ULN to 10 ULN 
 or 
 AST/ALT is 3ULN to 5ULN 
 at baseline and increases to 
 8ULN to 10ULN 
 ● 
 Monitor LFTs more frequently until return to baseline values. 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 Events of  5 days' duration: 
 ● 
 Consider  initiating  treatment  with  corticosteroids  equivalent  to 
 1-2 mg/kg/day oral prednisone. 
 ● 
 If  event  resolves  to  baseline  or  to  Grade  1  or  better,  resume 
 atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  baseline  or  to  Grade  1  or  better 
 while  withholding  atezolizumab,  permanently  discontinue 
 atezolizumab and contact Medical Monitor.  c 
 AST or ALT increases to 
 10ULN or total bilirubin 
 increases to 3ULN 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Consider  patient  referral  to  gastrointestinal  specialist  for 
 evaluation  and  liver  biopsy  to  establish  etiology  of  hepatic 
 injury. 
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 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  baseline,  taper  corticosteroids  over  ≥1 
 month. 
 LFT  liver function test; ULN = upper limit of normal. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >  12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
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 C)  Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
 Event 
 Management 
 Diarrhea or colitis, 
 Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Initiate symptomatic treatment. 
 ● 
 Endoscopy is recommended if symptoms persist for > 7 days. 
 ● 
 Monitor closely. 
 Diarrhea or colitis, 
 Grade 2 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Initiate symptomatic treatment. 
 ● 
 Patient referral to GI specialist is recommended. 
 ● 
 For  recurrent  events  or  events  that  persist  >  5  days,  initiate 
 treatment  with  corticosteroids  equivalent  to  1-2  mg/kg/day 
 oral prednisone. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Diarrhea or colitis, 
 Grade 3 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer  patient  to  GI  specialist  for  evaluation  and  confirmatory 
 biopsy. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Diarrhea or colitis, 
 Grade 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer  patient  to  GI  specialist  for  evaluation  and  confirmatory 
 biopsy. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over 1 month. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >  12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  both  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
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 D)  Management Guidelines for Endocrine Events 
 Event 
 Management 
 Asymptomatic 
 hypothyroidism 
 ● 
 Continue atezolizumab. 
 ● 
 Initiate treatment with thyroid replacement hormone. 
 ● 
 Monitor TSH closely. 
 Symptomatic 
 hypothyroidism 
 ● 
 Withhold atezolizumab. 
 ● 
 Initiate treatment with thyroid replacement hormone. 
 ● 
 Monitor TSH closely. 
 ● 
 Consider patient referral to endocrinologist. 
 ● 
 Resume  atezolizumab  when  symptoms  are  controlled  and 
 thyroid function is improving. 
 Asymptomatic 
 hyperthyroidism 
 TSH  ≥  0.1 mU/L and < 0.5 mU/L: 
 ● 
 Continue atezolizumab. 
 ● 
 Monitor TSH every 4 weeks. 
 ● 
 Consider patient referral to endocrinologist. 
 TSH < 0.1 mU/L: 
 ● 
 Follow guidelines for symptomatic hyperthyroidism. 
 ● 
 Consider patient referral to endocrinologist. 
 Symptomatic 
 hyperthyroidism 
 ● 
 Withhold atezolizumab. 
 ● 
 Initiate  treatment  with  anti-thyroid  drug  such  as  methimazole 
 or carbimazole as needed. 
 ● 
 Consider patient referral to endocrinologist. 
 ● 
 Resume  atezolizumab  when  symptoms  are  controlled  and 
 thyroid function is improving. 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor 
 for 
 life-threatening 
 immune-mediated 
 hyperthyroidism. 
 Symptomatic adrenal 
 insufficiency, 
 Grades 2 - 4 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer patient to endocrinologist. 
 ● 
 Perform appropriate imaging. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If  event  resolves  to  Grade  1  or  better  and  patient  is  stable  on 
 replacement therapy, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  or  patient  is  not 
 stable 
 on 
 replacement 
 therapy 
 while 
 withholding 
 atezolizumab,  permanently  discontinue  atezolizumab  and 
 contact Medical Monitor.  c 
 Hyperglycemia, 
 Grade 1 or 2 
 ● 
 Continue atezolizumab. 
 ● 
 Investigate  for  diabetes.  If  patient  has  Type  1  diabetes,  treat  as 
 a  Grade  3  event.  If  patient  does  not  have  Type  1  diabetes,  treat 
 as per institutional guidelines. 
 ● 
 Monitor for glucose control. 
 Hyperglycemia, 
 Grade 3 or 4 
 ● 
 Withhold atezolizumab. 
 ● 
 Initiate treatment with insulin. 
 ● 
 Evaluate  for  diabetic  ketoacidosis  and  manage  as  per 
 institutional guidelines. 
 ● 
 Monitor for glucose control. 
 ● 
 Resume  atezolizumab  when  symptoms  resolve  and  glucose 
 levels are stable. 
 Hypophysitis 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
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 (pan-hypopituitarism), 
 Grade 2 or 3 
 ● 
 Refer patient to endocrinologist. 
 ● 
 Perform brain MRI (pituitary protocol). 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 Initiate hormone replacement if clinically indicated. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 ● 
 For recurrent hypophysitis, treat as a Grade 4 event. 
 Hypophysitis 
 (pan-hypopituitarism), 
 Grade 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer patient to endocrinologist. 
 ● 
 Perform brain MRI (pituitary protocol). 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 Initiate hormone replacement if clinically indicated. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
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 E)  Management Guidelines for Ocular Events 
 Event 
 Management 
 Ocular event, 
 Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Patient referral to ophthalmologist is strongly recommended. 
 ● 
 Initiate  treatment  with  topical  corticosteroid  eye  drops  and 
 topical immunosuppressive therapy. 
 ● 
 If symptoms persist, treat as a Grade 2 event. 
 Ocular event, 
 Grade 2 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Patient referral to ophthalmologist is strongly recommended. 
 ● 
 Initiate  treatment  with  topical  corticosteroid  eye  drops  and 
 topical immunosuppressive therapy. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Ocular event, 
 Grade 3 or 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer patient to ophthalmologist. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over 1 month. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
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 F)  Management Guidelines for Immune-Mediated Myocarditis 
 Event 
 Management 
 Immune-mediated 
 myocarditis, Grade 2-4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  a 
 ● 
 Refer patient to cardiologist. 
 ● 
 Initiate  treatment  as  per  institutional  guidelines  and  consider 
 antiarrhythmic  drugs,  temporary  pacemaker,  ECMO,  or  VAD 
 as appropriate. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over  ≥  1 month. 
 a  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  Patients  can  be  re-challenged  with  atezolizumab  only  after  approval  has  been  documented  by 
 both the investigator (or an appropriate delegate) and the Medical Monitor. 
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 G)  Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
 Event 
 Management 
 Grade 1  a 
 fever  b  with or 
 without 
 constitutional 
 symptoms 
 ● 
 Immediately interrupt infusion. 
 ● 
 Upon  symptom  resolution,  wait  for  30  minutes  and  then 
 restart  infusion  at  half  the  rate  being  given  at  the  time  of  event 
 onset. 
 ● 
 If  the  infusion  is  tolerated  at  the  reduced  rate  for  30  minutes, 
 the infusion rate may be increased to the original rate. 
 ● 
 If symptoms recur, discontinue infusion of this dose. 
 ● 
 Administer  symptomatic  treatment,  c  including  maintenance  of 
 IV fluids for hydration. 
 ● 
 In  case  of  rapid  decline  or  prolonged  CRS  (2  days)  or  in 
 patients  with  significant  symptoms  and/or  comorbidities, 
 consider managing as per Grade 2. 
 ● 
 For  subsequent  infusions,  consider  administration  of  oral 
 premedication  with  antihistamines,  anti-pyretics,  and/or 
 analgesics, and monitor closely for IRRs and/or CRS. 
 Grade 2  a 
 fever  b  with 
 hypotension not 
 requiring 
 vasopressors 
 and/or 
 hypoxia requiring 
 low-flow oxygen d 
 by nasal cannula or 
 blow-by 
 ● 
 Immediately interrupt infusion. 
 ● 
 Upon  symptom  resolution,  wait  for  30  minutes  and  then 
 restart  infusion  at  half  the  rate  being  given  at  the  time  of  event 
 onset. 
 ● 
 If symptoms recur, discontinue infusion of this dose. 
 ● 
 Administer symptomatic treatment.  c 
 ● 
 For hypotension, administer IV fluid bolus as needed. 
 ● 
 Monitor  cardiopulmonary  and  other  organ  function  closely  (in 
 the  ICU,  if  appropriate).  Administer  IV  fluids  as  clinically 
 indicated,  and  manage  constitutional  symptoms  and  organ 
 toxicities as per institutional practice. 
 ● 
 Rule  out  other  inflammatory  conditions  that  can  mimic  CRS 
 (e.g.,  sepsis).  If  no  improvement  within  24  hours,  initiate 
 workup and assess for signs and symptoms of HLH or MAS. 
 ● 
 Consider  IV  corticosteroids  (e.g.,  methylprednisolone  2 
 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 ● 
 Consider anti-cytokine therapy.  e 
 ● 
 Consider 
 hospitalization 
 until 
 complete 
 resolution  of 
 symptoms.  If  no  improvement  within  24  hours,  manage  as  per 
 Grade  3,  that  is,  hospitalize  patient  (monitoring  in  the  ICU  is 
 recommended),  permanently  discontinue  atezolizumab,  and 
 contact Medical Monitor. 
 ● 
 If  symptoms  resolve  to  Grade  1  or  better  for  3  consecutive 
 days,  next  dose  of  atezolizumab  may  be  administered.  For 
 subsequent 
 infusions, 
 consider  administration  of  oral 
 premedication 
 with  antihistamines,  antipyretics,  and/or 
 analgesics and monitor closely for IRRs and/or CRS. 
 ● 
 If  symptoms  do  not  resolve  to  Grade  1  or  better  for  3 
 consecutive days, contact Medical Monitor. 
 Grade 3  a 
 fever  b  with 
 hypotension 
 requiring a 
 vasopressor (with 
 or without 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  e 
 ● 
 Administer symptomatic treatment.  c 
 ● 
 For  hypotension,  administer  IV  fluid  bolus  and  vasopressor  as 
 needed. 
 ● 
 Monitor  cardiopulmonary  and  other  organ  function  closely; 
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 vasopressin) 
 and/or 
 hypoxia requiring 
 high-flow oxygen d 
 by nasal cannula, 
 face mask, 
 non-rebreather 
 mask, or venturi 
 mask 
 monitoring  in  the  ICU  is  recommended.  Administer  IV  fluids 
 as  clinically  indicated,  and  manage  constitutional  symptoms 
 and organ toxicities as per institutional practice. 
 ● 
 Rule  out  other  inflammatory  conditions  that  can  mimic  CRS 
 (e.g.,  sepsis).  If  no  improvement  within  24  hours,  initiate 
 workup and assess for signs and symptoms of HLH or MAS. 
 ● 
 Administer  IV  corticosteroids  (e.g.,  methylprednisolone  2 
 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 ● 
 Consider anti-cytokine therapy.  e 
 ● 
 Hospitalize  patient  until  complete  resolution  of  symptoms.  If 
 no  improvement  within  24  hours,  manage  as  per  Grade  4,  that 
 is,  admit  patient  to  ICU  and  initiate  hemodynamic  monitoring, 
 mechanical  ventilation,  and/or  IV  fluids  and  vasopressors  as 
 needed;  for  patients  who  are  refractory  to  anti-cytokine 
 therapy,  experimental  treatments  may  be  considered  at  the 
 discretion  of  the  investigator  and  in  consultation  with  the 
 Medical Monitor. 
 Grade 4  a 
 fever  b  with 
 hypotension 
 requiring multiple 
 vasopressors 
 (excluding 
 vasopressin) 
 and/or 
 hypoxia requiring 
 oxygen by positive 
 pressure (e.g., 
 CPAP, BiPAP, 
 intubation and 
 mechanical 
 ventilation) 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  e 
 ● 
 Administer symptomatic treatment.  c 
 ● 
 Admit  patient  to  ICU  and  initiate  hemodynamic  monitoring, 
 mechanical  ventilation,  and/or  IV  fluids  and  vasopressors  as 
 needed.  Monitor  other  organ  function  closely.  Manage 
 constitutional 
 symptoms  and  organ  toxicities  as  per 
 institutional practice. 
 ● 
 Rule  out  other  inflammatory  conditions  that  can  mimic  CRS 
 (e.g.,  sepsis).  If  no  improvement  within  24  hours,  initiate 
 workup and assess for signs and symptoms of HLH or MAS. 
 ● 
 Administer  IV  corticosteroids  (e.g.,  methylprednisolone  2 
 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 ● 
 Consider  anti-cytokine  therapy. 
 e  For  patients  who  are 
 refractory  to  anti-cytokine  therapy,  experimental  treatments  f 
 may  be  considered  at  the  discretion  of  the  investigator  and  in 
 consultation with the Medical Monitor. 
 ● 
 Hospitalize patient until complete resolution of symptoms. 
 ASTCT  =  American  Society  for  Transplantation  and  Cellular  Therapy;  BiPAP  =  bi-level  positive  airway  pressure;  CAR 
 =  chimeric  antigen  receptor;  CPAP  =  continuous  positive  airway  pressure;  CRS  =  cytokine-release  syndrome;  CTCAE 
 =  Common  Terminology  Criteria  for  Adverse  Events;  eCRF  =  electronic  Case  Report  Form;  HLH  =  hemophagocytic 
 lymphohistiocytosis;  ICU  =  intensive  care  unit;  IRR  =  infusion-related  reaction;  IV=  intravenous;  MAS  =  macrophage 
 activation syndrome; NCCN = National Cancer Comprehensive Network; NCI  National Cancer Institute. 
 Note:  These  management  guidelines  have  been  adapted  from  the  NCCN  guidelines  for  the  management  of  CAR 
 T-cell-related toxicities (Version 2.2019). 
 a  Grading  system  for  these  management  guidelines  is  based  on  ASTCT  consensus  grading  for  CRS.  NCI  CTCAE 
 (version  as  specified  in  the  protocol)  should  be  used  when  reporting  severity  of  IRRs,  CRS,  or  organ  toxicities 
 associated  with  CRS  on  the  Adverse  Event  eCRF.  Organ  toxicities  associated  with  CRS  should  not  influence  overall 
 CRS grading. 
 b  Fever  is  defined  as  temperature  38C  not  attributable  to  any  other  cause.  In  patients  who  develop  CRS  and  who  then 
 receive  anti-pyretic,  anti-cytokine,  or  corticosteroid  therapy,  fever  is  no  longer  required  when  subsequently  determining 
 event severity (grade). In this case, the grade is driven by the presence of hypotension and/or hypoxia. 
 c  Symptomatic  treatment  may  include  oral  or  IV  antihistamines,  anti-pyretics,  analgesics,  bronchodilators,  and/or 
 oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional practice. 
 d  Low flow is defined as oxygen delivered at  6 L/min,  and high flow is defined as oxygen delivered at  6 L/min. 
 e  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available  to  advise  as  needed.  For  subsequent  infusions,  administer  oral  premedication  with  antihistamines, 
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 anti-pyretics,  and/or  analgesics,  and  monitor  closely  for  IRRs  and/or  CRS.  Premedication  with  corticosteroids  and 
 extending the infusion time may also be considered after assessing the benefit-risk ratio. 
 f  Refer to  Riegler et al. (2019) . 
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 H)  Management Guidelines for Pancreatic Events, Including Pancreatitis 
 Event 
 Management 
 Amylase and/or lipase 
 elevation, Grade 2 
 Amylase and/or lipase > 1.5 - 2.0 ULN: 
 ● 
 Continue atezolizumab. 
 ● 
 Monitor amylase and lipase weekly. 
 ● 
 For prolonged elevation (e.g., > 3 weeks), consider treatment 
 ● 
 with corticosteroids equivalent to 10 mg/day oral prednisone. 
 Asymptomatic with amylase and/or lipase > 2.0 - 5.0 x ULN: 
 ● 
 Treat as Grade 3. 
 Amylase and/or lipase 
 elevation, Grade 3 or 4 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer patient to GI specialist. 
 ● 
 Monitor amylase and lipase every other day. 
 ● 
 If  no  improvement,  consider  treatment  with  corticosteroids 
 equivalent to 1-2 mg/kg/day oral prednisone. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 ● 
 For  recurrent  events,  permanently  discontinue  atezolizumab 
 and contact Medical Monitor.  c 
 Immune-mediated 
 pancreatitis, Grade 2 or 3 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer patient to GI specialist. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 ● 
 For  recurrent  events,  permanently  discontinue  atezolizumab 
 and contact Medical Monitor.  c 
 Immune-mediated 
 pancreatitis, Grade 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer patient to GI specialist. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over  ≥  1 month. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
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 available to advise as needed. 
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 I)  Management Guidelines for Dermatologic Events 
 Event 
 Management 
 Dermatologic 
 event, Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Consider  treatment  with  topical  corticosteroids  and/or  other 
 symptomatic therapy (e.g., antihistamines). 
 Dermatologic 
 event, Grade 2 
 ● 
 Continue atezolizumab. 
 ● 
 Consider  patient  referral  to  dermatologist  for  evaluation  and, 
 if indicated, biopsy. 
 ● 
 Initiate treatment with topical corticosteroids. 
 ● 
 Consider  treatment  with  higher-potency  topical  corticosteroids 
 if event does not improve. 
 ● 
 If  unresponsive  to  topical  corticosteroids,  consider  oral 
 prednisone 0.5 mg/kg/day. 
 Dermatologic 
 event, Grade 3 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer  patient  to  dermatologist  for  evaluation  and,  if  indicated, 
 biopsy.. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  10  mg/day 
 oral  prednisone,  increasing  dose  to  1-2  mg/kg/day  if  event 
 does not improve within 48-72 hours. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Dermatologic 
 event, Grade 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 Stevens Johnson syndrome 
 or toxic epidermal 
 necrolysis, (any grade) 
 Additional  guidance  for  Stevens  Johnson  syndrome  or  toxic 
 epidermal necrolysis: 
 ● 
 Withhold  atezolizumab  for  suspected  Stevens  Johnson 
 syndrome or toxic epidermal necrolysis. 
 ● 
 Confirm  diagnosis  by  referring  patient  to  a  specialist 
 (dermatologist,  ophthalmologist  or  urologist  as  relevant)  for 
 evaluation and, if indicated, biopsy. 
 ● 
 Follow  the  applicable  treatment  and  management  guidelines 
 above. 
 ● 
 If  Stevens  Johnson  syndrome  or  toxic  epidermal  necrolysis, 
 permanently discontinue atezolizumab. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed.. 
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 J)  Management Guidelines for Neurologic Disorders 
 Event 
 Management 
 Immune-mediated 
 neuropathy, Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Investigate etiology 
 Immune-mediated 
 neuropathy, Grade 2 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Investigate etiology and refer patient to neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Immune-mediated 
 neuropathy, Grade 3 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer patient to neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 Myasthenia gravis and 
 Guillain-Barré syndrome 
 (any grade) 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer patient to neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 ● 
 Consider  initiation  of  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral or IV prednisone. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  90  of  100 


 K)  Management Guidelines for Immune-Mediated Meningoencephalitis 
 Event 
 Management 
 Immune-mediated 
 meningoencephalitis, all 
 grades 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  a 
 ● 
 Refer  patient  to  neurologist. 
 Initiate  treatment  with 
 corticosteroids 
 equivalent 
 to 
 1-2 
 mg/kg/day 
 IV 
 methylprednisolone  and  convert  to  1-2  mg/kg/day  oral 
 prednisone or equivalent upon improvement. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over  ≥  1 month 
 a  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  91  of  100 


 L)  Management Guidelines for Renal Events 
 Event 
 Management 
 Renal event, Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Monitor  kidney  function  closely,  including  creatinine  and 
 urine  protein,  until  values  resolve  to  within  normal  limits  or  to 
 baseline values. 
 Renal event, Grade 2 
 ● 
 Withhold atezolizumab for up to 12 weeks after event onset.  a 
 ● 
 Refer patient to renal specialist. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Renal event, Grade 3 or 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor. 
 ● 
 Refer patient to renal specialist and consider renal biopsy. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day oral prednisone. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids,  consider  adding  an  immunosuppressive  agent. 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over  ≥  1 month. 
 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.  Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  92  of  100 


 M)  Management Guidelines for Immune-Mediated Myositis 
 Event 
 Management 
 Immune-mediated myositis, 
 Grade 1 
 ● 
 Continue atezolizumab. 
 ● 
 Refer patient to rheumatologist or neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 Immune-mediated myositis, 
 Grade 2 
 ● 
 Withhold  atezolizumab  for  up  to  12  weeks  after  event  onset  a 
 and contact Medical Monitor. 
 ● 
 Refer patient to rheumatologist or neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 ● 
 Consider  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone  and  convert  to  1-2 
 mg/kg/day oral prednisone or equivalent upon improvement. 
 ● 
 If  corticosteroids  are  initiated  and  event  does  not  improve 
 within  48  hours  after  initiating  corticosteroids,  consider 
 adding an immunosuppressive agent. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 Immune-mediated myositis, 
 Grade 3 
 ● 
 Withhold  atezolizumab  for  up  to  12  weeks  after  event  onset  a 
 and contact Medical Monitor. 
 ● 
 Refer patient to rheumatologist or neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 ● 
 Respiratory support may be required in more severe cases. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone,  or  higher-dose  bolus  if 
 patient  is  severely  compromised  (e.g.,  cardiac  or  respiratory 
 symptoms,  dysphagia,  or  weakness  that  severely  limits 
 mobility);  convert  to  1-2  mg/kg/day  oral  prednisone  or 
 equivalent upon improvement. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If event resolves to Grade 1 or better, resume atezolizumab.  b 
 ● 
 If  event  does  not  resolve  to  Grade  1  or  better  while 
 withholding 
 atezolizumab, 
 permanently 
 discontinue 
 atezolizumab and contact Medical Monitor.  c 
 ● 
 For recurrent events, treat as a Grade 4 event. 
 Immune-mediated myositis, 
 Grade 4 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor.  c 
 ● 
 Refer patient to rheumatologist or neurologist. 
 ● 
 Initiate treatment as per institutional guidelines. 
 ● 
 Respiratory support may be required in more severe cases. 
 ● 
 Initiate  treatment  with  corticosteroids  equivalent  to  1-2 
 mg/kg/day  IV  methylprednisolone,  or  higher-dose  bolus  if 
 patient  is  severely  compromised  (e.g.,  cardiac  or  respiratory 
 symptoms,  dysphagia,  or  weakness  that  severely  limits 
 mobility);  convert  to  1-2  mg/kg/day  oral  prednisone  or 
 equivalent upon improvement. 
 ● 
 If  event  does  not  improve  within  48  hours  after  initiating 
 corticosteroids, consider adding an immunosuppressive agent. 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids 
 over  ≥  1 month. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  93  of  100 


 a  Atezolizumab  may  be  withheld  for  a  longer  period  of  time  (i.e.,  >12  weeks  after  event  onset)  to  allow  for 
 corticosteroids  (if  initiated)  to  be  reduced  to  the  equivalent  of  ≤  10  mg/day  oral  prednisone.  The  acceptable  length  of  the 
 extended  period  of  time  must  be  based  on  the  assessment  of  benefit-risk  by  the  investigator  and  in  alignment  with  the 
 protocol  requirement  for  duration  of  treatment  and  documented  by  the  investigator.Medical  Monitor  is  available  to 
 advise as needed. 
 b  If  corticosteroids  have  been  initiated,  they  must  be  tapered  over  ≥  1  month  to  the  equivalent  of  ≤  10  mg/day  oral 
 prednisone before atezolizumab can be resumed. 
 c  Resumption  of  atezolizumab  may  be  considered  in  patients  who  are  deriving  benefit  and  have  fully  recovered  from  the 
 immune-mediated  event.  The  decision  to  rechallenge  patients  with  atezolizumab  should  be  based  on  investigator’s 
 assessment  of  benefit-risk  and  documented  by  the  investigator  (or  an  appropriate  delegate).  Medical  Monitor  is 
 available to advise as needed. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  94  of  100 


 N) Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
 Event 
 Management 
 Suspected HLH 
 or MAS 
 ● 
 Permanently  discontinue  atezolizumab  and  contact  Medical 
 Monitor. 
 ● 
 Consider patient referral to hematologist. 
 ● 
 Initiate  supportive  care,  including  intensive  care  monitoring  if 
 indicated per institutional guidelines. 
 ● 
 Consider 
 initiation 
 of 
 IV 
 corticosteroids, 
 an 
 immunosuppressive agent, and/or anti-cytokine therapy. 
 ● 
 If  event  does  not  respond  to  treatment  within  24  hours,  contact 
 Medical  Monitor  and  initiate  treatment  as  appropriate 
 according  to  published  guidelines  (La  Rosée  2015;  Schram  and 
 Berliner 2015; La Rosée et al. 2019). 
 ● 
 If  event  resolves  to  Grade  1  or  better,  taper  corticosteroids  over 
 ≥ 1 month. 
 HLH  hemophagocytic lymphohistiocytosis; IVintravenous; MAS  macrophage activation syndrome. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  95  of  100 


 O) Severe skin adverse reactions related to the immune system (SCARS) 
 Event 
 Management 
 Skin reaction 
 Grade 3 
 ● 
 Temporary  discontinue  atezolizumab  and  start  corticosteroid 
 treatment with prednisona 1-2 mg/kg/day or equivalent. 
 ● 
 Treatment  with  atezolizumab  can  be  resumed  if  the  event 
 improves  to  ≤  Grade  1  in  12  weeks,  and  corticosteroids  have 
 been reduced to ≤ 10 mg of prednisolone or equivalent per day. 
 Skin reaction 
 Grade 4 
 ● 
 Permanently  discontinue  atezolizumab  and  start  corticosteroid 
 treatment. 
 Stevens-Johnson 
 syndrome (SJS) and toxic 
 epidermal necrolysis 
 (TEN) 
 ● 
 Temporary  discontinue  atezolizumab  and  contact  Medical 
 Monitor for confirmation. 
 ● 
 If  SJS  or  NET  is  confirmed,  atezolizumab  should  be 
 permanently discontinued. 
 ● 
 Caution  should  be  exercised  when  considering  the  use  of 
 atezolizumab  in  a  patient  who  has  previously  had  serious  or 
 life-threatening  skin  adverse  reactions  with  prior  treatment 
 with other immunostimulatory anticancer drugs. 
 SJS  Stevens-Johnson syndrome; TEN  Toxic epidermal necrolysis. 
 CABATEN - Protocol version 4.0 February 18th 2022 - confidential 
 Page  96  of  100 


 Appendix 2. EORTC QLQ-C30 Questionnaire (Version 3.0 Spanish) 
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 Appendix 3. EuroQol-5D questionnaire (Spanish) 
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StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
1 
 
 
 
 
CABATEN 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
                    
 
 
              
27th of October 2020 (version 1.1) 
Written by: Clara de Caralt  
Reviewed by: Jordi Curto 
 
 
Exploratory basket trial of cabozantinib plus 
atezolizumab in   advanced and progressive 
neoplasms of the endocrine system 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
2 
GENERAL INFORMATION 
 
TITLE 
Exploratory basket trial of cabozantinib plus atezolizumab in advanced and progressive 
neoplasms of the endocrine system  
 
STUDY DESIGN 
 
This is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and 
progressive tumors from endocrine system.  
Dosing scheme:  
• 
Level 0 (starting dose): cabozantinib 40 mg qd + atezolizumab 1200 mg iv every 21 
days (one cycle).  
• 
Level -1: cabozantinib 20 mg qd + atezolizumab 1200 mg iv every 21 days (one cycle).  
Cohorts of tumor types:  
1. Well-differentiated neuroendocrine tumors of lung origin or thymus (WHO grade 1 and 
2, typical and atypical carcinoids)  
2. Anaplastic thyroid cancer  
3. Adrenocortical carcinoma  
4. Pheochromocytoma and paraganglioma  
5. Well-differentiated neuroendocrine tumors of gastroenteropancreatic origin (WHO 
grade 1 and 2)  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
3 
6. Poorly differentiated neuroendocrine tumors (WHO grade 3), excluding small cell lung 
cancer  
 
 
TREATMENT 
All the subjects will be treated with the combination until disease progression, unacceptable 
toxicity, or patient consent withdrawal (whichever occurs first) according to section 7 of the 
protocol.  
• 
Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously. 
• 
Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle).  
Dosing scheme:  
• 
 Level 0 (starting dose): cabozantinib 40 mg qd + atezolizumab 1200 mg iv every 21 
days (one cycle).  
• 
Level -1: cabozantinib 20 mg qd + atezolizumab 1200 mg iv every 21 days (one cycle).  
 
SPONSOR 
GETNE (Spanish Group of Neuroendocrine and Endocrine Tumors)  
C/ Pau Alsina, 64-68, Esc. B entresuelo 5ª, 08024 Barcelona 
Phone: +34 93 434 44 12  
E-mail: getne@getne.org  
 
STUDY CHIEF INVESTIGATOR 
Jaume Capdevila, M.D., Ph.D. Vall d’Hebrón University Hospital Medical Oncology Department 
P. Vall d’Hebron, 119-129 08035 – Barcelona 
Phone: +34 93 274 60 85 E-mail: jcapdevila@vhio.net  
Enrique Grande. M.D., Ph.D. MD Anderson Cancer Center Madrid Medical Oncology 
Department. Calle de Arturo Soria, 270, 28033 – Madrid 
Phone: +34 91 787 86 00 e-mail: egrande@mdanderson.es  
 
MONITORING ORGANISATION (CRO) 
MFAR Clinical Research 
C/ Sinfonía, 28, 2ª planta Nº1 - 28054 Madrid 
Tel: 93.434.44.12 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
4 
Fax: 93.253.11.68 
e-mail: investigacion@mfar.net 
www.mfar.es 
 
INDEX OF CONTENTS DE CONTENIDOS 
ABREVIATURAS Y DEFINICIONES ……………………………………………… 7 
1. 
MATERIAL AND METHODS .......................................................................................................... 14 
1.1. INTRODUCTION ............................................................................................................... 14 
1.1.1. 
BACKGROUND ....................................................................................................... 14 
1.2. PURPOSE OF THE ANALYSIS .............................................................................................. 17 
1.2.1. 
STUDY OBJECTIVES ................................................................................................ 18 
1.2.2. 
ENDPOINTS ........................................................................................................... 18 
1.3. STUDY METHODS ............................................................................................................ 19 
1.3.1. 
INCLUSION-EXCLUSION CRITERIA ........................................................................... 19 
1.3.1.1 
INCLUSION CRITERIA ............................................................................................. 19 
1.3.1.2 
EXCLUSION CRITERIA ............................................................................................. 20 
1.3.2. 
STUDY VARIABLES ................................................................................................. 23 
1.4. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........................... 25 
1.4.1. 
DETERMINATION OF SAMPLE SIZE .......................................................................... 25 
1.4.2. 
GENERAL CONSIDERATIONS ................................................................................... 26 
1.4.3. 
DESCRIPTION OF ANALYSIS SETS ............................................................................ 26 
1.4.4. 
MISSING DATA ...................................................................................................... 26 
1.4.5. 
INTERIM ANALYSES AND DATA MONITORING ......................................................... 26 
1.5. SUMMARY OF STUDY DATA ...................................................................................... 26 
1.5.1. 
PROTOCOL DEVIATIONS ......................................................................................... 27 
1.6. REPORTING CONVENTIONS .............................................................................................. 27 
1.7. TECHNICAL DETAILS ......................................................................................................... 27 
2. 
RESULTS ...................................................................................................................................... 28 
2.1. STUDY POPULATION ........................................................................................................ 28 
2.1.1. 
RECRUITED PATIENTS (CENTRES/INVESTIGATORS) .................................................. 28 
2.1.2. 
EVALUABLE PATIENTS ............................................................................................ 28 
2.2. BASELINE PATIENT CHARACTERISTICS ............................................................................... 30 
2.2.1. 
TUMOR DATA AND PRIOR TREATMENTS ................................................................. 34 
2.2.2. 
PREVIOUS MEDICAL HISTORY ................................................................................. 38 
2.2.3. 
BASELINE PATIENT CHARACTERISTICS IN COHORT 1 ................................................ 39 
2.2.3.1 
TUMOR DATA AND PRIOR TREATMENTS IN COHORT 1 ............................................ 43 
2.2.3.2 
PREVIOUS MEDICAL HISTORY IN COHORT 1 ............................................................ 46 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
5 
2.2.4. 
BASELINE PATIENT CHARACTERISTICS IN COHORT 2 ................................................ 48 
2.2.4.1 
TUMOR DATA AND PRIOR TREATMENTS IN COHORT 2 ............................................ 51 
2.2.4.2 
PREVIOUS MEDICAL HISTORY IN COHORT 2 ............................................................ 55 
2.2.5. 
BASELINE PATIENT CHARACTERISTICS IN COHORT 3 ................................................ 56 
2.2.5.1 
TUMOR DATA AND PRIOR TREATMENTS IN COHORT 3 ............................................ 60 
2.2.5.2 
PREVIOUS MEDICAL HISTORY IN COHORT 3 ............................................................ 64 
2.2.6. 
BASELINE PATIENT CHARACTERISTICS IN COHORT 4 ................................................ 65 
2.2.6.1 
TUMOR DATA AND PRIOR TREATMENTS IN COHORT 4 ............................................ 69 
2.2.6.2 
PREVIOUS MEDICAL HISTORY IN COHORT 4 ............................................................ 72 
2.2.7. 
BASELINE PATIENT CHARACTERISTICS IN COHORT 5 ................................................ 74 
2.2.7.1 
TUMOR DATA AND PRIOR TREATMENTS IN COHORT 5 ............................................ 77 
2.2.7.2 
PREVIOUS MEDICAL HISTORY IN COHORT 5 ............................................................ 81 
2.2.8. 
BASELINE PATIENT CHARACTERISTICS IN COHORT 6 ................................................ 83 
2.2.8.1 
TUMOR DATA AND PRIOR TREATMENTS IN COHORT 6 ............................................ 86 
2.2.8.2 
PREVIOUS MEDICAL HISTORY IN COHORT 6 ............................................................ 90 
2.3. TREATMENT EXPOSURE ................................................................................................... 92 
2.3.1. 
TREATMENT EXPOSURE IN COHORT 1 ..................................................................... 94 
2.3.2. 
TREATMENT EXPOSURE IN COHORT 2 ..................................................................... 95 
2.3.3. 
TREATMENT EXPOSURE IN COHORT 3 ..................................................................... 97 
2.3.4. 
TREATMENT EXPOSURE IN COHORT 4 ..................................................................... 99 
2.3.5. 
TREATMENT EXPOSURE IN COHORT 5 ................................................................... 101 
2.3.6. 
TREATMENT EXPOSURE IN COHORT 6 ................................................................... 103 
2.3.7. 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT .............................. 105 
2.3.7.1 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 1 .......... 106 
2.3.7.2 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 2 .......... 108 
2.3.7.3 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 3 .......... 109 
2.3.7.4 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 4 .......... 111 
2.3.7.5 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 5 .......... 112 
2.3.7.6 
WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 6 .......... 113 
2.4. ANALYSIS SETS .............................................................................................................. 116 
2.5. EFFICACY ANALYSIS ....................................................................................................... 117 
2.5.1. 
PRIMARY EFFICACY ANALYSIS .............................................................................. 117 
2.5.2. 
SECONDARY EFFICACY ANALYSIS .......................................................................... 118 
2.5.2.1 
DURATION OF RESPONSE ..................................................................................... 118 
2.5.2.2 
PROGRESSION FREE SURVIVAL ............................................................................. 119 
2.5.2.2.1 
Progression free survival ITT POPULATION ...................................................... 119 
2.5.2.2.2 
Progression free survival PP POPULATION ....................................................... 121 
2.5.2.3 
OVERALL SURVIVAL ............................................................................................. 123 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
6 
2.5.2.3.1 
OVERALL survival ITT POPULATION .................................................................. 123 
2.5.2.3.2 
OVERALL survival PP POPULATION .................................................................. 125 
2.5.2.4 
FOLLOW UP ......................................................................................................... 126 
2.6. SAFETY ANALYSIS .......................................................................................................... 127 
2.6.1. 
SAFETY SUMMARY: ALL EVENTS IN OVERALL ........................................................ 127 
2.6.2. 
TOXICITIES (AE RELATED TO ANY TREATMENT) ..................................................... 128 
2.6.3. 
TOXICITIES GRADE ≥3 .......................................................................................... 130 
2.6.4. 
TOXICITIES RELATED TO BOTH TREATMENTS ......................................................... 130 
2.6.5. 
TOXICITIES RELATED ONLY TO CABOZANTINIB ...................................................... 130 
2.6.6. 
TOXICITIES RELATED ONLY TO ATEZOLIZUMAB ..................................................... 131 
2.6.7. 
MOST FREQUENT AES .......................................................................................... 132 
2.6.8. 
AE GRADE ≥3 ....................................................................................................... 133 
2.6.9. 
SAE ..................................................................................................................... 134 
2.6.10. 
SAE RELATED TO ANY TREATMENT ....................................................................... 135 
2.6.11. 
SAFETY SUMMARY: ALL EVENTS PER COHORTS ..................................................... 137 
2.6.12. 
TOXICITIES (AE RELATED TO ANY TREATMENT) PER COHORTS ................................ 139 
2.6.13. 
TOXICITIES GRADE ≥3 PER COHORTS ..................................................................... 140 
2.6.14. 
MOST FREQUENT AES .......................................................................................... 142 
2.6.15. 
AE GRADE ≥3 PER COHORTS ................................................................................. 143 
2.6.16. 
SAE PER COHORTS ............................................................................................... 145 
2.6.17. 
SAE RELATED TO ANY TREATMENT PER COHORTS ................................................. 145 
2.7. ANNEX: LIST OF ALL TOXICITIES ...................................................................................... 147 
3. 
CONCLUSIONS .......................................................................................................................... 148 
4. 
ANEXES ..................................................................................................................................... 149 
4.1. ANEX I: DATABASE MANAGEMENT ................................................................................. 149 
5. 
REFERENCES ............................................................................................................................. 150 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
7 
INDEX OF TABLES 
Table 1. Recruited patients by site ...................................................................................................... 28 
Table 2. Non evaluable patients ......................................................................................................... 28 
Table 3. Patients evaluable by Site ..................................................................................................... 28 
Table 4. Evaluable patients and Analysis sets ..................................................................................... 29 
Table 5. Patients allocated in each cohort by hospital ........................................................................ 29 
Table 6. Baseline patient characteristics ............................................................................................. 30 
Table 7. Haematology and Coagulation .............................................................................................. 31 
Table 8. Biochemistry ......................................................................................................................... 31 
Table 9. Tumor Markers ..................................................................................................................... 32 
Table 10. Serology .............................................................................................................................. 32 
Table 11. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) ........................................................ 33 
Table 12. Cancer History ..................................................................................................................... 34 
Table 13. Baseline surgery .................................................................................................................. 35 
Table 14. Baseline Radiotherapy ........................................................................................................ 36 
Table 15. Previous treatments ............................................................................................................ 36 
Table 16. Other cancer history ............................................................................................................ 37 
Table 17. Relevant Comorbidiities ...................................................................................................... 38 
Table 18. Prior Concomitant medication ............................................................................................. 38 
Table 19. Urinalysis ............................................................................................................................ 38 
Table 20. Pregnancy test .................................................................................................................... 39 
Table 21. Electrocardiogram ............................................................................................................... 39 
Table 22. Baseline patient characteristics in cohort 1 ......................................................................... 39 
Table 23. Haematology and Coagulation in cohort 1 ........................................................................... 40 
Table 24. Biochemistry in cohort 1 ..................................................................................................... 41 
Table 25. Tumor Markers in cohort 1 .................................................................................................. 42 
Table 26. Serology in cohort 1 ............................................................................................................ 42 
Table 27. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 1 ...................................... 42 
Table 28. Cancer History in cohort 1 ................................................................................................... 43 
Table 29. Baseline surgery in cohort 1 ................................................................................................ 44 
Table 30. Baseline Radiotherapy in cohort 1 ....................................................................................... 45 
Table 31. Previous treatments in cohort 1 .......................................................................................... 45 
Table 32. Other cancer history ............................................................................................................ 46 
Table 33. Relevant Comorbidiities in cohort 1 ..................................................................................... 46 
Table 34. Prior Concomitant medication in cohort 1 ........................................................................... 47 
Table 35. Urinalysis in cohort 1 ........................................................................................................... 47 
Table 36. Pregnancy test in cohort 1 ................................................................................................... 47 
Table 37. Electrocardiogram in cohort 1 ............................................................................................. 48 
Table 38. Baseline patient characteristics in cohort 2 ......................................................................... 48 
Table 39. Haematology and Coagulation in cohort 2 ........................................................................... 49 
Table 40. Biochemistry in cohort 2 ..................................................................................................... 50 
Table 41. Tumor Markers in cohort 2 .................................................................................................. 50 
Table 42. Serology in cohort 2 ............................................................................................................ 51 
Table 43. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 2 ...................................... 51 
Table 44. Cancer History in cohort 2 ................................................................................................... 51 
Table 45. Baseline surgery in cohort 2 ................................................................................................ 53 
Table 46. Baseline Radiotherapy in cohort 2 ....................................................................................... 53 
Table 47. Previous treatments in cohort 2 .......................................................................................... 54 
Table 48. Other cancer history ............................................................................................................ 55 
Table 49. Relevant Comorbidiities in cohort 2 ..................................................................................... 55 
Table 50. Prior Concomitant medication in cohort 2 ........................................................................... 55 
Table 51. Urinalysis in cohort 2 ........................................................................................................... 55 
Table 52. Pregnancy test in cohort 2 ................................................................................................... 56 
Table 53. Electrocardiogram in cohort 2 ............................................................................................. 56 
Table 54. Baseline patient characteristics in cohort 3 ......................................................................... 57 


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Table 55. Haematology and Coagulation in cohort 3 ........................................................................... 58 
Table 56. Biochemistry in cohort 3 ..................................................................................................... 58 
Table 57. Tumor Markers in cohort 3 .................................................................................................. 59 
Table 58. Serology in cohort 3 ............................................................................................................ 59 
Table 59. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 3 ...................................... 60 
Table 60. Cancer History in cohort 3 ................................................................................................... 60 
Table 61. Baseline surgery in cohort 3 ................................................................................................ 61 
Table 62. Baseline Radiotherapy in cohort 3 ....................................................................................... 62 
Table 63. Previous treatments in cohort 3 .......................................................................................... 62 
Table 64. Other cancer history ............................................................................................................ 63 
Table 65. Relevant Comorbidiities in cohort 3 ..................................................................................... 64 
Table 66. Prior Concomitant medication in cohort 3 ........................................................................... 64 
Table 67. Urinalysis in cohort 3 ........................................................................................................... 64 
Table 68. Pregnancy test in cohort 3 ................................................................................................... 65 
Table 69. Electrocardiogram in cohort 3 ............................................................................................. 65 
Table 70. Baseline patient characteristics in cohort 4 ......................................................................... 65 
Table 71. Haematology and Coagulation in cohort 4 ........................................................................... 66 
Table 72. Biochemistry in cohort 4 ..................................................................................................... 67 
Table 73. Tumor Markers in cohort 4 .................................................................................................. 68 
Table 74. Serology in cohort 4 ............................................................................................................ 68 
Table 75. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 4 ...................................... 68 
Table 76. Cancer History in cohort 4 ................................................................................................... 69 
Table 77. Baseline surgery in cohort 4 ................................................................................................ 70 
Table 78. Baseline Radiotherapy in cohort 4 ....................................................................................... 71 
Table 79. Previous treatments in cohort 4 .......................................................................................... 71 
Table 80. Other cancer history ............................................................................................................ 72 
Table 81. Relevant Comorbidiities in cohort 4 ..................................................................................... 72 
Table 82. Prior Concomitant medication in cohort 4 ........................................................................... 73 
Table 83. Urinalysis in cohort 4 ........................................................................................................... 73 
Table 84. Pregnancy test in cohort 4 ................................................................................................... 73 
Table 85. Electrocardiogram in cohort 4 ............................................................................................. 74 
Table 86. Baseline patient characteristics in cohort 5 ......................................................................... 74 
Table 87. Haematology and Coagulation in cohort 5 ........................................................................... 75 
Table 88. Biochemistry in cohort 5 ..................................................................................................... 75 
Table 89. Tumor Markers in cohort 5 .................................................................................................. 76 
Table 90. Serology in cohort 5 ............................................................................................................ 77 
Table 91. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 5 ...................................... 77 
Table 92. Cancer History in cohort 5 ................................................................................................... 77 
Table 93. Baseline surgery in cohort 5 ................................................................................................ 79 
Table 94. Baseline Radiotherapy in cohort 5 ....................................................................................... 79 
Table 95. Previous treatments in cohort 5 .......................................................................................... 80 
Table 96. Other cancer history ............................................................................................................ 81 
Table 97. Relevant Comorbidiities in cohort 5 ..................................................................................... 81 
Table 98. Prior Concomitant medication in cohort 5 ........................................................................... 81 
Table 99. Urinalysis in cohort 5 ........................................................................................................... 81 
Table 100. Pregnancy test in cohort 5 ................................................................................................. 82 
Table 101. Electrocardiogram in cohort 5 ........................................................................................... 82 
Table 102. Baseline patient characteristics in cohort 6 ........................................................................ 83 
Table 103. Haematology and Coagulation in cohort 6 ......................................................................... 84 
Table 104. Biochemistry in cohort 6 .................................................................................................... 84 
Table 105. Tumor Markers in cohort 6 ................................................................................................ 85 
Table 106. Serology in cohort 6 .......................................................................................................... 85 
Table 107. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 6 .................................... 86 
Table 108. Cancer History in cohort 6 ................................................................................................. 86 
Table 109. Baseline surgery in cohort 6 .............................................................................................. 88 
Table 110. Baseline Radiotherapy in cohort 6 ..................................................................................... 88 
Table 111. Previous treatments in cohort 6 ........................................................................................ 88 


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Table 112. Other cancer history .......................................................................................................... 89 
Table 113. Relevant Comorbidiities in cohort 6 ................................................................................... 90 
Table 114. Prior Concomitant medication in cohort 6 ......................................................................... 90 
Table 115. Urinalysis in cohort 6 ......................................................................................................... 90 
Table 116. Pregnancy test in cohort 6 ................................................................................................. 91 
Table 117. Electrocardiogram in cohort 6 ........................................................................................... 91 
Table 118. Cabozantinib compliance ................................................................................................... 92 
Table 119. List of patients that did not receive Cabozantinib .............................................................. 93 
Table 120. Atezolizumab compliance .................................................................................................. 93 
Table 121. List of patients that did not receive Atezolizumab ............................................................. 93 
Table 122. Cabozantinib compliance in cohort 1 ................................................................................. 94 
Table 123. List of patients that did not receive Cabozantinib in cohort 1 ............................................ 95 
Table 124. Atezolizumab compliance in cohort 1 ................................................................................ 95 
Table 125. List of patients that did not receive Atezolizumab in cohort 1 ............................................ 95 
Table 126. Cabozantinib compliance in cohort 2 ................................................................................. 95 
Table 127. List of patients that did not receive Cabozantinib in cohort 2 ............................................ 96 
Table 128. Atezolizumab compliance in cohort 2 ................................................................................ 96 
Table 129. List of patients that did not receive Atezolizumab in cohort 2 ............................................ 97 
Table 130. Cabozantinib compliance in cohort 3 ................................................................................. 97 
Table 131. List of patients that did not receive Cabozantinib in cohort 3 ............................................ 98 
Table 132. Atezolizumab compliance in cohort 3 ................................................................................ 98 
Table 133. List of patients that did not receive Atezolizumab in cohort 3 ............................................ 99 
Table 134. Cabozantinib compliance in cohort 4 ................................................................................. 99 
Table 135. List of patients that did not receive Cabozantinib in cohort 4 .......................................... 100 
Table 136. Atezolizumab compliance in cohort 4 .............................................................................. 100 
Table 137. List of patients that did not receive Atezolizumab in cohort 4 .......................................... 100 
Table 138. Cabozantinib compliance in cohort 5 ............................................................................... 101 
Table 139. List of patients that did not receive Cabozantinib in cohort 5 .......................................... 102 
Table 140. Atezolizumab compliance in cohort 5 .............................................................................. 102 
Table 141. List of patients that did not receive Atezolizumab in cohort 5 .......................................... 102 
Table 142. Cabozantinib compliance in cohort 6 ............................................................................... 103 
Table 143. List of patients that did not receive Cabozantinib in cohort 6 .......................................... 104 
Table 144. Atezolizumab compliance in cohort 6 .............................................................................. 104 
Table 145. List of patients that did not receive Atezolizumab in cohort 6 .......................................... 104 
Table 146. Study treatment premature interruption ......................................................................... 105 
Table 147. Reason for end of treatment for Cabozantinib ................................................................. 105 
Table 148. Reason for end of treatment for Atezolizumab ................................................................ 106 
Table 149. Study treatment length ................................................................................................... 106 
Table 150. Study treatment premature interruption in cohort 1 ....................................................... 106 
Table 151. Reason for end of treatment for Cabozantinib in cohort 1 ............................................... 107 
Table 152. Reason for end of treatment for Atezolizumab in cohort 1 .............................................. 107 
Table 153. Study treatment length in cohort 1 .................................................................................. 107 
Table 154. Study treatment premature interruption in cohort 2 ....................................................... 108 
Table 155. Reason for end of treatment for Cabozantinib in cohort 2 ............................................... 108 
Table 156. Reason for end of treatment for Atezolizumab in cohort 2 .............................................. 108 
Table 157. Study treatment length in cohort 2 .................................................................................. 109 
Table 158. Study treatment premature interruption in cohort 3 ....................................................... 109 
Table 159. Reason for end of treatment for Cabozantinib in cohort 3 ............................................... 109 
Table 160. Reason for end of treatment for Atezolizumab in cohort 3 .............................................. 110 
Table 161. Study treatment length in cohort 3 .................................................................................. 110 
Table 162. Study treatment premature interruption in cohort 4 ....................................................... 111 
Table 163. Reason for end of treatment for Cabozantinib in cohort 4 ............................................... 111 
Table 164. Reason for end of treatment for Atezolizumab in cohort 4 .............................................. 111 
Table 165. Study treatment length in cohort 4 .................................................................................. 112 
Table 166. Study treatment premature interruption in cohort 5 ....................................................... 112 
Table 167. Reason for end of treatment for Cabozantinib in cohort 5 ............................................... 112 
Table 168. Reason for end of treatment for Atezolizumab in cohort 5 .............................................. 113 


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Table 169. Study treatment length in cohort 5 .................................................................................. 113 
Table 170. Study treatment premature interruption in cohort 6 ....................................................... 113 
Table 171. Reason for end of treatment for Cabozantinib in cohort 6 ............................................... 114 
Table 172. Reason for end of treatment for Atezolizumab in cohort 6 .............................................. 114 
Table 173. Study treatment length in cohort 6 .................................................................................. 115 
Table 174. Analysis sets .................................................................................................................... 116 
Table 175. List of patients that are excluded from ITT, PP and/or security population ...................... 116 
Table 176. ORR (ITT) ......................................................................................................................... 117 
Table 177. ORR (PP) .......................................................................................................................... 117 
Table 178. Duration of response (DOR) (ITT) ..................................................................................... 118 
Table 179. Duration of response (DOR) (PP) ..................................................................................... 118 
Table 180. Progression free survival at 6 and 12 months (ITT) ........................................................... 119 
Table 181. Progression free survival events at 6 months (ITT) ........................................................... 119 
Table 182. Progression free survival at 6 and 12 months (PP) ........................................................... 121 
Table 183. Progression free survival events at 6 months (PP) ........................................................... 121 
Table 184. Overall survival at 6 and 12 months (ITT) ......................................................................... 123 
Table 185. Overall survival events at 6 months (ITT) ......................................................................... 123 
Table 186. Overall survival at 6 and 12 months (PP) ......................................................................... 125 
Table 187. Overall survival events at 6 months (PP) .......................................................................... 125 
Table 188. Follow up: mean and median ITT ..................................................................................... 126 
Table 189. Follow up: mean and median PP ...................................................................................... 126 
Table 189. Safety .............................................................................................................................. 127 
Table 190. Most frequent toxicities (>10%, n>2) ............................................................................... 128 
Table 191. Most frequent toxicities by grade .................................................................................... 128 
Table 192. Frequency of toxicities grade ≥3 ...................................................................................... 130 
Table 193. List of toxicities grade ≥3 ................................................................................................. 130 
Table 194. Toxicities related to both treatments .............................................................................. 130 
Table 194. Toxicities related only with cabozantinib ......................................................................... 131 
Table 195. Toxicities related only with atezolizumab ........................................................................ 131 
Table 196. Most frequent AEs (>20%, n>4) ....................................................................................... 132 
Table 197. Most frequent AEs by grade ............................................................................................ 133 
Table 198. Frequency of AEs grade ≥3 ............................................................................................... 133 
Table 199. List of AEs with grade ≥3 .................................................................................................. 134 
Table 200. SAEs ................................................................................................................................ 134 
Table 201. List of all SAEs ................................................................................................................. 135 
Table 202. SAEs RELATED ................................................................................................................. 135 
Table 203. List of all SAEs RELATED ................................................................................................... 136 
Table 204. Safety per cohorts ........................................................................................................... 137 
Table 205. Most frequent toxicities (>10%, n>2) per cohorts ............................................................ 139 
Table 206. Most frequent toxicities by grade per cohorts ................................................................. 139 
Table 207. Frequency of toxicities grade  ≥3 per cohorts ................................................................... 140 
Table 211. Most frequent AEs (>20%, n>4) per cohorts ..................................................................... 142 
Table 212. Most frequent AEs by grade per cohorts .......................................................................... 142 
Table 213. Frequency of AEs grade ≥3 per cohorts ............................................................................ 143 
Table 215. SAEs per cohorts .............................................................................................................. 145 
Table 217. SAEs RELATED per cohorts ............................................................................................... 145 
Table 219. List of all toxicities ........................................................................................................... 147 
 
INDEX OF FIGURES 
FIGURE 1 KAPLAN MEIER CURVE: PFS (ITT) .............................................................................. 120 
FIGURE 2 KAPLAN MEIER CURVE: PFS (PP) .............................................................................. 122 
FIGURE 3 KAPLAN MEIER CURVE: OS (ITT) ............................................................................... 124 
FIGURE 4 KAPLAN MEIER CURVE: OS (PP) ............................................................................... 126 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation Explanation 
ADL 
Activities of Daily Living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AP 
Anatomic pathology 
ASCO 
American Society of Clinical Oncology 
AUC 
Area Under Curve 
BED 
Biological efficacious dose 
beta-hCG 
Beta-human chorionic gonadotropin 
BID 
bis in die, (Latin for "twice daily") 
BMI 
Body mass index 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
CIs 
Confidence intervals 
CK 
Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine 
kinase 
CL/F 
Apparent total clearance of the drug from plasma after administration 
Cmax 
Maximum (or peak) serum concentration 
CB 
Clinical benefit 
CDR 
Control disease rate 
CR 
Complete Response 
CRF 
Controlled Release Form 
CSR 
Central Serous Retinopathy 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computed Tomography Scan 
DBP 
Diastolic Blood Pressure 
DLT 
Dose Limiting Toxicity 
DM 
Distant metastasis 
DR 
Duration of response 
DVP 
Data Validation Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ESMO 
European society of Medical Oncology 
FBE 
Full blood examination 
FDA 
United States Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
Fluorescence in situ hybridization 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GEP-NET 
Gastroenteropancreatic Neuroendocrine Tumors 
GH 
Growth hormone 
Hb 
Haemoglobin 
H/E 
Haematoxylin/eosin 
HFSR 
Hand Foot Skin Reaction 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intention To Treat 
KA 
Keratoacanthoma 
Ke 
Elimination rate constant 
KPS 
Karnofsky Performance Status 
LLN 
Lower Limit of Normality 
LVEF 
Left Ventricular Ejection Fraction 
LOCF 
Last Observation Carried Forward 
MAP 
Mitogen-Activated Protein 
MASCC 
Multinational Association of Supportive Care 
MDM2 
Mouse double minute 2 homolog 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase kinase 
MEN 
Multiple endocrine neoplasms 
MLPA 
Multiplex ligation-dependent probe amplification 
MRI 
Magnetic Resonance Imaging 
MRT 
Mean Residence Time 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
NET 
Neuroendocrine Tumor 
OAE 
Other significant adverse event 
ORR 
Overall response rate 
OS 
Overall Survival 
OTEL 
Open To Enrolment Letter 
P2RD 
Phase two recommended dose 
PCR 
Polymerase Chain Reaction 
PD 
Progression disease 
PE 
Physical examination 
PET-CT 
Positron emission tomography–computed tomography 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PLGA 
Poly (lactic-co-glycolic acid) 
pNET 
Pancreatic NET 
PP 
Per Protocol 
PR 
Partial Response 
PRT 
Primary retroperitoneal tumours 
PS 
Performance Status 
QD 
Quaque die, every day “once daily” 
QLQ 30 
Quality of Life Questionnaire Core 30 
QoL 
Quality of Life 
RDD 
Retinal Degenerative Disease 
RECIST 
Response Evaluation Criteria In Solid Tumours 
REEC 
Registro Español de Estudios Clínicos (Spanish Registry of Clinical Studies) 
RLS 
Retroperitoneal Liposarcoma 
RP 
Retroperitoneum 
RP2D 
Recommended Phase II dose 
RVO 
Retinal Vein Occlusion 
Rx 
Radiography 
 
 
 


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SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse reaction 
SBP 
Systolic Blood Pressure 
SC 
Subcutaneous 
SCC 
Squamous Cell Carcinoma 
SD 
Stable disease 
SDV 
Source Data Verification 
SmPC 
Summary of Product Characteristics 
SP 
Safety Population 
SRS 
Stereotactic Radiosurgery 
SSAs 
Somatostatin Analogues 
SSTR 
Somatostatin Receptors 
SUSAR 
Suspected unexpected serious adverse reaction 
Sx 
Surgery 
Tmax 
Time of the sample identified as Cmax 
TR 
Translational Research 
TTLR 
Time to Local Relapse 
ULN 
Upper Limit of Normality 
Vd/F 
Apparent volume of distribution after non-intravenous administration 
VS 
Vital signs 
VMAT 
Volumetric Modulated Arc Therapy 
WBC 
White Blood Count 
WBRT 
Whole Brain Radiotherapy 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. MATERIAL AND METHODS 
1.1. INTRODUCTION 
1.1.1. BACKGROUND 
Neuroendocrine tumours (NETs) comprise a heterogeneous group of neoplasms originating 
from neural crest cells, endocrine glands, endocrine islets or the diffuse endocrine system, which 
explains the heterogeneity in the characteristics of these tumours and their clinical presentation 
(1). Although considered rare malignancies, available data suggest an increase in the incidence 
of NETs over the past 30 years, with around 7 cases per 100,000 populations per year (2), with 
NETs of pancreatic, intestinal, and bronchopulmonary origin as the most common types.  
Clinical diagnoses of NETs are reliable at the advanced stages when many subjects present with 
metastases and inoperable disease, thereby receiving first line therapy towards controlling the 
progression of the disease and relieving associated symptoms (2).  
Well and poorly-differentiated neuroendocrine tumours of lung origin  
The origin and tumour development of neuroendocrine neoplasms are discussed 
controversially, but most theories point to an association with Kulchitsky cells (or 
enterochromaffin cells), which are normally present in the bronchial mucosa and are part of the 
diffuse neuroendocrine system, comprising single cells or clusters of 4 to 10 cells (3,4,5).  
NETs were first described as carcinoid tumours by Siegfried Oberndorfer in 1904, and are 
developed from hormone producing (endocrine) cells which can be found throughout the 
foregut (thymus, lung, bronchi, and trachea), midgut (small intestine, gallbladder, and pancreas), 
and hindgut (Colon, excluding appendix, rectum), with the small intestine (30.4 %) and the lung 
(29.8 %) (5,6) as the most common locations. NETs of the lung are also characterised by their 
abilities to take up and decarboxylate the amine precursors (APUD system cells) (7,8,9).  
According to the World Health Organization (WHO) classification 2004, NETs share common 
morphological, immunohistochemical and molecular characteristics and can be divided into 
three main entities (10):  
• 
Carcinoid tumours: typical (TC) or atypical (AC),  
• 
Large cell neuroendocrine carcinomas (LCNEC),  
• 
Small cell carcinomas (SCLC).  
These are further summarised into two groups according to their biological 
aggressiveness:  
• 
Well-differentiated low grade (G1) typical and intermediate grade (G2) atypical 
carcinoids,  
• 
Poorly-differentiated high grade (G3) LCNEC and SCLC.  
Unlike those of typical and atypical carcinoids, genetic and epigenetic characteristics of 
LCNEC and SCLC are not closely related, and there are no precursor lesions known for 
SCLCs and LCNECs (10,11).  
Anaplastic thyroid cancer  


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Anaplastic thyroid cancer (ATC) occurs in less than 2 % of all thyroid cancer cases but uniformly 
lethal; and it affects 1–2 individuals per million every year in the United States. 
Patients are usually in their sixth or seventh decade of life at the time of disease presentation, 
and average median survival has been reported as 5 months, with < 20 % of survivors at 1 year 
after diagnosis (12,13). ATC is thought to originate from differentiated thyroid cancers of 
follicular cell origin, as a result of dedifferentiation. Up to 80 % of ATC occurs in the setting of a 
long-standing goitre, possibly in the background of an undiagnosed, well-differentiated thyroid 
cancer (15).  
Dedifferentiation is associated with gains and deletions in multiple chromosomal regions and 
involves a complex process involving multiple events, including cell cycle derangement and 
signal transduction pathway disturbances (16-18). Due to its extremely aggressive behaviour, 
the American Joint Committee on Cancer (AJCC) defines all of ATC stages as stage IV, which is 
further staged into IVa, IVb, and IVc, depending on the extension of the primary tumour, lymph 
node involvement, or presence of distant metastases (DM). Although survival rates have not 
significantly improved in six decades, multimodality treatments including surgery, radiation, 
chemotherapy, and targeted therapy are considered the best strategy for improving outcome in 
patients diagnosed with ATC (14).  
Adrenocortical carcinoma  
Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million 
inhabitants/year (19) whose malignancy features relies on careful investigations of the clinical, 
biological, and imaging features before surgery and the anatomopathological examination after 
tumour removal. Most patients present with excess steroid hormone or abdominal mass effects, 
but about 15 % of patients with ACC are initially diagnosed incidentally (20).  
The stage classification proposed by the European Network for the Study of Adrenal Tumours 
(ENSAT) is recommended (21). Pathology reports define the Weiss score, the resection status, 
and the proliferative index, including the mitotic count and the Ki67 index. 
As far as the treatment is concerned, the complete resection of the tumour is the first option for 
tumours that are limited to the adrenal gland.  
In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs 
should be added in case of progression. Recently, the First International Randomised (FIRM-ACT) 
Trial 
in 
metastatic 
ACC 
reported 
the 
association 
between 
mitotane 
and 
etoposide/doxorubicin/cisplatin (EDP) as the new standard in first line treatment of ACC. In the 
last few years, new targeted therapies, including the IGF-1 receptor inhibitors, have been 
investigated, but their efficacy remains limited. Thus, new treatment concepts are urgently 
needed (19).  
 
Pheochromocytoma and paraganglioma  
Pheochromocytomas and paragangliomas (PPGLs) are highly vascular neuroendocrine tumours 
that arise from chromaffin cells of the adrenal medulla or their neural crest progenitors located 
outside of the adrenal gland, respectively (22). PPGLs are estimated to occur in about 2–8 of 1 
million persons per year and about 0.1 % of hypertensive patients harbour a PPGL. About 10 % 
of patients with PPGL present with adrenal incidentaloma (23). According to 2017–WHO 
classification of tumours (fourth edition) based on their location/origin, the neuroendocrine 
tumours are classified as tumours of the adrenal medulla and extra-adrenal paraganglia (24). 
These tumours are derived either from sympathetic tissue in adrenal or extra-adrenal abdominal 


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locations (sympathetic PPGLs) or from parasympathetic tissue in the thorax or head and neck 
(parasympathetic PPGLs). Sympathetic PPGLs frequently produce considerable amounts of 
catecholamines, and in approximately 80 % of patients, they are found in the adrenal medulla 
(22,25). The remaining 20 % of these tumours are located outside of the adrenal glands, in the 
prevertebral and paravertebral sympathetic ganglia of the chest, abdomen, and pelvis. Extra-
adrenal PPGLs in the abdomen most commonly arise from a collection of chromaffin tissue 
around the origin of the inferior mesenteric artery (the organ of Zuckerkandl) or aortic 
bifurcation. In contrast, most parasympathetic PPGLs are chromaffin-negative tumours mostly 
confined to the neck and at the base of the skull region along the glossopharyngeal and vagal 
nerves, and only 4 % of these tumours secrete catecholamines (25). These head and neck PGLs 
were formerly known as glomus tumour or carotid body tumours. Most PPGLs represent 
sporadic tumours and about 35 % of PPGLs are of familial origin with about 20 known 
susceptibility genes making them the most hereditary amongst all human tumours (26,27). 
Based on these genetic mutations and pathogenetic pathways, PPGLs can be classified into three 
broad clusters—cluster 1, cluster 2, and cluster 3. Cluster 1 includes mutations involving in 
overexpression of vascular endothelial growth factor (VEGF) (due to pseudohypoxia) and 
impaired DNA methylation leading to increased vascularization. Cluster 2 involves the activation 
of the mutations of Wnt-signalling pathway (Wnt receptor signalling and Hedgehog signalling). 
The activation of Wnt and Hedgehog signalling is secondary to somatic mutations of Cold shock 
domain containing E1(CSDE1) and Mastermind like transcriptional coactivator 3 (MAML3) genes 
(28). Abnormal activation of kinase signalling pathways like PI3Kinase/AKT, RAS/RAF/ERK, and 
mTOR pathways account for cluster 3 mutations (24). On the other hand, based on biochemical 
secretory patterns, PPGLs can be characterised into three different phenotypical categories—
noradrenergic phenotype (predominant norepinephrine secreting), adrenergic phenotype 
(predominant epinephrine secreting), and dopamine secreting. These biochemical phenotypes 
of PPGL lead to a constellation of symptoms (based on the predominant hormone secreted) 
leading to different clinical manifestations.  
Well-differentiated neuroendocrine tumours of gastroenteropancreatic origin  
Gastroenteropancreatic neuroendocrine neoplasms (NENs) are rare tumours defined by the 
expression of specific diagnostic biomarkers (29-31). Cell differentiation is a major prognostic 
marker of neuroendocrine neoplasms (32, 33). Indeed, regardless of the stage or the location of 
the primary tumour, it has been highlighted (31) that well-differentiated lesions have a better 
prognosis than poorly differentiated ones [32, 34-36).  
In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was 
reviewed and the crucial role of the proliferative rate was validated (37-42). The WHO 
Classification 2010 defined three groups of tumours (Grades 1-3) according to the combination 
of the morphological characteristics, mitotic index, and Ki-67 index (43). Grades 1 and 2 
corresponded to well-differentiated neuroendocrine tumours (NETs), whereas grade 3 
corresponded to poorly differentiated lesions called neuroendocrine carcinomas (NECs). 
Initially, it was assumed that no NET with a mitotic or a Ki-67 index above 20 % could exist.  
The majority of gastroenteropancreatic NENs are classified in the well-differentiated category 
because they retain the organoid architecture typical of neuroendocrine organs and have a 
relatively low proliferative rate. It is stated that all gastroenteropancreatic NETs—with the 
exception of the pancreatic microadenomas, gastrin-driven type 1 neuroendocrine tumours in 
the stomach are potentially malignant neoplasms. Different classifications have been used to 
distinguish pure neuroendocrine tumours from mixed endocrine-exocrine tumours, and to 
distinguish within pure neuroendocrine tumours according to their behaviour (well-
differentiated NETs with benign behaviour, well-differentiated NETs with uncertain behaviour, 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
17 
well-differentiated NETs with malignant behaviour, and poorly differentiated endocrine 
carcinomas with high-grade malignant behaviour) (44, 45). These classifications are based on 
their site of origin, size, gross and/or microscopic tumour extension, vascular invasion, and/or 
proliferative activity (Ki-67 index), as well as their syndromic clinical/functioning features.  
High-grade neuroendocrine neoplasms (WHO G3) of the pancreas include both well-
differentiated neuroendocrine tumour (WD-NET) and poorly differentiated neuroendocrine 
carcinoma (PD-NEC). According to the WHO classification scheme, the diagnosis of this group of 
tumours is based on both the histopathology of the tumour and the assessment of proliferation 
fraction. However, the former can be challenging due to the lack of well-defined histologic 
criteria, and the latter alone (i.e, > 20 mitoses/10 high-power fields or Ki67 > 20 %) may not 
sufficiently distinguish WD-NETs from PD-NECs. Given the considerable differences in treatment 
strategies and clinical outcome, additional practical modalities are required to facilitate the 
accurate diagnosis of high-grade pancreatic neuroendocrine neoplasms. We examined 33 cases 
of WHO G3 neuroendocrine neoplasms of the pancreas and attempted to classify them into WD-
NET, small cell PD-NEC (PD-NEC-SCC), and large cell PD-NEC (PD-NEC-LCC), or to designate them 
as "ambiguous" when an uncertain diagnosis was rendered by any of the observers or there was 
any disagreement in classification among the three observers. To simplify the interpretation, 
both PD-NEC-SCC and PD-NEC-LCC were considered together as PD-NECs in the final analysis. 
The initial approach was to assess microscopically a single morphologically challenging 
hematoxylin and eosin section from each case without the knowledge of Ki67 values. This was 
performed independently by three pathologists to assess the degree of diagnostic concordance, 
and the immunohistochemical staining for surrogate biomarkers of known genotypes of WD-
NET and PD-NEC was evaluated. Lastly, a clinicopathologic review was completed to establish a 
final definitive classification. Loss of DAXX or ATRX protein expression defined WD-NET, and 
abnormal expression of p53, Rb, SMAD4 signified PD-NEC. When the chosen section displayed 
an element of WD histopathology, or other tumour sections contained WHO G1/G2 
components, or there had been a prior established diagnosis of a primary WD-NET, the final 
diagnosis was considered a WD-NET with high-grade (G3) progression. If a component of 
conventional adenocarcinoma was present (in slides not seen in the initial review), the diagnosis 
was established as a combined adenocarcinoma and PD-NEC. All the three pathologists agreed 
on the morphologic classification of 33 % of the cases (6 WD-NET, 3 PD-NEC-SCC, and 2 PD-NEC-
LCC), were conflicted on two cases, between PD-NEC-SCC and PD-NEC-LCC, and disagreed or 
were uncertain on the classification of the remaining 20 cases (61%), which were therefore 
categorised as ambiguous. In the group of cases in which all pathologists agreed on the 
classification, the six WD-NET cases had either loss of DAXX or ATRX or had evidence of a WD-
NET based on additional or prior pathology slides. The seven PD-NEC cases had abnormal 
expression of p53, Rb, and/or SMAD4 or a coexisting adenocarcinoma. In the ambiguous group 
(n = 20), 14 cases were established as WD-NETs based upon the loss of DAXX or ATRX in seven 
cases and additional pathology evidence of high-grade progression from WD-NET in the other 
seven cases; five cases were established as PD-NEC based upon abnormal expression of p53, Rb, 
and/or SMAD4; one case remained undetermined with normal expression of all markers and no 
evidence of entity-defining histologic findings in other slides. On the basis of the final pathologic 
classifications, the disease-specific survival was 75 and 11 months for the WD-NET and PD-NEC 
groups, respectively. Thus, we conclude that morphologic diagnosis of high-grade pancreatic 
neuroendocrine neoplasms is challenging, especially when limited pathologic materials are 
available, and necessitates better defined criteria. The analysis of both additional sections and 
prior material, along with an immunohistochemical evaluation, can facilitate accurate diagnosis 
in the majority of cases and guide the appropriate clinical management and prognosis (46).  
1.2.  PURPOSE OF THE ANALYSIS 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
18 
1.2.1. STUDY OBJECTIVES 
Primary objective: 
To assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological 
objective response rate (ORR) in advanced endocrine tumors.  
Secondary objectives are: 
• 
Safety Profile  
• 
Duration of Response (DoR)  
• 
Progression-free Survival (PFS)  
• 
Overall Survival (OS)  
• 
Biomarkers  
1.2.2. ENDPOINTS 
Primary endpoint:  
Overall Response Rate (ORR): includes patients with confirmed partial (PR) and complete 
response (CR) as best response according to RECIST v 1.1.  
Secondary endpoints:  
• 
Safety profile of cabozantinib and atezolizumab: The number of patients with AEs and 
SAEs, changes in laboratory values, vital signs, ECGs, and results of physician 
examinations graded according to the CTCAE v 5.0. This will be analysed using 
descriptive statistics techniques such as frequency and contingency tables. The final 
statistical analysis of this endpoint is expected to be performed within 6 months after 
database closure, which is expected at 12 months after last patient inclusion. However, 
interim analysis may be performed when analysing other primary endpoints.  
• 
Duration of response (DOR) as per RECIST 1.1: DOR calculated as the time from the date 
of first documented CR or PR to the first documented progression or death due to 
underlying cancer.  
• 
Progression-free Survival (PFS): Median Progression free survival (mPFS) is defined as 
the time from the date of inclusion to the date of the first documented disease 
progression or death due to any cause, whichever occurs first. PFS will be determined 
based on tumour assessment (RECIST version 1.1 criteria). The local Investigator's 
assessments will be used for analyses. Patients who are alive and have not progressed 
at the last follow-up will be censored at the date of the last available image 
determination (CT Scan or MRI). Patient with no additional image test other than that 
at baseline will be censored to the day after inclusion.  
• 
Overall Survival (OS): Median Overall Survival (mOS) is calculated as the time from date 
of inclusion to date of death due to any cause.  
• 
Biomarkers: To be determined according to study results and Sponsor feasibility.  
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
19 
1.3. STUDY METHODS 
This is an open labelled, single arm, multicohort phase II multicentre clinical trial of cabozantinib 
plus atezolizumab in advanced and refractory tumours from endocrine system.  
The design includes screening phase, treatment phase (including medical consultation and drug 
administration Q3w ± 3 days) unless otherwise specified, disease progression follow up by 
RECIST 1.1 every 12 weeks, translational research with biopsies and blood samples and long 
term follow-up.  
This is a study with Simon's two-stage design; it requires that an event is observed (confirmed 
response) in the first nine patients before continuing to the second stage where there is a 
possible inclusion of 15 additional patients (up to a maximum of 24 patients per cohort).  
 
1.3.1. INCLUSION-EXCLUSION CRITERIA 
 
1.3.1.1 INCLUSION CRITERIA 
Patients eligible for inclusion in this study must meet all the following criteria:  
1. Male or female subjects ≥ 18 years old.  
2. Willingness to participate in the study by signing ICF approved by the trial Central Ethic 
Committee (CEIm).  
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
4. Measurable disease per RECIST 1.1 as determined by the investigator.  
5. Patients with advanced and progressive neuroendocrine tumors histopathologically 
confirmed (as per local pathology report), meeting one of the following (according to 
WHO 2010 classification):  
a. Cohort 1: Well-differentiated neuroendocrine tumours of the lung and thymus 
(WHO grade 1 and 2, typical and atypical carcinoids) after progression to 
somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.  
b. Cohort 2: Advanced anaplastic thyroid cancer in first-line or after progression to 
chemotherapy or investigational drugs, that underwent prior primary tumor 
surgical resection or not. In patients that primary tumor has not been resected, 
the risk of aerodigestive compression or bleeding should be ruled out to ensure 
no interference with the administration of the investigational product and 
undesirable potential side effects related to the route of administration.  
c. Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or 
mitotane.  
d. Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide 
receptor radionuclide therapy (PRRT) if indicated. Prior chemotherapy and 
biological therapy, such as somatostatin analogs, are allowed.  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
20 
e. Cohort 5: Well-differentiated neuroendocrine tumours of digestive system 
(WHO grade 1 and 2) after progression to somatostatin analogs, targeted 
agents, PRRT, and/or chemotherapy.  
f. Cohort 6: Grade 3 neuroendocrine neoplasm (WHO grade 3, including NET and 
NEC G3) of any origin, excluding small cell lung cancer, after progression to 
chemotherapy or targeted agents/PRRT.  
6. Recovery from toxicity related to any prior treatments to ≤ Grade 1, unless the AE(s) are 
clinically non-significant and/or stable on supportive therapy.  
7. Ability to swallow tablets.  
8. Adequate normal organ and marrow function as defined below:  
a. Haemoglobin ≥ 9.0 g/dL.  
b. Absolute neutrophil count (ANC) > 1500 per mm3.  
c. Platelet count ≥ 100,000 per mm3.  
d. Serum bilirubin ≤ 1.5X institutional upper limit of normal (ULN) unless liver 
metastases are present, in which case it must be ≤ 2X ULN. This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
haemolysis or hepatic pathology); however, they will be allowed only in 
consultation with their physician.  
e. AST (SGOT)/ALT (SGPT) ≤ 2.5X institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 3X ULN.  
f. Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 
40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-
hour urine collection for the determination of creatinine clearance:  
 
1.3.1.2 EXCLUSION CRITERIA 
Patients that meet any of the following criteria will be excluded from the study:  
1. Prior treatment with cabozantinib or any immune checkpoint inhibitor therapy (e.g, 
CTLA4, PD-1, or PD-L1 targeting agent).  
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer. Patients should 
have been out of mitotane for at least 4 weeks.  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
21 
3. Receipt of any type of anticancer antibody (including investigational antibody) or 
systemic chemotherapy within 2 weeks before starting treatment.  
4. Current or prior use of immunosuppressive medication within 2 weeks before the first 
dose of cabozantinib and atezolizumab, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to 
exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 
5. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects 
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the 
past 2 years) are not excluded.  
6. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and 
ulcerative colitis).  
7. History of allogeneic organ transplant.  
8. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 28 days prior to the 
first dose of trial treatment.  
9. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation 
therapy within 4 weeks before inclusion. Subjects with clinically relevant ongoing 
complications from prior radiation therapy that have not completely resolved are not 
eligible (e.g, radiation esophagitis or other inflammation of the viscera).  
10. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks 
before inclusion. Eligible subjects must be neurologically asymptomatic and without 
corticosteroid treatment at the time of study treatment.  
11. Concomitant anticoagulation with oral anticoagulants (e.g, warfarin, direct thrombin 
and factor Xa inhibitors) or platelet inhibitors (e.g, clopidogrel), except for the following 
allowed anticoagulants:  
• 
Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-
dose low molecular weight heparins (LMWH).  
• 
Anticoagulation with therapeutic doses of LMWH in subjects without known 
brain metastases and who are on a stable dose of LMWH for at least 6 weeks 
before inclusion and who have had no clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumour.  
12. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions:  
a. Cardiovascular disorders:  
i. 
Class 3 or 4 congestive heart failure as defined by the New York Heart Association, 
unstable angina pectoris, and serious cardiac arrhythmias.  
ii. 
Uncontrolled hypertension defined as sustained blood press > 150 mm hg systolic or > 
100 mm hg diastolic despite optimal antihypertensive treatment.  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
22 
iii. 
Stroke (including transient ischemic attack [TIA]), myocardial infarction, other ischemic 
event, or thromboembolic event (e.g, deep venous thrombosis [DVT] and pulmonary 
embolism) within 6 months before inclusion. Subjects with a more recent diagnosis of 
DVT are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks 
before study treatment.  
b. Gastrointestinal disorders (e.g, malabsorption syndrome or gastric outlet obstruction) 
including those associated with a high risk of perforation or fistula formulation:  
i. 
Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, 
ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, 
acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet 
obstruction.  
ii. 
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 
6 months before inclusion. Note: complete healing of an intra-abdominal abscess must 
be confirmed prior to start of the treatment.  
c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 ml) of red blood or 
history of other significant bleeding within 3 months before treatment.  
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.  
e. Lesions invading major pulmonary blood vessels.  
f. Other clinically significant disorders such as:  
i. 
Active infection requiring systemic treatment, infection with human 
immunodeficiency virus or acquired immunodeficiency syndrome-related 
illness, or chronic hepatitis B or C infection.  
ii. 
Serious non-healing wound/ulcer/bone fracture.  
iii. 
Moderate to severe hepatic impairment (child-pugh B or C).  
iv. 
Requirement for hemodialysis or peritoneal dialysis.  
v. 
Uncontrolled diabetes mellitus.  
vi. 
History of solid organ transplantation.  
13. Major surgery (e.g, GI surgery and removal or biopsy of brain metastasis) within 8 weeks 
before inclusion. Complete wound healing from major surgery must have occurred 4 
weeks before study treatment and from minor surgery (e.g, simple excision, tooth 
extraction) at least 10 days before study treatment. Subjects with clinically relevant 
ongoing complications from prior surgery are not eligible.  
14. Corrected QT interval calculated by the Fridericia formula (QTcf) > 500 ms within 28 days 
before study treatment.  
Note: if a single ECG shows a QTCf with an absolute value > 500 ms, two additional EGGs 
at intervals of approximately 3 min must be performed within 30 min after the initial 
ECG, and the average of these 3 consecutive results for qtcf will be used to determine 
eligibility.  
15. Pregnant or lactating females.  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
23 
16. Inability to swallow tablets.  
17. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations.  
18. Diagnosis of another malignancy within 3 years before study treatment, except for 
superficial skin cancers, or localised, low grade tumours deemed cured and not treated 
with systemic therapy.  
  
1.3.2. STUDY VARIABLES 
 
 
Screenin
g 
C1 
C2 
C3 
C4 
C5 to PD 
EOT 
Up to 
EOS 
Week 
-4 To -1 
0 
Q3w ±3 days unless dosing 
needs to be held for toxicity 
reasons 
Day 
-28 To -
1 
1a 
Q21 Days ±3 days unless 
dosing needs to be held for 
toxicity reasons 
Informed Consent 
Informed Consentb 
X 
 
 
 
 
 
 
 
Consent and Collection of Specimens 
for Future Biomedical Research 
X 
 
 
 
 
 
 
 
Study Procedures 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam (Full) 
X 
 
 
 
 
 
 
 
Targeted Physical Exam (Based On 
Symptoms) 
 
X 
X 
X 
X 
X 
X 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
 
ECGd 
X 
As clinically indicated 
X 
 
Prior and Concomitant Medications 
<-------------------------------------------------------------------------> 
 
Demography, 
Including 
Baseline 
Characteristics And Tobacco Use 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
Laboratory Assessments 
Clinical Chemistrye 
X 
Xf 
X 
X 
X 
X 
X 
 
Hematologye 
X 
Xf 
X 
X 
X 
X 
X 
 
TSHg (Reflex Free T3 Or Free T4h) 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B, C and HIVi 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
Pregnancy Testj 
X 
if clinically indicated 
 
 
Monitoring 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
AE/SAE/AESI Assessmentk 
 
X 
X 
X 
X 
X 
X 
 
Post-treatment Follow-upl 
 
 
 
 
 
 
 
X 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
24 
IMPs Administration 
Cabozantinibm 
 
X  
(p.o. daily, until PD or unacceptable 
toxicity) 
 
 
Atezolizumabm 
 
X 
X 
X 
X 
X 
 
 
Biological samples collection 
Tumor Biopsy (Archival, If Available) 
(X) 
 
 
 
 
 
 
 
Processed blood samplesn 
X 
 
X 
 
 
 
X 
 
Efficacy Evaluations 
Tumor evaluation (CT scan or MRI) 
(RECIST 1.1) o 
X 
q12w ± 1w until confirmed objective disease 
progression/death (whichever comes first). 
(X) 
Note: all assessments on treatment days are to be performed prior to atezolizumab infusion, unless otherwise 
indicated. C: cycle; ECG: electrocardiogram; IM: intramuscular; LFT: liver function test; QxW: every x weeks; 
T3:  triiodothyronine; T4:  thyroxine; TSH: thyroid-stimulating hormone. EOT: end of treatment, EOS: end of 
study. 
 
a) 
Every effort should be made to minimise the time between inclusion and start of treatment. 
(i.e. within 1 day of inclusion) 
b) Informed consent of study procedures may be obtained prior to the 28-day screening 
window. If laboratory or imaging procedures were performed for different reasons prior 
to signing consent, these can be used for the screening purposes with the consent of the 
patient. However, all screening laboratory and imaging results must have been obtained 
within 28 days of inclusion. 
c) 
Body weight is to be recorded at each visit along with vital signs. 
d) Any clinically significant abnormalities detected require triplicate ECG results. 
e) Complete blood count that includes total white blood cell count with leukocyte formula, 
haemoglobin, and platelet count. The analytical studies may be performed up to 72 hours 
before the scheduled visits in order to have the results at the time of the patient’s visit. 
Biochemistry tests include albumin, alkaline phosphatase, lactate dehydrogenase (LDH), 
calcium, magnesium, phosphorus, sodium, potassium, creatinine, creatine kinase, direct 
bilirubin, indirect bilirubin, total bilirubin, total protein, urea, uric acid, amylase, lipase, 
and glucose tests. Liver test panel function include alanine transaminase (ALT), aspartate 
transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase 
(GGT) tests. Tests for pancreatic enzymes include lipase, protease, amylase, and 
trypsinogen tests. 
f) 
If clinical chemistry screening and haematology assessments are performed within 3 days 
prior to day 1 (first infusion day), they do not need to be repeated at day 1. 
g) 
If TSH is measured within 14 days prior to C1D1 (first infusion day), it does not need to be 
repeated at day 1. 
h) Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion 
of an AE related to the endocrine system. 
i) 
Serology including HIV, hepatitis B (HBsAg and anti-HBc), and hepatitis C virus (HCV). 
j) 
Women of childbearing potential are required to have a pregnancy test within 72 hours 
prior to the first dose of the study drug, and every 3 cycles (9 weeks) thereafter (if clinically 
indicated). Latest pregnancy results (maximum 9 weeks old) must be available and 
reviewed by the treating physician or investigator prior to commencing a new cycle of 
infusion. A urine or serum pregnancy test is acceptable. 
k) 
For AEs/SAEs reported during screening, additional information such as medical history 
and concomitant medications may be needed. 
l) 
Post-treatment follow up: all patients will be followed up according to RECIST 1.1 every 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
25 
12 weeks (+/-7 days) up to disease progression or death (whichever occurs first), 
regardless of the reason for ending the treatment. Neuroendocrine markers are to be 
analysed according to local practice. The follow-up period according to the protocol is 12 
months considering last patient inclusion. Information on subsequent treatments should 
include the list of post-treatment therapies, the drugs administered, and the date of 
initiation and discontinuation of each drug. All the data will be recorded in the medical 
record and in the eCRF. 
m) The initial dose of atezolizumab will be administered before cabozantinib and must be 
administered over 60 minutes. If the first infusion is well tolerated, all subsequent 
infusions may be administered over 30 minutes. For the rest of the cycles, cabozantinib 
will be self-administered by the patients daily and as per principal investigator indications. 
Results for LTFs, electrolytes, and creatinine must be available before commencing an 
infusion (within 3 days) and reviewed by the treating physician or investigator prior to 
dosing. 
n) Biomarker study: Collection of the most recent archived tumour-biopsy sections. 
Processed blood samples at baseline, day 1 of cycle 2 (D1C2), at EOT/progression. Blood 
samples should be obtained in all patients at the time of EOT (even by toxicity without 
progressing) and samples are to be stored at site at -80 ºC and are to be sent at the end 
of study (1 dry ice shipment per site). 
o) CT Scan or MRI is to be performed at baseline and q12w ± 1w until the confirmation of 
objective disease progression or death (whichever comes first). The schedule of q12w ± 1 
week must be followed regardless of any delays in dosing, in case of suspected pseudo-
progression; treatment should be continued until progression of disease is confirmed from 
the imaging results. RECIST assessments will be performed on images from CT scans 
(preferred) or MRI, each preferably with IV contrast of the neck, chest, abdomen 
(including liver and adrenal glands), and pelvis. Pelvic imaging is recommended only when 
primary or metastatic disease in the pelvic region is likely. Additional anatomy should be 
imaged based on signs and symptoms of individual patients at baseline and follow-up. 
Baseline assessments should be performed no more than 28 days before the date of 
inclusion and, ideally, should be performed as close as possible to and prior to the start of 
treatment. The confirmatory scans should be performed preferably at the next scheduled 
imaging visit and no less than 4 weeks after the prior assessment of PD (in the absence of 
clinically significant deterioration). If an unscheduled assessment was performed and the 
patient has not progressed, every attempt should be made to perform the subsequent 
assessment at the next scheduled visit. 
 
1.4. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
1.4.1. DETERMINATION OF SAMPLE SIZE 
Simon-II optimal two-stage design was applied for sample size estimation. We hypothesise that 
the experimental therapy will improve the probability of expected objective response rate in 
refractory settings, from less than 5 % in previous reports, to 20 % in the current study. With 
80 % of power (0.2) and unilateral alpha (0.1), 24 patients per cohort are needed to demonstrate 
the primary hypothesis. The Simon-II design suggested the observation of ≥ 1 patient with 
objective response within the first nine patients included in the first stage. If ≥ 1 out of nine 
patients in each cohort achieve an objective radiological response in the first stage, the study 
will continue to recruit 15 additional patients up to 24 patients per cohort. If ≥ 3 out of a total 
of 24 patients achieve a radiological objective response at the final analysis, the study should be 
declared positive. If stage I is reached only in one cohort, recruitment will continue in the 
successful cohort and stopped in the non-effective cohorts.  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
26 
 
1.4.2. GENERAL CONSIDERATIONS 
‘Last patient last visit’, as defined in the protocol, is 12 months after the enrolment of last 
patient. Subjects may continue to receive IMPs after the cut-off because treatment cannot be 
discontinued for ethical reasons, but in such cases, Sponsor agrees to continue with cabozantinib 
supply to sites to cover patient treatment until it's finalisation and atezolizumab for a maximum 
of 6 months after the end of the study (LPLV). For these 6 additional months (since LPLV), the 
principal investigators must inform on any suspicion on adverse events/special situations in 
patients receiving atezolizumab’s, to the marketing authorisation holder.  
 
1.4.3. DESCRIPTION OF ANALYSIS SETS 
Data will be analysed in the following populations:  
1. Intent-To-Treat (ITT): All patients that has been enrolled in the trial.  
2. Evaluable population per protocol (PP): All patients fulfilling all eligibility criteria 
without any protocol deviation that makes patient invalid for the primary endpoint 
evaluation.  
3. Safety population: All patients receiving at least one dose of treatment.  
1.4.4. MISSING DATA 
The missing data will not be inputed and will be left as lost (missing value), however it will be 
presented. Missing data for drop-outs are not replaced by methods like LOCF (last option carried 
forward).  
 
1.4.5. INTERIM ANALYSES AND DATA MONITORING 
Interim analysis may be performed when analysing other primary endpoints.  
 
1.5. SUMMARY OF STUDY DATA 
For each categorical variable, the results will be summarised by frequencies and percentages. 
For each continuous variable, the results will be summarised by descriptive statistics such as 
median, range, and interquartile range or by means, standard deviations, and 95 % confidence 
intervals (CIs). For proportions, point estimates and exact 95 % confidence intervals will be 
calculated. For time to event endpoints, Kaplan-Meier estimates at selected time points and 
corresponding curves will be presented. Time to event is derived relative to the first study 
treatment administration. Laboratory values will be expressed as absolute values and in grades 
(ordinal categorical variables) according to NCI CTCAE v 5.0.  
Treatment-emergent AE (AEs starting after the administration of study treatment and up to 
study completion) will be summarised by system organ class and preferred term. Grading will 
be presented by type and in tables showing the frequency and percentage of the within-patient 
worst grades. In addition, grade ≥ 3 AEs will be summarised separately. Full analysis details will 
be outlined in the statistical analysis plan (SAP).  


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Continuous data will be presented with the number of observations, mean value, standard 
deviation, minimum, maximum, and median. Categorical data will be presented as counts and 
percentages. Individual subject data will be listed.  
Vital signs, ECG parameters, clinical laboratory data (haematology, serum biochemistry, and 
urinalysis) will be presented in tabular form. Values outside the reference range will be flagged, 
and the clinically significantly abnormal values will be listed in tabular form. Adverse events will 
be tabulated by system organ class and preferred term after medical coding using the according 
to NCI CTCAE v 5.0.  
1.5.1. PROTOCOL DEVIATIONS 
Compliance with the IMP schema is critical for patients and trial outcomes, and any deviation 
from the IMP schema may jeopardise trial results or may affect patient safety; for these reasons, 
non-compliance may be considered a protocol deviation. When an investigational product is 
dispensed in a clinical trial, the investigator or a person designated by the investigator will 
ensure high level of compliance with the investigational product administration procedures.  
1.6. REPORTING CONVENTIONS 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported 
as “<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data.  
 
1.7. TECHNICAL DETAILS 
All analysis, tables, listing and figures will be produced with R (3.6.3), RStudio 1.3.1093 y SPSS 
(26.0). 
 
 
 


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2. RESULTS 
2.1. STUDY POPULATION 
2.1.1. RECRUITED PATIENTS (CENTRES/INVESTIGATORS) 
Initially XXX patients were recruited in XXX Spanish sites. The recruited period lasted from 
xxxxxx 20xx until xxxxxx 20xx. The distribution of patients by centres will be shown in the 
following table: 
Table 1. Recruited patients by site 
Centre 
Investigator 
Patients 
 
 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
xx (100.0) 
 
2.1.2. EVALUABLE PATIENTS  
Following protocol indications, it was analysed which patients could be included in the analysis: 
General inclusion criteria (see section ¡Error! No se encuentra el origen de la referencia..1 for 
detailed list of inclusion criteria). 
In the following table the number of non evaluable patients along with the reason why, will be 
reported. 
Table 2. Non evaluable patients  
No. 
ID patient 
Cohort 
Hospital 
Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 The evaluable population by sites will be described in ¡Error! No se encuentra el origen de la 
referencia.: 
Table 3. Patients evaluable by Site 
 
 
 
Total 
 
N (%) 
Hospital 1 
 
Hospital 2 
 
… 
 


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Total 
xx (100.0) 
 
In this report, data from xxx patients from xx Spanish sites will be analysed.  A database cut-off 
was made in xxxxxx 20XX for this analysis.  
 
Table 4. Evaluable patients and Analysis sets 
 
 
n 
%1 
Total number of recruited patients 
  
100,0 
Total number of non recruited patients 
 
 
- 
Reason of exclusion  
 
 
Intent-To-Treat (ITT): All patients that has been enrolled in the trial.  
Yes  
 
No  
 
Evaluable population per protocol (PP): All patients fulfilling all eligibility 
criteria without any protocol deviation that makes patient invalid for the 
primary endpoint evaluation.  
Yes  
 
No  
 
Safety population: All patients receiving at least one dose of treatment.  
Yes  
 
No  
 
1 Calculated percentage from the total of patients with available data 
 
 
Table 5. Patients allocated in each cohort by hospital 
  
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Cohort 6 
Total 
Hospital 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
 n (%) 
n (%) 
Hospital 1 
  
  
  
  
  
  
n (100%) 
Hospital 2 
  
  
  
  
  
  
n (100%) 
Hospital 3 
  
  
  
  
  
  
n (100%) 
Hospital 4 
  
  
  
  
  
  
n (100%) 
Hospital 5 
  
  
  
  
  
  
n (100%) 
Hospital 6 
  
  
  
  
  
  
n (100%) 
… 
  
  
  
  
  
  
n (100%) 
Total 
  
  
  
  
  
  
n (100%) 
 


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2.2. BASELINE PATIENT CHARACTERISTICS 
For the descriptive analysis of the patients, the evaluable population will be used. 
The mean age of the patients included in the study was XXXX years. 
 
Table 6. Baseline patient characteristics 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  
Race 
Caucasian 
 
  
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  
Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  


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Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 7. Haematology and Coagulation 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Hematocrit 
 
 
 
Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 
Table 8. Biochemistry 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 
Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 


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Uric Acid 
 
 
 
LDH 
 
 
 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 
Table 9. Tumor Markers 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 
 
Table 10. Serology 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  


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1 Calculated percentage from the total of patients with available data 
 
 
Table 11. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 
 
 
 


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2.2.1. TUMOR DATA AND PRIOR TREATMENTS 
Baseline cancer characteristics will be reported in this section. 
 
Table 12. Cancer History 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  
  
N (%, CI95%) 
Histological type 
  
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  
M stage 
  
Stage 
  
I 
  
II 
  
III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  
Poorly differentiated 
  
Grade 
  
1 
  


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2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non-Functioning  
  
  
  
  
 
N (%, CI95%)  
Metastasis 
 
  
  
  
Yes 
  
  
  
  
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
Details of previous surgery will be shown below: 
 
Table 13. Baseline surgery 
  
  
N (%, CI95%) 
Surgery 
Yes 
  
No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD 
(CI95%) 
Median (CI95%) [Range] 
Time since surgery date until Inclusion date 
(months) 
  
  
  


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Time since diagnosis until surgery date 
(months) 
  
  
  
 
 
Details of previous radiotherapy will be shown below: 
 
Table 14. Baseline Radiotherapy 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  
Compulative dose  
… 
  
… 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 15. Previous treatments 
 
 
N (%, CI95%) 
Treatment type 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 


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Mitotane 
 
Other 
 
2nd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Table 16. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.2.2. PREVIOUS MEDICAL HISTORY 
 
In this section previous relevant comorbidities will be shown.  
Table 17. Relevant Comorbidiities 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 
 
In this section concomitant medications will be shown.  
Table 18. Prior Concomitant medication 
 
 
 
N (%, CI95%) 
Prior Concomitant 
Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 19. Urinalysis 
 
 
N (%, CI95%) 
Result 
Negative 
 
Traces 
 
1 
 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 
Nitrite 
 


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Ketones 
 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 20. Pregnancy test 
 
N (%, CI95%) 
Positive 
 
Negative 
 
NA 
 
 
 
Table 21. Electrocardiogram 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 
 
2.2.3. BASELINE PATIENT CHARACTERISTICS IN COHORT 1 
Baseline patient characteristics in cohort 1 is shown in this section.  Cohort 1 tumor type is the 
Well-differentiated neuroendocrine tumors of lung origin or thymus (WHO grade 1 and 2, typical 
and atypical carcinoids)  
The mean age of the patients included in the study was XXXX years. 
 
Table 22. Baseline patient characteristics in cohort 1 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  


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Race 
Caucasian 
 
  
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  
Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  
Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 23. Haematology and Coagulation in cohort 1 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 


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Hematocrit 
 
 
 
Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 
Table 24. Biochemistry in cohort 1 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 
Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 
Uric Acid 
 
 
 
LDH 
 
 
 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 


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Table 25. Tumor Markers in cohort 1 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 
 
Table 26. Serology in cohort 1 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  
1 Calculated percentage from the total of patients with available data 
 
 
 
Table 27. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 1 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 


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2.2.3.1 TUMOR DATA AND PRIOR TREATMENTS IN COHORT 1 
Baseline cancer characteristics in cohort 1 will be reported in this section. 
 
Baseline cancer characteristics in cohort 1 will be reported in this section. 
 
Table 28. Cancer History in cohort 1 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  
  
N (%, CI95%) 
Histological type 
  
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  
M stage 
  
Stage 
  
I 
  
II 
  
III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  


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Poorly differentiated 
  
Grade 
  
1 
  
2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non Functioning  
  
  
  
  
 
N (%, CI95%)  
Metastasis 
 
  
  
  
Yes 
  
  
  
  
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
 
Details of previous surgery will be shown below: 
 
Table 29. Baseline surgery in cohort 1 
  
  
N (%, CI95%) 
Surgery 
Yes 
  
No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 


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Time since surgery date until Inclusion date 
(months) 
  
  
  
Time since diagnosis until surgery date 
(months) 
  
  
  
 
 
Details of previous radiotherapy will be shown below: 
 
Table 30. Baseline Radiotherapy in cohort 1 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  
Compulative dose  
… 
  
… 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 31. Previous treatments in cohort 1 
 
 
N (%, CI95%) 
Treatment type 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 


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Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
2nd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
 
Table 32. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.3.2 PREVIOUS MEDICAL HISTORY IN COHORT 1 
In this section previous relevant comorbidities in cohort 1 will be shown.  
 
Table 33. Relevant Comorbidiities in cohort 1 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 


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In this section concomitant medications will be shown.  
Table 34. Prior Concomitant medication in cohort 1 
 
 
 
N (%, CI95%) 
Prior Concomitant Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 35. Urinalysis in cohort 1 
 
 
N (%, CI95%) 
Result 
Negative 
 
Traces 
 
1 
 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 
Nitrite 
 
Ketones 
 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 36. Pregnancy test in cohort 1 
 
N (%, CI95%) 
Positive 
 


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Negative 
 
NA 
 
 
 
Table 37. Electrocardiogram in cohort 1 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 
 
2.2.4. BASELINE PATIENT CHARACTERISTICS IN COHORT 2 
Baseline patient characteristics in cohort 2 is shown in this section.  Cohort 2 tumor type is the 
Anaplastic thyroid cáncer.  
The mean age of the patients included in the study was XXXX years. 
 
Table 38. Baseline patient characteristics in cohort 2 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  
Race 
Caucasian 
 
  
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  


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49 
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  
Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  
Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 39. Haematology and Coagulation in cohort 2 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Hematocrit 
 
 
 
Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 


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50 
Table 40. Biochemistry in cohort 2 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 
Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 
Uric Acid 
 
 
 
LDH 
 
 
 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 
Table 41. Tumor Markers in cohort 2 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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Table 42. Serology in cohort 2 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  
1 Calculated percentage from the total of patients with available data 
 
 
Table 43. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 2 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 
2.2.4.1 TUMOR DATA AND PRIOR TREATMENTS IN COHORT 2 
Baseline cancer characteristics in cohort 2 will be reported in this section. 
 
Table 44. Cancer History in cohort 2 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  
  
N (%, CI95%) 
Histological type 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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52 
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  
M stage 
  
Stage 
  
I 
  
II 
  
III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  
Poorly differentiated 
  
Grade 
  
1 
  
2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non Functioning  
  
  
  
  
 
N (%, CI95%)  
Metastasis 
 
  
  
  
Yes 
  
  
  
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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53 
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
 
Details of previous surgery will be shown below: 
 
Table 45. Baseline surgery in cohort 2 
  
  
N (%, CI95%) 
Surgery 
Yes 
  
No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Time since surgery date until Inclusion date 
(months) 
  
  
  
Time since diagnosis until surgery date 
(months) 
  
  
  
 
 
Details of previous radiotherapy will be shown below: 
 
Table 46. Baseline Radiotherapy in cohort 2 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  
Compulative dose  
… 
  
… 
  


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N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 47. Previous treatments in cohort 2 
 
 
N (%, CI95%) 
Treatment type 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
2nd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 


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55 
Other 
 
 
Table 48. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.4.2 PREVIOUS MEDICAL HISTORY IN COHORT 2 
 
In this section previous relevant comorbidities in cohort 2 will be shown.  
Table 49. Relevant Comorbidiities in cohort 2 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 
 
In this section concomitant medications will be shown.  
Table 50. Prior Concomitant medication in cohort 2 
 
 
 
N (%, CI95%) 
Prior Concomitant Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 51. Urinalysis in cohort 2 
 
 
N (%, CI95%) 
Result 
Negative 
 
Traces 
 
1 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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56 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 
Nitrite 
 
Ketones 
 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 52. Pregnancy test in cohort 2 
 
N (%, CI95%) 
Positive 
 
Negative 
 
NA 
 
 
 
Table 53. Electrocardiogram in cohort 2 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 
2.2.5. BASELINE PATIENT CHARACTERISTICS IN COHORT 3 
Baseline patient characteristics in cohort 3 is shown in this section.  Cohort 3 tumor type is the 
Adrenocortical carcinoma.  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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The mean age of the patients included in the study was XXXX years. 
 
Table 54. Baseline patient characteristics in cohort 3 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  
Race 
Caucasian 
 
  
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  
Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  
Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 55. Haematology and Coagulation in cohort 3 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Hematocrit 
 
 
 
Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 
Table 56. Biochemistry in cohort 3 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 
Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 
Uric Acid 
 
 
 
LDH 
 
 
 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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59 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 
Table 57. Tumor Markers in cohort 3 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 
 
Table 58. Serology in cohort 3 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  
1 Calculated percentage from the total of patients with available data 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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60 
Table 59. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 3 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 
2.2.5.1 TUMOR DATA AND PRIOR TREATMENTS IN COHORT 3 
Baseline cancer characteristics in cohort 3 will be reported in this section. 
 
Table 60. Cancer History in cohort 3 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  
  
N (%, CI95%) 
Histological type 
  
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  
M stage 
  
Stage 
  
I 
  
II 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  
Poorly differentiated 
  
Grade 
  
1 
  
2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non Functioning  
  
  
  
  
 
N (%, CI95%)  
Metastasis 
 
  
  
  
Yes 
  
  
  
  
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
 
Details of previous surgery will be shown below: 
 
Table 61. Baseline surgery in cohort 3 
  
  
N (%, CI95%) 
Surgery 
Yes 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Time since surgery date until Inclusion date 
(months) 
  
  
  
Time since diagnosis until surgery date 
(months) 
  
  
  
 
 
Details of previous radiotherapy will be shown below: 
 
Table 62. Baseline Radiotherapy in cohort 3 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  
Compulative dose  
… 
  
… 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 63. Previous treatments in cohort 3 
 
 
N (%, CI95%) 
Treatment typer 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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63 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
2nd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
 
Table 64. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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64 
 
2.2.5.2 PREVIOUS MEDICAL HISTORY IN COHORT 3 
 
In this section previous relevant comorbidities in cohort 3 will be shown.  
Table 65. Relevant Comorbidiities in cohort 3 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 
 
In this section concomitant medications will be shown.  
Table 66. Prior Concomitant medication in cohort 3 
 
 
 
N (%, CI95%) 
Prior Concomitant Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 67. Urinalysis in cohort 3 
 
 
N (%, CI95%) 
Result 
Negative 
 
Traces 
 
1 
 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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Nitrite 
 
Ketones 
 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 68. Pregnancy test in cohort 3 
 
N (%, CI95%) 
Positive 
 
Negative 
 
NA 
 
 
 
Table 69. Electrocardiogram in cohort 3 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 
2.2.6. BASELINE PATIENT CHARACTERISTICS IN COHORT 4 
Baseline patient characteristics in cohort 4 is shown in this section.  Cohort 4 tumor type is the 
Pheochromocytoma and paraganglioma. 
The mean age of the patients included in the study was XXXX years. 
 
Table 70. Baseline patient characteristics in cohort 4 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  
Race 
Caucasian 
 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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66 
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  
Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  
Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 71. Haematology and Coagulation in cohort 4 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Hematocrit 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 
Table 72. Biochemistry in cohort 4 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 
Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 
Uric Acid 
 
 
 
LDH 
 
 
 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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Table 73. Tumor Markers in cohort 4 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 
 
Table 74. Serology in cohort 4 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  
1 Calculated percentage from the total of patients with available data 
 
 
 
Table 75. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 4 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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69 
 
2.2.6.1 TUMOR DATA AND PRIOR TREATMENTS IN COHORT 4 
Baseline cancer characteristics in cohort 4 will be reported in this section. 
 
Table 76. Cancer History in cohort 4 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  
  
N (%, CI95%) 
Histological type 
  
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  
M stage 
  
Stage 
  
I 
  
II 
  
III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  
Poorly differentiated 
  
Grade 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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70 
1 
  
2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non Functioning  
  
  
  
  
 
N (%, CI95%)  
Metastasis 
 
  
  
  
Yes 
  
  
  
  
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
 
Details of previous surgery will be shown below: 
 
Table 77. Baseline surgery in cohort 4 
  
  
N (%, CI95%) 
Surgery 
Yes 
  
No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Time since surgery date until Inclusion date 
(months) 
  
  
  
Time since diagnosis until surgery date 
(months) 
  
  
  


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71 
 
 
Details of previous radiotherapy will be shown below: 
 
Table 78. Baseline Radiotherapy in cohort 4 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  
Compulative dose  
… 
  
… 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 79. Previous treatments in cohort 4 
 
 
N (%, CI95%) 
Treatment type 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
2nd Line 
 


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Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
 
Table 80. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.6.2 PREVIOUS MEDICAL HISTORY IN COHORT 4 
 
In this section previous relevant comorbidities in cohort 4 will be shown.  
Table 81. Relevant Comorbidiities in cohort 4 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 
 
In this section concomitant medications will be shown.  


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Table 82. Prior Concomitant medication in cohort 4 
 
 
 
N (%, CI95%) 
Prior Concomitant Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 83. Urinalysis in cohort 4 
 
 
N (%, CI95%) 
Result 
Negative 
 
Traces 
 
1 
 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 
Nitrite 
 
Ketones 
 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 84. Pregnancy test in cohort 4 
 
N (%, CI95%) 
Positive 
 
Negative 
 
NA 
 


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Table 85. Electrocardiogram in cohort 4 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 
2.2.7. BASELINE PATIENT CHARACTERISTICS IN COHORT 5 
Baseline patient characteristics in cohort 5 is shown in this section.  Cohort 5 tumor type is the 
Well-differentiated neuroendocrine tumors of gastroenteropancreatic origin (WHO grade 1 
and 2).  
The mean age of the patients included in the study was XXXX years. 
 
Table 86. Baseline patient characteristics in cohort 5 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  
Race 
Caucasian 
 
  
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  


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Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  
Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 87. Haematology and Coagulation in cohort 5 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Hematocrit 
 
 
 
Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 
Table 88. Biochemistry in cohort 5 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 


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Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 
Uric Acid 
 
 
 
LDH 
 
 
 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 
Table 89. Tumor Markers in cohort 5 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 
 


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Table 90. Serology in cohort 5 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  
1 Calculated percentage from the total of patients with available data 
 
 
 
Table 91. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 5 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 
 
 
2.2.7.1 TUMOR DATA AND PRIOR TREATMENTS IN COHORT 5 
Baseline cancer characteristics in cohort 5 will be reported in this section. 
 
Table 92. Cancer History in cohort 5 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  


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N (%, CI95%) 
Histological type 
  
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  
M stage 
  
Stage 
  
I 
  
II 
  
III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  
Poorly differentiated 
  
Grade 
  
1 
  
2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non Functioning  
  
  
  
  
 
N (%, CI95%)  


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Metastasis 
 
  
  
  
Yes 
  
  
  
  
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
 
Details of previous surgery will be shown below: 
 
Table 93. Baseline surgery in cohort 5 
  
  
N (%, CI95%) 
Surgery 
Yes 
  
No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Time since surgery date until Inclusion date 
(months) 
  
  
  
Time since diagnosis until surgery date 
(months) 
  
  
  
 
 
Details of previous radiotherapy will be shown below: 
 
Table 94. Baseline Radiotherapy in cohort 5 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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Compulative dose  
… 
  
… 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 95. Previous treatments in cohort 5 
 
 
N (%, CI95%) 
Treatment type 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
2nd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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81 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
 
Table 96. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.7.2 PREVIOUS MEDICAL HISTORY IN COHORT 5 
 
In this section previous relevant comorbidities in cohort 5 will be shown.  
Table 97. Relevant Comorbidiities in cohort 5 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 
 
In this section concomitant medications will be shown.  
Table 98. Prior Concomitant medication in cohort 5 
 
 
 
N (%, CI95%) 
Prior Concomitant Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 99. Urinalysis in cohort 5 
 
 
N (%, CI95%) 
Result 
Negative 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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82 
Traces 
 
1 
 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 
Nitrite 
 
Ketones 
 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 100. Pregnancy test in cohort 5 
 
N (%, CI95%) 
Positive 
 
Negative 
 
NA 
 
 
 
Table 101. Electrocardiogram in cohort 5 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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83 
2.2.8. BASELINE PATIENT CHARACTERISTICS IN COHORT 6 
Baseline patient characteristics in cohort 6 is shown in this section.  Cohort 6 tumor type is the 
Poorly differentiated neuroendocrine tumors (WHO grade 3), excluding small cell lung cancer. 
The mean age of the patients included in the study was XXXX years. 
 
Table 102. Baseline patient characteristics in cohort 6 
Sociodemographic 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Age 
  
  
  
  
  
  
  
  
  
  
N (%, CI95%)  
Gender 
Male 
 
  
Female 
 
  
Race 
Caucasian 
 
  
Latin 
 
  
Asian 
 
  
African 
 
  
UK 
 
  
Other 
 
  
Vital signs 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Body weight (kg) 
  
  
  
Height (cm) 
  
  
  
BMI 
  
  
  
Blood pressure (mmHg) 
  
  
  
Pulse rate (bpm) 
  
  
  
Respiration rate (breaths/minute) 
  
  
  
Temperature (ºC) 
  
  
  
Physical examination 
N (%, CI95%) 
Normal 
  
Abnormal 
  
Functional status 
N (%, CI95%) 
ECOG 
0 
  
1 
  
2 
  
3 
  
4 
  
5 
  
Tobacco smoking history 
N (%, CI95%) 
Usage 
Never smoker (<=100 cigarrettes/life time) 
  


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84 
Former smoker (>=1 year) 
 
Smoker 
 
Unknown 
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Time smoking (years) 
  
  
  
 
N 
Mean, SD (CI95%)  
Median (CI95%) [Range] 
Pack/year 
  
  
  
 
 
Table 103. Haematology and Coagulation in cohort 6 
Haematology and Coagulation 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Hematocrit 
 
 
 
Hemoglobin 
 
 
 
Platelets 
 
 
 
Red blood cells 
 
 
 
White blood cells 
 
 
 
Neutrophils 
 
 
 
Lymphocytes 
 
 
 
Basophils 
 
 
 
Eosinophils 
 
 
 
Monocytes 
 
 
 
 
Table 104. Biochemistry in cohort 6 
Biochemical 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Creatinine 
 
 
 
Albumin 
 
 
 
Direct Bilirrubin 
 
 
 
Indirect Bilirrubi 
 
 
 
Total Bilirrubin 
 
 
 
AST 
 
 
 
ALT  
 
 
 
Alcaline P. 
 
 
 
GGT 
 
 
 
Urea 
 
 
 
BUN 
 
 
 
Uric Acid 
 
 
 
LDH 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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85 
Calcium 
 
 
 
Magnesium 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Phosphorus 
 
 
 
Glucose 
 
 
 
Amylase 
 
 
 
Lipase 
 
 
 
Total Protein 
 
 
 
Creatine kinase 
 
 
 
 
Table 105. Tumor Markers in cohort 6 
Tumor Markers 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
5-HIAA 
  
    
  
NSE 
  
    
  
CEA 
  
    
  
CGA 
  
    
  
Cortisol 
  
    
  
Methanephrines 
  
    
  
Adrenalin 
  
    
  
Norepinephrine 
  
    
  
 
 
Table 106. Serology in cohort 6 
  
N (%, CI95%) 
HC 
  
Positive 
  
Negative 
  
HB 
  
Positive 
  
Negative 
  
HIV 
  
Positive 
  
Negative 
  
1 Calculated percentage from the total of patients with available data 
 


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86 
 
 
Table 107. Baseline TSH, fT3 and fT4 in overall (Thyroid Funciton) in cohort 6 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
TSH 
  
  
  
Free T3 
  
  
  
Free T4 
  
  
  
 
 
 
 
2.2.8.1 TUMOR DATA AND PRIOR TREATMENTS IN COHORT 6 
Baseline cancer characteristics in cohort 6 will be reported in this section. 
 
Table 108. Cancer History in cohort 6 
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Time since diagnosis until Inclusion date 
(months) 
 
  
  
Time since progression disease date until 
Inclusion date (months) 
 
  
  
Time since diagnosis until progression 
disease date (months) 
 
  
  
  
N (%, CI95%) 
Histological type 
  
Well and poorly-differentiated neuroendocrine 
tumours of lung origin 
  
Anaplastic thyroiid cancer 
  
Adenocortical carcinoma 
  
Pheochromocytima and paraganglioma 
  
Well-differentiated neuroendocrine tumours of 
gastroeropancreatic origin 
  
Poorly differentiated neuroendocrine tumors  
  
TNM 
  
T stage 
  
N stage 
  


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87 
M stage 
  
Stage 
  
I 
  
II 
  
III 
  
IV 
  
Histological grade 
  
Well differentiated 
  
Moderately differentiated 
  
Poorly differentiated 
  
Grade 
  
1 
  
2 
  
3 
  
  
N 
Mean, SD (CI95%) Median (CI95%) [Range] 
Ki-67 Index  
  
  
    
Mitotic rate 
  
  
  
  
Functional status 
  
  
  
Functioning  
  
  
  
  
Non Functioning  
  
  
  
  
 
N (%, CI95%)  
Metastasis 
 
  
  
  
Yes 
  
  
  
  
No 
  
  
  
  
Metastasis location 
  
  
  
  
Anus 
    
    
Ascites 
    
    
… 
    
    
Study done with 
  
  
  
  
Octreoscan 
    
    
FDG-PET 
    
    
1 Calculated percentage from the total of patients with available data 
 
 
Details of previous surgery will be shown below: 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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88 
 
Table 109. Baseline surgery in cohort 6 
  
  
N (%, CI95%) 
Surgery 
Yes 
  
No 
  
On primary tumor 
Yes 
  
No 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Time since surgery date until Inclusion date 
(months) 
  
  
  
Time since diagnosis until surgery date 
(months) 
  
  
  
 
 
Details of previous radiotherapy will be shown below: 
 
Table 110. Baseline Radiotherapy in cohort 6 
  
  
N (%, CI95%) 
Radiotherapy 
Yes 
  
No 
  
Cyles of Radiotherapy 
1 
  
… 
  
Compulative dose  
… 
  
… 
  
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
 Time since Last cycle date 
until 
Inclusion 
date 
(months) 
  
  
  
 
 
Table 111. Previous treatments in cohort 6 
 
 
N (%, CI95%) 
Treatment type 
Neoadjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 


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89 
Other 
 
Adjuvant 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Line 
 
1st Line 
 
 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
2nd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
3rd Line 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
Maintenance 
 
Chemotherapy 
 
Radiotherapy 
 
Somatostatin analogs 
 
Antineoplastic target therapies 
 
Mitotane 
 
Other 
 
 
Table 112. Other cancer history 
 
 
N (%, CI95%) 
Other cancer history type 
Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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90 
2.2.8.2 PREVIOUS MEDICAL HISTORY IN COHORT 6 
 
In this section previous relevant comorbidities in cohort 6 will be shown.  
Table 113. Relevant Comorbidiities in cohort 6 
 
 
N (%, CI95%) 
Previous relevant illness 
(pathologies) 
No 
 
Yes 
 
Previous relevant illnesses 
(pathologies) 
Relevant illness 1 
 
Relevant illness 2 
 
Relevant illness 3 
 
… 
 
 
In this section concomitant medications will be shown.  
Table 114. Prior Concomitant medication in cohort 6 
 
 
 
N (%, CI95%) 
Prior Concomitant Medicantion 
Yes 
 
 
No 
 
 
Medication 
Acaclofenac 
 
… 
 
 
In this section other determinations will be shown: 
 
Table 115. Urinalysis in cohort 6 
 
 
N (%, CI95%) 
Result 
Negative 
 
Traces 
 
1 
 
2 
 
3 
 
4 
 
Bilirubin 
 
Color/apparence 
 
Leukocytes 
 
Urobilinogen 
 
Blood 
 
Glucose 
 
Nitrite 
 
Ketones 
 


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91 
Protein 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
pH 
 
 
 
Specific gravity 
 
 
 
 
 
Table 116. Pregnancy test in cohort 6 
 
N (%, CI95%) 
Positive 
 
Negative 
 
NA 
 
 
 
Table 117. Electrocardiogram in cohort 6 
 
 
N (%, CI95%) 
Result 
Normal 
 
Abnormal 
 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
QTc 
 
 
 
 
 
 
 


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2.3. TREATMENT EXPOSURE 
All the subjects will be treated with the combination until disease progression, unacceptable 
toxicity, or patient consent withdrawal (whichever occurs first) according to section 7 of the 
protocol.  
• 
Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously. 
• 
Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle).  
Dosing scheme:  
• 
 Level 0 (starting dose): cabozantinib 40 mg qd + atezolizumab 1200 mg iv every 21 
days (one cycle).  
• 
Level -1: cabozantinib 20 mg qd + atezolizumab 1200 mg iv every 21 days (one cycle).  
 
Details of treatment compliance will be shown in the following table:  
 
Table 118. Cabozantinib compliance 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 


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93 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 
Table 119. List of patients that did not receive Cabozantinib 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 120. Atezolizumab compliance 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 121. List of patients that did not receive Atezolizumab 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
94 
 
 
2.3.1. TREATMENT EXPOSURE IN COHORT 1 
 Details of treatment compliance in cohort 1 will be shown in the following table:  
Table 122. Cabozantinib compliance in cohort 1 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
95 
Table 123. List of patients that did not receive Cabozantinib in cohort 1 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 124. Atezolizumab compliance in cohort 1 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 125. List of patients that did not receive Atezolizumab in cohort 1 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
 
2.3.2. TREATMENT EXPOSURE IN COHORT 2 
Details of treatment compliance in cohort 2 will be shown in the following table: 
 
Table 126. Cabozantinib compliance in cohort 2 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
96 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 
Table 127. List of patients that did not receive Cabozantinib in cohort 2 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 128. Atezolizumab compliance in cohort 2 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
97 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 129. List of patients that did not receive Atezolizumab in cohort 2 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
 
 
 
 
2.3.3.  TREATMENT EXPOSURE IN COHORT 3 
Details of treatment compliance in cohort 3 will be shown in the following table: 
Table 130. Cabozantinib compliance in cohort 3 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
98 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 
Table 131. List of patients that did not receive Cabozantinib in cohort 3 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 132. Atezolizumab compliance in cohort 3 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
99 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 133. List of patients that did not receive Atezolizumab in cohort 3 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
2.3.4.  TREATMENT EXPOSURE IN COHORT 4 
 Details of treatment compliance in cohort 4 will be shown in the following table: 
Table 134. Cabozantinib compliance in cohort 4 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
100 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 
Table 135. List of patients that did not receive Cabozantinib in cohort 4 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 136. Atezolizumab compliance in cohort 4 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 137. List of patients that did not receive Atezolizumab in cohort 4 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
101 
2.3.5. TREATMENT EXPOSURE IN COHORT 5 
Details of treatment compliance in cohort 5 will be shown in the following table: 
Table 138. Cabozantinib compliance in cohort 5 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
102 
Table 139. List of patients that did not receive Cabozantinib in cohort 5 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 140. Atezolizumab compliance in cohort 5 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 141. List of patients that did not receive Atezolizumab in cohort 5 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
103 
 
2.3.6.  TREATMENT EXPOSURE IN COHORT 6 
Details of treatment compliance in cohort 6 will be shown in the following table: 
Table 142. Cabozantinib compliance in cohort 6 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Cabozantinb cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles with 
Cabozantinb 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with reductions 
No 
 
Yes (at least 1 reduction) 
 
Total number of dose 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Total number of treatment 
interruption 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruption 
Temporary 
 
Permanent 
 
Total number of treatment 
omissions 
1 intake 
 
… 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
 
N (%, CI95%) 
Medicine bottle NOT delivered 
In 1 cycle 
 
In 2 cycle 
 
… 
 
Reason for medicine bottle 
NOT delivered 
Reason 1 
 
Reason 2 
 
Reason 3 
 
 
If any patient did not receive Cabozantinib it will be listed below along with his/her details. 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
104 
Table 143. List of patients that did not receive Cabozantinib in cohort 6 
Patient ID 
code 
Total number of 
cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
Details of Atezolizumab compliance will be shown in the following table: 
Table 144. Atezolizumab compliance in cohort 6 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Number of Atezolizumab cycles 
 
 
 
 
 
N (%, CI95%) 
Total number of cycles  
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
… 
 
20 cycles 
 
Patients with interruptions 
No 
 
Yes (at least 1 interruption) 
 
Medicine bottle NOT delivered 
1 interruption 
 
… 
 
Reason for treatment 
interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Interruptions 
Temporary 
 
Permanent 
 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Atezolizumab it will be listed below along with his/her details. 
Table 145. List of patients that did not receive Atezolizumab in cohort 6 
Patient ID 
code 
Total number of 
Olparaib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle … 
 
0 
 
 
 
 
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
105 
2.3.7. WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT 
Patient is, at any time, free to withdraw from study (investigational product and study 
assessments), without prejudice to further treatment (withdrawal of consent).  Subjects that 
choose to withdraw early from the study will be voluntarily surveyed for reasons for withdrawal, 
including information of possible presence of any adverse events. If possible, he/she will be seen 
and assessed by an investigator.  
Adverse events will be followed up and all study material (if any) should be returned by the 
patient. The investigator may also, at his/her discretion, withdraw the subject from participating 
in this study at any time, or the sponsor may discontinue the study. Withdrawn patient will not 
be replaced.  
 
If any patient stopped the study treatment prematurely (before the 6 cycles), it will be listed 
below along with his/her details. 
 
Table 146. Study treatment premature interruption 
 
 
N (%, CI95%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 147. Reason for end of treatment for Cabozantinib 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
106 
Table 148. Reason for end of treatment for Atezolizumab 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 
Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 149. Study treatment length 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of study treatment 
(months) 
 
 
 
 
 
2.3.7.1 WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 1 
 
Details of the withdrawal of patients in cohort 1 are shown below:   
 
Table 150. Study treatment premature interruption in cohort 1 
 
 
N (%, CI95%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
107 
Table 151. Reason for end of treatment for Cabozantinib in cohort 1 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 
Table 152. Reason for end of treatment for Atezolizumab in cohort 1 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 
Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 153. Study treatment length in cohort 1 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
108 
Length of study treatment 
(months) 
 
 
 
 
 
2.3.7.2 WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 2 
 
Details of the withdrawal of patients in cohort 2 are shown below:   
 
Table 154. Study treatment premature interruption in cohort 2 
 
 
N (%, CI95%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 155. Reason for end of treatment for Cabozantinib in cohort 2 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 
Table 156. Reason for end of treatment for Atezolizumab in cohort 2 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)   
 
 
109 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 
Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 157. Study treatment length in cohort 2 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of study treatment 
(months) 
 
 
 
 
 
2.3.7.3 WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 3 
 
Details of the withdrawal of patients in cohort 3 are shown below:   
 
Table 158. Study treatment premature interruption in cohort 3 
 
 
N (%, CI95%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 159. Reason for end of treatment for Cabozantinib in cohort 3 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 


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110 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 
Table 160. Reason for end of treatment for Atezolizumab in cohort 3 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 
Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 161. Study treatment length in cohort 3 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of study treatment 
(months) 
 
 
 
 


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2.3.7.4 WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 4 
 
Details of the withdrawal of patients in cohort 4 are shown below:   
 
Table 162. Study treatment premature interruption in cohort 4 
 
 
N (%, CI95%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 163. Reason for end of treatment for Cabozantinib in cohort 4 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 
Table 164. Reason for end of treatment for Atezolizumab in cohort 4 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 


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Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 165. Study treatment length in cohort 4 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of study treatment 
(months) 
 
 
 
 
 
2.3.7.5 WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 5 
 
Details of the withdrawal of patients in cohort 5 are shown below:   
 
Table 166. Study treatment premature interruption in cohort 5 
 
 
N (%, CI95%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 167. Reason for end of treatment for Cabozantinib in cohort 5 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 


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Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 
Table 168. Reason for end of treatment for Atezolizumab in cohort 5 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 
Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
  
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 169. Study treatment length in cohort 5 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of study treatment 
(months) 
 
 
 
 
2.3.7.6 WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT IN COHORT 6 
 
Details of the withdrawal of patients in cohort 6 are shown below:   
 
Table 170. Study treatment premature interruption in cohort 6 
 
 
N (%, CI95%) 
Yes 
 


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Study treatment premature 
interruption 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 171. Reason for end of treatment for Cabozantinib in cohort 6 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 
 
 
 
Table 172. Reason for end of treatment for Atezolizumab in cohort 6 
 
 
N (%, CI95%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
AE not related to the treatment 
study 
 
 
Investigator decision 
 
Details of investigator decisions 
Investigator 
decision 1 
 
Investigator 
decision 1 
 
… 
 
Withdraw consent 
 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
Patients with treatment completion 
 


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N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Induction cycles received  
 
 
 
 
 
The median of the study treatment was XXX weeks: 
Table 173. Study treatment length in cohort 6 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Length of study treatment 
(months) 
 
 
 
 
 
 


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2.4. ANALYSIS SETS 
As defined in the protocol, all efficacy analyses will be based primarily on the Intention-to treat 
(ITT) analysis set and secondarily on the Per Protocol (PP) analysis set, which are defined as 
follows: 
• 
ITT analysis set: All patients who were enrolled (included) in the trial.  
• 
PP analysis set: All patients fulfilling all eligibility criteria without any protocol 
deviation that makes patient invalid for the primary endpoint evaluation. 
And the safety analysis set is defined as: 
• 
Any patient included in the study receiving at least a single dose of study medication 
will be evaluable for the toxicity analysis. 
 
Table 174. Analysis sets 
 
 
N (%) 
ITT population 
Yes 
 
No 
 
PP population 
Yes 
 
No 
 
Safety population 
Yes 
 
No 
 
 
If any patient is excluded either from the ITT, PP and/or security population, it will be listed 
below along with the reasons why: 
Table 175. List of patients that are excluded from ITT, PP and/or security population 
Patient ID 
code 
ITT 
population 
Reason excluded form 
ITT population 
PP 
population 
Reason excluded form 
PP population 
Security 
population 
Reason excluded form 
security population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.5. EFFICACY ANALYSIS 
Both ITT and PP populations will be used to present the efficacy analysis.  
2.5.1. PRIMARY EFFICACY ANALYSIS 
Overall Response Rate (ORR): includes patients with confirmed partial (PR) and complete 
response (CR) as best response according to RECIST v 1.1.  
The ORR is the proportion of patients with tumor size reduction (CR or PR), recorded between 
the date of the first dose and the last tumor evaluation before starting a subsequent treatment 
of each patient in the study. The proportion of response rates will be expressed with the 95% 
confidence interval. 
 
The Overall response rate by RECIST in the ITT population (n=XX) is shown in the following table: 
Table 176. ORR (ITT) 
 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Cohort 6 
 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
ORR 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
Total 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
CR or PR 
 
 
 
 
 
 
SD or PD 
 
 
 
 
 
 
Total 
n 100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
 
The Overall response rate by RECIST in the PP population (n=XX) is shown in the following table: 
Table 177. ORR (PP) 
 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Cohort 6 
 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
N (%, CI95%) 
ORR 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
Total 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
CR or PR 
 
 
 
 
 
 
SD or PD 
 
 
 
 
 
 
Total 
n 100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
n (100%) 
 
 
 
 


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2.5.2. SECONDARY EFFICACY ANALYSIS 
Duration of response (DOR) as per RECIST 1.1: DOR calculated as the time from the date of first 
documented CR or PR to the first documented progression or death due to underlying cancer.  
Progression-free Survival (PFS): Median Progression free survival (mPFS) is defined as the time 
from the date of inclusion to the date of the first documented disease progression or death due 
to any cause, whichever occurs first. PFS will be determined based on tumour assessment 
(RECIST version 1.1 criteria).  
Overall Survival (OS): Median Overall Survival (mOS) is calculated as the time from date of 
inclusion to date of death due to any cause.  
Biomarkers: To be determined according to study results and Sponsor feasibility.  
2.5.2.1 DURATION OF RESPONSE 
Duration of response (DOR) as per RECIST in the ITT set is shown in the following table: 
Table 178. Duration of response (DOR) (ITT) 
Duration of Response (months) 
n 
Mean (SD) 
Median (IQR) 
Min-Max 
CI95% of the mean 
Cohort1 
 
 
 
 
Cohort 2 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
Total 
 
 
 
 
 
 
Duration of response (DOR) as per RECIST in the PP set is shown in the following table: 
Table 179. Duration of response (DOR) (PP) 
Duration of Response (months) 
n 
Mean (SD) 
Median (IQR) 
Min-Max 
CI95% of the mean 
Cohort1 
 
 
 
 
Cohort 2 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 


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2.5.2.2 PROGRESSION FREE SURVIVAL 
The 6 months progression-free survival rate will be estimated and plotted using the Kaplan-
Meier product-limit method, along with their corresponding log-log transformed 95% 
confidence intervals. 
 
2.5.2.2.1 Progression free survival ITT POPULATION 
 
In the ITT population (n=XX), at 6 months the proportion of patents that survived without PD or 
death was XXXX with a CI95% XXXX-XXXX. The overall median of PFS was XXX months (CI95% 
XXX-XXX). 
Table 180. Progression free survival at 6 and 12 months (ITT) 
 
N events 
Patients at risk  % estimated cumulative 
survival ratio1 
95% CI 
% of  PFS 
at 6 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
at 12 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
 
N 
N (%) events 
Median 
(months) 
Standard  
error 
95% CI 
Estimated PFS1 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
1: Estimated using Kaplan-Meier product-limit method 
 
Table 181. Progression free survival events at 6 months (ITT) 
 
PFS event 
N (%, CI95%) 
Cohort 1 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 2 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 3 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 


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PFS event 
N (%, CI95%) 
Cohort 4 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 5 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 6 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
 
Figure 1 Kaplan Meier curve: PFS (ITT) 
 
 
 
 


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2.5.2.2.2 Progression free survival PP POPULATION 
 
 
In the PP population (n=XX), at 6 months the proportion of patents that survived without PD or 
death was XXXX with a CI95% XXXX-XXXX. The overall median of PFS was XXX months (CI95% 
XXX-XXX). 
Table 182. Progression free survival at 6 and 12 months (PP) 
 
N events 
Patients at risk  % estimated cumulative 
survival ratio1 
95% CI 
% of PFS 
at 6 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
at 12 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
 
N 
N (%) events 
Median 
(months) 
Standard  
error 
95% CI 
Estimated PFS1 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
1: Estimated using Kaplan-Meier product-limit method 
 
Table 183. Progression free survival events at 6 months (PP) 
 
PFS event 
N (%, CI95%) 
Cohort 1 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 2 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 3 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 4 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 


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PFS event 
N (%, CI95%) 
Cohort 5 
 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Cohort 6 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
Total 
Without PD/Death 
 
PD 
 
Death (without previous PD) 
 
Total 
 
 
 
Figure 2 Kaplan Meier curve: PFS (PP) 
 
 
 
 


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2.5.2.3 OVERALL SURVIVAL  
The overall survival rate will be estimated and plotted using the Kaplan-Meier product-limit 
method, along with their corresponding log-log transformed 95% confidence intervals. 
 
2.5.2.3.1 OVERALL survival ITT POPULATION 
In the ITT population (n=XX), at 6 months the proportion of patents that survived was XXXX with 
a CI95% XXXX-XXXX. The overall median of OS was XXX months (CI95% XXX-XXX). 
 
Table 184. Overall survival at 6 and 12 months (ITT) 
 
N events 
Patients at risk  % estimated cumulative 
survival ratio1 
95% CI 
% of OS 
at 6 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
at 12 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
 
N 
N (%) death 
Median 
(months) 
Standard  
error 
95% CI 
Estimated OS1 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
 
1: Estimated using Kaplan-Meier product-limit method 
 
 
 
Table 185. Overall survival events at 6 months (ITT) 
 
OS event 
N (%, CI95%) 
Cohort 1 
No death at end of follow-up 
Death 
Total 
Cohort 2 
No death at end of follow-up 
Death 
Total 
Cohort 3 
No death at end of follow-up 
Death 
Total 


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Cohort 4 
No death at end of follow-up 
Death 
Total 
Cohort 5 
No death at end of follow-up 
Death 
Total 
Cohort 6 
No death at end of follow-up 
Death 
Total 
Total 
No death at end of follow-up 
Death 
Total 
 
 
 
Figure 3 Kaplan Meier curve: OS (ITT) 
 
 
 
 


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2.5.2.3.2 OVERALL survival PP POPULATION 
In the PP population (n=XX), at 6 months the proportion of patents that survived was XXXX with 
a CI95% XXXX-XXXX. The overall median of OS was XXX months (CI95% XXX-XXX). 
Table 186. Overall survival at 6 and 12 months (PP) 
 
N events 
Patients at risk  % estimated cumulative 
survival ratio1 
95% CI 
% of OS 
at 6 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
at 12 months 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
 
N 
N (%) death 
Median 
(months) 
Standard  
error 
95% CI 
Estimated OS1 
Cohort 1 
 
 
 
 
Cohort 2 
 
 
 
 
Cohort 3 
 
 
 
 
Cohort 4 
 
 
 
 
Cohort 5 
 
 
 
 
Cohort 6 
 
 
 
 
Total 
 
 
 
 
1: Estimated using Kaplan-Meier product-limit method 
 
Table 187. Overall survival events at 6 months (PP) 
 
OS event 
N (%, CI95%) 
Cohort 1 
No death at end of follow-up 
Death 
Total 
Cohort 2 
No death at end of follow-up 
Death 
Total 
Cohort 3 
No death at end of follow-up 
Death 
Total 
Cohort 4 
No death at end of follow-up 
Death 
Total 
Cohort 5 
No death at end of follow-up 
Death 
Total 
Cohort 6 
No death at end of follow-up 
Death 
Total 


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Total 
No death at end of follow-up 
Death 
Total 
 
 
Figure 4 Kaplan Meier curve: OS (PP) 
 
 
 
 
2.5.2.4 FOLLOW UP  
 
Mean and median for the global follow up are shown below. 
Table 188. Follow up: mean and median ITT 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Follow up 
 
 
 
 
 
Table 189. Follow up: mean and median PP 
 
N 
Mean, SD (CI95%) 
Median (CI95%) [Range] 
Follow up 
 
 
 
 
 
 


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2.6. SAFETY ANALYSIS 
The safety analysis set will be used in this section and it is defined as: Any patient included in 
the study receiving at least a single dose of study medication will be evaluable for the toxicity 
analysis. 
Safety profile of cabozantinib and atezolizumab: The number of patients with AEs and SAEs, 
changes in laboratory values, vital signs, ECGs, and results of physician examinations graded 
according to the CTCAE v 5.0. This will be analysed using descriptive statistics techniques such 
as frequency and contingency tables. The final statistical analysis of this endpoint is expected to 
be performed within 6 months after database closure, which is expected at 12 months after last 
patient inclusion. However, interim analysis may be performed when analysing other primary 
endpoints.  ...............................................................................................................................  
2.6.1. SAFETY SUMMARY: ALL EVENTS IN OVERALL  
 
Table 190. Safety 
 
N (%, CI95%) 
AE related* (any) 
No 
 
Yes 
 
Total 
 
AE related* Grade≥3 
No 
 
Yes 
 
Total 
 
AE related*  to both 
treatments 
No 
 
Yes 
 
Total 
 
AE related*  to Cabozantinib 
(only) 
No 
 
Yes 
 
Total 
 
AE related * to Atezolizumab 
(only) 
No 
 
Yes 
 
Total 
 
AE 
No 
 
Yes 
 
Total 
 
AE Grade≥3 
No 
 
Yes 
 
Total 
 
SAE 
No 
 
Yes 
 
Total 
 


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SAE related (any) 
No 
 
Yes 
 
Total 
 
*Toxicities 
2.6.2. TOXICITIES (AE RELATED TO ANY TREATMENT) 
The following table shows those toxicities (AEs related to any of the study treatments) which 
had a frequency higher than 10% (presented in more than 2 patients). 
 
Table 191. Most frequent toxicities (>10%, n>2) 
Toxicities 
N, % (CI 95%) 
Toxicity 1 
No 
 
Yes 
 
Total 
 
Toxicity 2 
No 
 
Yes 
 
Total 
 
…. 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
 
Table 192. Most frequent toxicities by grade 
Toxicities 
No 
G1 
G2 
G3 
G4 
G5 
Total 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
Toxicity 1 
 
 
 
 
 
 
 
Toxicity 2  
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 


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2.6.3. TOXICITIES GRADE ≥3 
 
Table 193. Frequency of toxicities grade ≥3 
Toxicities 
N, % (CI 95%) 
Toxicity 1 grade ≥3 
 
Toxicity 2 grade ≥3 
 
… 
 
 
 
 
 
 
Table 194. List of toxicities grade ≥3 
 
Patient 
ID 
Cohort 
Adverse 
Event 
(CTC) 
Adverse 
Event (CTC 
specify) 
AE 
relationship 
to 
treatment 
Date AE 
started 
Date 
AE 
ended 
Dur. 
(days) 
Continuous 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.6.4. TOXICITIES RELATED TO BOTH TREATMENTS  
 
Table 195. Toxicities related to both treatments 
 
Patient 
ID 
Cohort 
Adverse Event (CTC) 
Adverse 
Event 
(CTC 
specify) 
AE 
relationship 
to 
treatment 
Date AE 
started 
Date AE 
ended 
Duration 
(days) 
Continuous 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.6.5. TOXICITIES RELATED ONLY TO CABOZANTINIB  
 


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Table 196. Toxicities related only with cabozantinib 
 
Patient 
ID 
Cohort 
Adverse Event (CTC) 
Adverse 
Event 
(CTC 
specify) 
AE 
relationship 
to 
treatment 
Date AE 
started 
Date AE 
ended 
Duration 
(days) 
Continuous 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.6.6. TOXICITIES RELATED ONLY TO ATEZOLIZUMAB  
 
Table 197. Toxicities related only with atezolizumab 
 
Patient 
ID 
Cohort 
Adverse Event 
(CTC) 
Adverse 
Event 
(CTC 
specify) 
AE 
relationship 
to 
treatment 
Date AE 
started 
Date AE 
ended 
Duration 
(days) 
Continuous 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.6.7. MOST FREQUENT AES  
 
Table 198. Most frequent AEs (>20%, n>4) 
AEs 
N, % (CI 95%) 
AE 1 
No 
 
Yes 
 
Total 
 
AE 2 
No 
 
Yes 
 
Total 
 
… 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 


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No 
 
Yes 
 
Total 
 
 
No 
 
Yes 
 
Total 
 
 
Table 199. Most frequent AEs by grade 
 
 
2.6.8. AE GRADE ≥3 
 
Table 200. Frequency of AEs grade ≥3 
AEs 
N (%, CI95%) 
AE 1 grade ≥3  
 
AE 2 grade ≥3 
 
… 
 
 
 
 
 
 
 
 
 
AEs 
No 
G1 
G2 
G3 
G4 
G5 
Total 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
N, % (CI 
95%) 
AE 1 
 
 
 
 
 
 
 
AE 2 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In this table, AEs are grouped using the maximum grade reported for each patient 
 
Table 201. List of AEs with grade ≥3 
 
Patient 
ID 
Cohort 
Adverse Event 
(CTC) 
Adverse Event 
(CTC specify) 
AE 
relationship 
to treatment 
Date AE 
started 
Date AE 
ended 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.6.9. SAE 
 
Table 202. SAEs 
SAEs 
N (%, CI95%) 
SAE 1 
 
SAE 2 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 203. List of all SAEs  
 Patient ID 
Cohort 
Adverse Event 
(CTC) 
Adverse Event (CTC 
specify) 
Intensity 
AE relationship 
to treatment 
Date 
AE 
started 
Date 
AE 
ended 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1: SAE reported in the period after signing the informed consent form and previous to the start of the 
study treatment. 
 
 
2.6.10. SAE RELATED TO ANY TREATMENT 
 
 
Table 204. SAEs RELATED 
Relates SAEs 
N (%, CI95%) 
SAE 1 
 
SAE 2 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 205. List of all SAEs RELATED 
 Patient ID 
Cohort 
Adverse Event 
(CTC) 
Adverse Event (CTC 
specify) 
Intensity 
AE relationship 
to treatment 
Date 
AE 
started 
Date 
AE 
ended 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.6.11. SAFETY SUMMARY: ALL EVENTS PER COHORTS 
 
Table 206. Safety per cohorts 
 
Cohort 
1 
Cohort 
2 
Cohort 
3 
Cohort 
4 
Cohort 
5 
Cohort 
6 
 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
AE related* (any) 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
AE related* Grade≥3 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
AE related*  to both treatments 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
AE related*  to Cabozantinib 
(only) 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
AE related * to Atezolizumab 
(only) 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
AE 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
AE Grade≥3 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
SAE 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
SAE related (any) 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
*Toxicities 
 
 


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2.6.12. TOXICITIES (AE RELATED TO ANY TREATMENT) PER COHORTS 
 
Table 207. Most frequent toxicities (>10%, n>2) per cohorts 
Toxicities 
Cohort 
1 
Cohort 
2 
Cohort 
3 
Cohort 
4 
Cohort 
5 
Cohort 
6 
 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
Toxicity 1 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Toxicity 2 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
…. 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
Table 208. Most frequent toxicities by grade per cohorts 
Toxicities 
Cohort 
No 
G1 
G2 
G3 
G4 
G5 
Total 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Toxicity 1 
C1 
  
  
  
  
  
  
 
C2 
  
  
  
  
  
  
 
C3 
  
  
  
  
  
  
 
C4 
  
  
  
  
  
  
  
C5 
  
  
  
  
  
  
  
C6 
  
  
  
  
  
  
  
Toxicity 2 
C1 
  
  
  
  
  
  
  


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C2 
  
  
  
  
  
  
  
C3 
  
  
  
  
  
  
  
C4 
  
  
  
  
  
  
  
C5 
  
  
  
  
  
  
  
C6 
  
  
  
  
  
  
  
Toxicity 3 
C1 
  
  
  
  
  
  
  
C2 
  
  
  
  
  
  
  
C3 
  
  
  
  
  
  
  
C4 
  
  
  
  
  
  
  
C5 
  
  
  
  
  
  
  
C6 
  
  
  
  
  
  
  
 
 
 
2.6.13. TOXICITIES GRADE ≥3 PER COHORTS 
 
Table 209. Frequency of toxicities grade  ≥3 per cohorts 
Toxicities 
Cohort 
N (%, CI95%) 
Toxicity 1 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
Toxicity 2 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
… 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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C6 
  
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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2.6.14. MOST FREQUENT AES  
 
Table 210. Most frequent AEs (>20%, n>4) per cohorts 
AEs 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Cohort 6 
  
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
AE 1  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
 AE2 
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
 … 
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
  
No 
  
  
  
  
  
  
Yes 
  
  
  
  
  
  
Total 
  
  
  
  
  
  
 
Table 211. Most frequent AEs by grade per cohorts 
AEs 
Cohort 
No 
G1 
G2 
G3 
G4 
G5 
Total 


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N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
N (%, 
CI95%) 
AE1 
C1 
  
  
  
  
  
  
 
C2 
  
  
  
  
  
  
 
C3 
  
  
  
  
  
  
 
C4 
  
  
  
  
  
  
  
C5 
  
  
  
  
  
  
  
C6 
  
  
  
  
  
  
  
AE2 
C1 
  
  
  
  
  
  
  
C2 
  
  
  
  
  
  
  
C3 
  
  
  
  
  
  
  
C4 
  
  
  
  
  
  
  
C5 
  
  
  
  
  
  
  
C6 
  
  
  
  
  
  
  
 
C1 
  
  
  
  
  
  
  
C2 
  
  
  
  
  
  
  
C3 
  
  
  
  
  
  
  
C4 
  
  
  
  
  
  
  
C5 
  
  
  
  
  
  
  
C6 
  
  
  
  
  
  
  
 
 
2.6.15. AE GRADE ≥3 PER COHORTS 
 
Table 212. Frequency of AEs grade ≥3 per cohorts 
AEs  
Cohort 
N (%, CI95%) 
AE 1 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
AE 2 
C1 
  
C2 
  
C3 
  


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C4 
  
C5 
  
C6 
  
AE 3 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
 
 
 
 
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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2.6.16. SAE PER COHORTS 
 
Table 213. SAEs per cohorts 
SAEs 
Cohort 
N (%, CI95%) 
SAE 1 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
SAE 2 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
SAE 3 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
 
 
2.6.17. SAE RELATED TO ANY TREATMENT PER COHORTS 
 
Table 214. SAEs RELATED per cohorts 
Relates SAEs  
Cohort 
N (%, CI95%) 
SAE 1 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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SAE 2 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
SAE 3 
C1 
  
C2 
  
C3 
  
C4 
  
C5 
  
C6 
  
 


StudyCABATEN                                                                                                                                                      STATISTICAL ANALYSIS PLAN 
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2.7. ANNEX: LIST OF ALL TOXICITIES 
 
Table 215. List of all toxicities 
 
Patient ID 
Cohort 
Adverse Event (CTC) 
Adverse Event 
(CTC specify) 
AE relationship to 
treatment 
Date AE started Date AE ended 
Duration 
(days) 
Continuous 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. CONCLUSIONS 
 


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4. ANEXES 
4.1. ANEX I: DATABASE MANAGEMENT 
In this section, the process of data base management and data cleaning will be 
described. 
 
 
 


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5. REFERENCES 
Provide references for any citations in the main body of the SAP.