A Multicenter, Single Arm, Phase 2 Clinical Study on the Combination of Radiation Therapy and Ipilimumab, for the Treatment of Patients With Melanoma and Brain Metastases
Phase: PHASE2
Conditions: Melanoma, Brain Metastases
Sponsor: Grupo Español Multidisciplinar de Melanoma

 
 
 
 
  
  
  
GEM  1202:  
 
A  MULTICENTER,  SINGLE  ARM,  PHASE  2  CLINICAL  STUDY  ON  THE   
COMBINATION  OF  RADIATION  THERAPY  AND  IPILIMUMAB,  FOR  THE   
TREATMENT  OF  PATIENTS  WITH  MELANOMA  AND  BRAIN   
METASTASES.  
 
S HORT  T ITLE :  GRAY-B  
 
( G EM  STUDY:  R ADIATION  A ND  Y ERVOY  IN  PATIENTS  WITH  MELANOMA  AND  B RAIN   
METASTASES )  
 
E UDRA CT  S TUDY  N UMBER :  2013-001132-22  
 
 
 
Sponsor: GE M  (Spanish  Multidisciplinary  Melanoma  Group)  Study   
Coordinator:   
Jose  A.  Lopez-Martin,  MD   
”12  de  Octubre”  University  Hospital   
Av  Cordoba  S/N.  28041-Madrid  (Spain)   
0034913908003   
0034914603310   
jalopezmartin@gmail.com   
  
Version  1.0  /  28  Nov  2013   
 

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
PROTOCOL  SIGNATURE  PAGE   
  
Protocol  Number:  GEM  1202/GRAY-B   
Protocol  Version:  1.0  November  28th  2013   
  
I  have  read  this  protocol  and  I  agree  to  conduct  this  clinical  study  in  accordance  with  the  specific  
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
provisions  of  this  protocol,  GCPs  and  Helsinki  Declaration.   
  
  
 
  
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Clinical  Trial  Chief  Investigator   
Principal  Investigator   
  
Dr.  José  Antonio  López-Martín   
  
Signature:   
  
  
  
Name:   
  
Signature:   
Sponsor   
Dr.  Salvador  Martín  Algarra   
Chairman  of  GEM   
Signature:.   
  
  
  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
TABLE  OF  C ONTENTS   
TABLE  OF  C ONTENTS 
 
 
P ROTOCOL  SYNOPSIS 
 
 
L IST  OF  A BBREVIATIONS 
 
 
1 
INTRODUCTION 
 
 
1.1 
Research  Hypothesis 
 
 
1.2 
Product  Development  Rationale 
 
 
1.2.1. 
Melanoma  and  brain  metastases:  clinical  relevance  of  the  condition. 
 
 
1.2.2.   
Management  of  patients  with  melanoma  metastatic  to  the  brain  with  favorable  prognosis. 
 
 
1.2.3.   
Management  of  patients  with  melanoma  metastatic  to  the  brain  with  intermediate  and  poor  prognosis. 
 
 
1.2.4.   
Systemic  therapy  for  melanoma  patients  with  brain  metastases. 
 
 
1.2.5.   
Glucocorticoids  in  brain  metastases 
 
 
1.2.6.   
Abscopal  effect  of  radiation  therapy. 
 
 
1.2.7.   
CTLA-4  and  T  Cell  Activation 
 
 
1.3 
Summary  of  Results  of  Investigational  Program 
 
 
1.3.1 
Pharmacology  of  Ipilimumab 
 
 
1.3.2 
Animal  Toxicology  of  Ipilimumab 
 
 
1.3.3 
Clinical  Pharmacology 
 
 
1.3.3.a 
Mechanism  of  Action 
 
 
1.3.3.b 
Pharmacokinetics 
 
 
1.3.4 
Clinical  Safety  with  Ipilimumab 
 
 
1.3.4.a 
Overview  of  Clinical  Trials  Experience 
 
 
1.3.4.b 
Immunogenicity 
 
 
1.3.4.c 
Pregnancy  Outcomes 
 
 
1.3.4.d 
Immune-mediated  Adverse  Reactions  with  Ipilimumab. 
 
 
1.3.5 
Clinical  Efficacy:  Melanoma  Program 
 
 
1.3.5.a 
Rationale  for  Using  Immune-Related  Tumor  Assessment  Criteria  (irRC) 
 
 
1.3.5.b 
MDX010-20  (Phase  3,  3  mg/kg,  previously  treated  melanoma) 
 
 
1.3.5.c 
CA184024  (Phase  3,  previously  untreated  melanoma,  10  mg/kg) 
 
 
1.3.5.d 
10  mg/kg  Dosing  with  Ipilimumab 
 
 
1.3.5.e 
Advanced  Melanoma 
 
 
1.4 
Overall  Risk/Benefit  Assessment 
 
 
  
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1.5 
Study  Rationale 
 
 
2 
STUDY  OBJECTIVES 
 
 
2.1 
Primary  Objective. 
 
 
2.2 
Secondary  Objectives 
 
 
3 
STUDY  DESIGN 
 
 
4 
S UBJECT  SELECTION  CRITERIA 
 
 
4.1 
Inclusion  Criteria 
 
 
4.2 
Exclusion  Criteria 
 
 
4.3 
Data  Safety  Monitoring  Plan 
 
 
5. 
STUDY  THERAPY 
 
 
5.1. 
Ipilimumab 
 
 
5.1.1. 
Dose  Calculations 
 
 
5.1.2. 
Storage,  Preparation,  and  Administration 
 
 
5.1.3. 
Dose  Modification 
 
 
5.1.4. 
Discontinuation  of  Study  Therapy 
 
 
5.1.5. 
Permanent  Discontinuation  of  Ipilimumab 
 
 
5.1.5.a 
Permanent  Discontinuation  for  Related  Adverse  Events 
 
 
5.1.5.b 
Exceptions  to  Permanent  Discontinuation 
 
 
5.1.6. 
Immune-Related  Adverse  Events  (irAEs)Reactions  and  Immune-mediated  Adverse  Reactions:  Definition,   
Monitoring,  and  Treatment 
 
 
5.1.7. 
Other  Guidance 
 
 
5.1.8. 
Treatment  of  Infusion  Reactions  Associated  with  Ipilimumab 
 
 
5.1.9. 
Treatment  of  Ipilimumab-Related  Isolated  Drug  Fever 
 
 
5.1.10. 
Monitoring  and  Management  of  Immune-mediated  Adverse  Reactions 
 
 
Immune-mediated  Enterocolitis 
 
 
Immune-mediated  Hepatitis 
 
 
Immune-mediated  Dermatitis 
 
 
Immune-mediated  Neuropathies 
 
 
Immune-mediated  Endocrinopathies 
 
 
Other  Immune-mediated  Adverse  Reactions,  Including  Ocular  Manifestations 
 
 
5.1.11. 
Liver  Function  Test  (LFT)  Assessments  Required  Before  Administration  of  Ipilimumab 
 
 
5.2. 
Radiation  therapy 
 
 
  
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5.3. 
Glucocorticoid  therapy 
 
 
5.4. 
Prohibited  and  Restricted  Therapies  During  the  Study 
 
 
5.4.1. 
Prohibited  Therapies 
 
 
5.4.2. 
Restricted  Therapies 
 
 
6. 
STUDY  PROCEDURES  AND  OBSERVATIONS 
 
 
6.1. 
Time  and  Events  Schedule  (Table  12) 
 
 
6.2. 
Procedures  by  Visit 
 
 
6.2.1. 
Study  Procedures  by  Visit  and  Treatment  Cycle 
 
 
6.2.1.a 
Registration  visit. 
 
 
6.2.1.b 
Screening/Baseline  Visit 
 
 
6.2.1.c 
Treatment  Visits 
 
 
6.2.1.d 
End  of  Treatment  visit. 
 
 
6.2.1.e 
Follow-up  visits. 
 
 
6.2.2. 
Study  Completion  or  Early  Discontinuation  Visit 
 
 
6.2.3. 
Study  Drug  Discontinuation 
 
 
6.3. 
Details  of  Procedures 
 
 
6.3.1. 
Study  Materials 
 
 
6.3.2. 
Safety  Assessments 
 
 
6.4. 
Criteria  for  Evaluation 
 
 
6.4.1. 
Safety  Evaluation 
 
 
6.4.1.a 
Medical  History,  Physical  Exam,  Physical  Measurements 
 
 
6.4.1.b 
Vital  Signs 
 
 
6.4.1.c 
Pregnancy  Testing 
 
 
6.4.1.d 
Performance  Status  and  Barthel  Index 
 
 
6.4.1.e 
Laboratory  Testing 
 
 
6.4.1.f 
Endocrine  Tests 
 
 
6.4.1.g 
HIV  and  Hepatitis  Panel 
 
 
6.4.2. 
Efficacy  Evaluation 
 
 
6.4.2.a 
Radiological  Assessment  of  Tumor  Lesions 
 
 
6.4.2.b 
Non-radiographic  Assessments 
 
 
6.4.2.c 
Definition  of  Measurable/Non-measurable  Lesions 
 
 
6.4.2.d 
Definition  of  Index/Non-index  Lesions 
 
 
  
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6.4.2.e 
Definition  of  Tumor  Response  per  mWHO 
 
 
6.4.2.f 
Response  per  Time  Point 
 
 
6.4.2.g 
Best  Overall  Response  (BOR)per  Subject  (Including  all  TimePoints) 
 
 
6.4.2.h 
Local  Radiotherapy  for  Symptomatic  Bone  Lesions 
 
 
6.4.2.i 
Response  Kinetics  and  Immune-related  Endpoints 
 
 
6.4.2.j 
Definition  of  Tumor  Response  Using  irRC 
 
 
6.4.2.k 
Immune-Related  Best  Overall  Response  Using  irRC  (irBOR) 
 
 
6.4.3. 
Exploratory  endpoints:  predictive  biomarkers 
 
 
6.4.3.a 
Background  for  Biomarker  Research  in  Melanoma 
 
 
6.4.3.b 
Biomarker  Measures 
 
 
6.4.3.c. 
Blood/Lab  Biomarkers  timepoints 
 
 
6.4.3.d 
Archival  Tumor  Tissue 
 
 
6.4.4. 
Difussion-Weighted  MRI  (DW-MRI). 
 
 
7. 
IN VESTIGATIONAL  P RODUCT :  IPILIMUMAB 
 
 
7.1. 
Identification 
 
 
7.2. 
Packaging  and  Labeling 
 
 
7.3. 
Storage,  Handling,  and  Dispensing 
 
 
7.3.1. 
Storage 
 
 
7.3.2. 
Handling  and  Disposal 
 
 
7.3.3. 
Dispensing 
 
 
7.4. 
Drug  Ordering  and  Accountability 
 
 
7.4.1. 
Initial  Orders 
 
 
7.4.2. 
Re-Supply 
 
 
7.5. 
Ipilimumab  Accountability 
 
 
7.6. 
Ipilimumab  Destruction 
 
 
8. 
ADVERSE  EVENT  REPORTING 
 
 
8.1. 
Collection  of  Safety  Information 
 
 
8.1.1. 
Serious  Adverse  Events 
 
 
8.1.2. 
Nonserious  Adverse  Events 
 
 
8.2. 
Assignment  of  Adverse  Event  Intensity  and  Relationship  to  Investigational  Product 
 
 
8.3. 
Collection  and  Reporting 
 
 
8.3.1. 
Serious  Adverse  Events 
 
 
  
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8.3.2. 
Handling  of  Expedited  Safety  Reports 
 
 
8.3.3. 
Nonserious  Adverse  Events 
 
 
8.3.4. 
Pregnancy 
 
 
8.3.5. 
Other  Safety  Considerations 
 
 
9. 
S TATISTICAL  M ETHODOLOGY 
 
 
9.1. 
Sample  size. 
 
 
9.2 
Populations  for  Analyses 
 
 
9.3 
Endpoint  Definitions 
 
 
9.3.1 
Primary  Endpoint 
 
 
9.3.1.1 
Overall  Survival  (OS) 
 
 
9.3.2 
Secondary  and  Exploratory  Endpoints 
 
 
9.3.2.1 
Progression  Free  Survival  (PFS) 
 
 
9.3.2.2 
Best  Overall  Response  Rate  (BORR) 
 
 
9.3.2.3 
Disease  Control  Rate  (DCR) 
 
 
9.3.2.4 
Duration  of  Response 
 
 
9.3.2.5 
Duration  of  Stable  Disease 
 
 
9.4 
Analyses 
 
 
9.4.1 
Demographics  and  Baseline  Characteristics 
 
 
9.4.2 
Efficacy  Analyses 
 
 
9.4.2.1 
Methods  for  Time  to  Event  Primary  Endpoint 
 
 
9.4.2.2 
Methods  for  Time  to  Event  Secondary  Endpoints 
 
 
9.4.2.3 
Methods  for  Proportion  Based  Rates  Secondary  Endpoints 
 
 
9.4.3 
Safety  Analyses 
 
 
Immune-related  Adverse  Events  (irAEs) 
 
 
Immune-mediated  Adverse  Reactions  (imARs) 
 
 
9.4.5 
Exploratory   Analyses 
 
 
9.5 
Interim  Analyses 
 
 
10. 
ADMINISTRATIVE  SECTION 
 
 
10.1. 
Compliance  with  the  Protocol  and  Protocol  Revisions 
 
 
10.2. 
Informed  Consent 
 
 
10.3.   
Records  and  Reports 
 
 
10.4.   
Good  Clinical  Practice 
 
 
  
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10.5.   
Institutional  Review  Board/Independent  Ethics  Committee  (IRB/IEC) 
 
 
10.6.   
Records  Retention 
 
 
11.   
RE FERENCE S 
 
 
APPENDIX  1 
KARNOFSKY  PERFORMANCE  STATUS  SCALE 
 
 
APPENDIX  2 
B ARTHEL  I NDEX  OF  A CTIVITIES  OF  D AILY  L IVING 
 
 
11. 
RE FERENCE S 
 
 
  
 
 
 
  
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P ROTOCOL  SYNOPSIS   
  
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Protocol  Title:  
 
GEM  1202   
A  MULTICENTER,  SINGLE  ARM,  PHASE  2  CLINICAL  STUDY   
ON  THE  COMBINATION  OF  RADIATION  THERAPY  AND   
IPILIMUMAB,  FOR  THE  TREATMENT  OF  PATIENTS  WITH   
MELANOMA  AND  BRAIN  METASTASES. 
  
Short  Title  
 
GRAY-B   
(GEM  STUDY  RADIATION  AND  YERVOY  IN  PATIENTS  WITH   
MELANOMA  AND  BRAIN  METASTASES   
EUDRACT  STUDY  NUMBER  
 
2013-001132-2   
Country  (ies)  and  Site   
Numbers.  
 
Spain,  12  sites  (Appendix  3)   
Research  Hypothesis:  
 
Ipilimumab  adds  a  clinical  benefit  to  radiation  therapy  in  patients  with   
melanoma  metastatic  to  the  brain.   
  
  
• 
Melanoma  is  the  third  most  common  cancer  causing  brain   
metastases,  after  cancers  of  the  lung  and  breast,  which  appears  to   
reflect  the  relative  propensity  of  melanoma  to  metastasize  to  the  central   
nervous  system  (CNS).  Brain  metastases  are  responsible  for  20  to  54   
percent  of  deaths  in  patients  with  melanoma,  and  among  those  with   
documented  brain  metastases,  these  lesions  contribute  to  death  in  up  to   
95  percent  of  cases,  with  an  estimated  median  overall  survival  ranging   
between  1.8  and  10.5  months,  depending  upon  other  prognostic  factors.  
• 
Ipilimumab  is  an  anti-CTLA4  monoclonal  antibody  that  has   
demonstrated  a  clinically  relevant  and  statistically  significant   
improvement  in  overall  survival,  either  alone  (second  line)  or  in   
combination  with  DTIC  (1st  line).   
• 
Ipilimumab  has  shown  activity  against  brain  metastases   
• 
According  to  the  EMA-approved  label  for  Yervoy ® ,  the  use  of   
glucocorticoids  at  baseline  (commonly  prescribed  when  brain   
metastases  are  diagnosed)  should  be  avoided  before  the  administration   
of  ipilimumab.  Data  show  that  the  use  of  even  high  doses  of   
glucocorticoids  for  the  management  of  immune-related  adverse  events 
do  not  decrease  the  efficacy  of  Yervoy ® .  There  is  no  documented   
experience  on  the  efficacy  of  Yervoy ®   when  given  concomitantly  with   
radiation  therapy  and  glucocorticoids.   
  
• 
In  experimental  models,  radiation  therapy  is  synergistic  to   
anti-CTLA-4  strategies  (abscopal  effect)   
• 
There  are  no  published  results  from  clinical  trials  on  the   
interaction  between  radiation  therapy  and  ipilimumab.   
Study  Schema:  
 
Drugs  /  Doses  /  
 
Length  of  Treatment)  
 
●
Ipilimumab  3mg/Kg  iv  q  3  weeks  for  4  cycles   
●
WBRT  30  Gy  in  10  fractions  (or  radiobiological  equivalent   
schedule,  after  Sponsor  approval),  starting  between  C1D2  and   
C2D1   
  
Study  Objectives:  
 
Primary:  
 
Secondary:  
 
Primary  Objective   
●
Efficacy  -  Primary  endpoint:  1-year  survival  rate   
  
Secondary  Objectives   
●
Efficacy  –  Endpoints:   
  
o
Progression-Free  survival-PFS  (median,  6-month  PFS  rate)   
▪
Intracranial  PFS  (median,  6-month  PFS  rate)   

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▪
Extracranial  PFS  (median,  6-month  PFS  rate)   
o
Overall  survival  (median)   
o
Response  rate:  (global,  intracranial,  extracranial)   
(“Immune-related  response  criteria”)   
●
Safety:  Adverse  Event  rates   
●
Feasibility:  dose  delays/reductions,  treatment  exposure   
Study  Design:  
 
Multicenter,  single  arm,  phase  2  clinical  study  on  the  combination  of   
radiation  therapy  and  ipilimumab   
Accrual  Goal:  
 
(Total  number  of  patients)  
 
56  patients  treated  66  included   
Accrual  Rate:  
 
(Number  of  patients   
expected  per  month)  
 
3  to  4  patients  per  month   
FPFV:  
 
LPFV:  
 
Follow  Up:  
 
(dd-mm-yy)  
 
03/2014   
10/2015   
10/2016   
  
Correlative  Studies:  
 
(PK/PD,  etc.)  
 
Exploratory  Objectives.   
o
Potential  baseline  predictors  of  efficacy  (in  tumor  tissue  and   
peripheral  blood)   
Potential  early  surrogates  for  response:   intrapatient  variation  of   
quantitative  apparent  diffusion  coefficients  of  serial   
diffussion-weighted  magnetic  resonance  imaging   
Inclusion  Criteria:  
 
1)
Willing  and  able  to  give  written  informed  consent.   
2)
Histologic  diagnosis  of  melanoma.   
3)
First  episode  of  radiological  evidence  of  brain  metastases   
4)
Age>18  years.   
5)
RTOG-RPA  class  2  (Appendix  1)   
6)
Karnofsky  performance  status  (PS)  >  70%.(Appendix  2)   
7)
Barthel  Index  of  Activities  of  Daily  Living  >  10  (Appendix  3)   
8)
Measurable  disease  (mWHO  criteria).   
9)
Adequate  organ  function  as  determine  by  the  following  criteria:   
a.
WBC  ≥  2000/uL   
b.
Absolute  neutrophil  count  (ANC)  >1.5  x  10 9 /L.   
c.
Platelet  count  >75  x  10 9 /L.   
d.
Hemoglobin  >9  g/dL.  If  the  patient  received  a  RBC   
transfusion,  the  required  value  of  hemoglobin  should  be   
met  at  least  1  week  after  the  most  recent  transfusion.   
  
e.
Serum  creatinine  ≤  2.0  x  ULN.   
f.
Serum  aspartate  aminotransferase  (AST)  and  serum   
alanine  aminotransferase  (ALT)  ≤  2.5  x  ULN  for   
patients  without  liver  metastasis,  or  ≤ 5  times  for  liver   
metastases.   
g.
Total  bilirubin  ≤  2.0  x  ULN,  (except  patients  with   
Gilbert’s  Syndrome,  who  must  have  a  total  bilirubin  less   
than  3.0  mg/dL)   
10) Persons  of  reproductive  potential  must  agree  to  use  an  adequate   
method  of  contraception  throughout  treatment  and  for  at  least  26   
weeks  after  ipilimumab  is  stopped:  (see  definitions  in  protocol   
text)   
Exclusion  Criteria:  
 
1)  Patients  with  melanoma  and  brain  metastases  with  any  of  the   
following  disease-specific  characteristics:   

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a. Documented  evidence  of  prior  progression  of  melanoma  to  an   
ipilimumab-containing  regimen  (i.e.  received  at  least  2  doses  of   
ipilimumab  for  either  advanced  disease  or  in  the  adjuvant  setting   
and  the  disease  progressed/relapsed  -according  to  mWHO  criteria-   
within  24  weeks  since  the  first  dose  of  ipilimumab) 
b. Prior  radiation  therapy  to  the  brain   
c. Other  prior  antineoplastic  therapies  for  brain  metastases.   
d. Patients  with  cerebral  metastases  as  the  only  location  of  the   
disease,  for  which  local  therapy  (neurosurgery,  radiosurgery)  could   
achieve  a  disease-free  status   
e. Patients  with  a  rapid  clinical  deterioration,  or  with  risk  of   
herniation,  or  who  require  unstable  ascending  dosing  of  supportive   
medication  in  the  last  week  -including  anti-convulsivants,  steroids   
and  analgesics-,  or  who  require  dexamethasone  >  16  mg/d  (or  other   
glucocorticoid  at  an  equipotent  dose),  or  with  a  high  LDH  (>  2  x   
ULN).   
  
2) Any  other  malignancy  form  which  the  patient  has  been  disease-free   
for  less  than  5  years,  with  the  exception  of  adequately  treated  and   
cured  basal  or  squamous  cell  skin  cancer,  superficial  bladder   
cancer  or  carcinoma  in  situ  of  the  cervix,  or  incidental  prostate   
cancer.   
3) Uncontrolled  diabetes  mellitus  (HbA1c  >  9%)   
  
4) Autoimmune  disease  other  than  vitiligo  or  past  thyroiditis  under   
substitutive  hormone  therapy:  Patients  with  a  history  of   
inflammatory  bowel  disease,  including  ulcerative  colitis  and 
Crohn’s  Disease,  are  excluded  from  this  study,  as  are  patients  with   
a  history  of  symptomatic  disease  (eg,  rheumatoid  arthritis,  systemic   
progressive  sclerosis  [scleroderma],  systemic  lupus  erythematosus,   
autoimmune  vasculitis  [eg,  Wegener’s  Granulomatosis]);  motor   
neuropathy  considered  of  autoimmune  origin  (e.g.  Guillain-Barre   
Syndrome  and  Myasthenia  Gravis).   
5) Other  chronic  intestinal  diseases  associated  with  diarrhea.   
6) Active  infection  or  other  serious  illness  or  medical  condition.   
7) Known  active  or  chronic  infection  with  HIV,  Hepatitis  B,  or   
Hepatitis  C.   
8)  Concomitant  therapy  with  any  of  the  following:  IL-2,  interferon,  or   
other  non-study  immunotherapy  regimens;  cytotoxic   
chemotherapy;  immunosuppressive  agents;  target  molecular   
inhibitors  (BRAF,  MEK,  KIT);  or  chronic  use  of  systemic   
corticosteroids  (used  for  the  management  of  non-cancer  related   
illnesses),  either  concomitantly  or  during  the  last  3  weeks  prior  to   
the  beginning  of  the  treatment.   
9)  Any  experimental  therapy  administered  in  the  past  30  days  prior  to   
the  beginning  of  the  treatment.   
10) Any  non-oncology  vaccine  therapy  used  for  the  prevention  of   
infectious  diseases   (for  up  to  4  weeks  prior  to  or  after  any  dose  of   
blinded  study  drug)   (see  definitions  in  protocol  text)   
11)  Women  of  childbearing  potential  (WOCBP),  as  defined  above  in  
 
 
 
 
 
 
 
 
 
 
“Inclusion  criteria”,  who:   
a.
are  unwilling  or  unable  to  use  an  acceptable  method  
 
 
 
 
 
 
 
 
 
of  contraception  to  avoid  pregnancy  for  their  entire  
 
 
 
 
 
 
 
 

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study  period  and  for  at  least  26  weeks  after  cessation  
 
 
 
  
 
 
 
 
 
of  study  drug,  or   
b.
have  a  positive  pregnancy  test  at  baseline,  or   
c.
are  pregnant  or  breastfeeding.   
  
12) 
Prisoners  or  subjects  who  are  compulsorily  detained   
(involuntarily  incarcerated)  for  treatment  of  either  a  psychiatric  or   
physical  (eg,  infectious)  illness.   
  
13) 
Any  other  general,  medical  or  psychological  conditions  which 
in  the  opinion  of  the  investigator  will  make  the  administration  of   
ipilimumab  hazardous,  or  that  would  preclude  appropriate  informed   
consent  or  compliance  with  the  protocol,  or  obscure  the  interpretation   
of  eventual  AEs.   
  
Criteria  for  Evaluation:  
 
(Efficacy,  safety,  
 
stopping  rules,  etc.)  
 
Efficacy  Assessments   
Survival  status  will  be  assessed  after  1  year  since  the  start  of  therapy,   
and  will  constitute  the  primary  endpoint.   
Tumor  response  evaluations  will  be  based  on  immune  related  response   
criteria   (irRC)  and  they  will  be  performed  during  the  induction  period   
at  week  12,  17  +  1,  and  every  9  +  1weeks  until  progression.   
Safety  Assessments   
Will  be  evaluated  for  all  treated  subjects  using  the  NCI  CTC  (Common   
Toxicity  Criteria)  version  4.0   
Statistics:  
 
A  one-stage  Fleming  design  has  been  adopted.  Assuming  a  historical   
1-year  survival  rate  of  20%  (with  radiation  therapy  +  best  supportive   
care)  for  the  selected  population,  a  sample  size  of  56  evaluable  patients   
would  be  needed  to  show  that  the  addition  of  ipilimumab  to   
radiotherapy  generates  a  1-year  survival  rate  of  35%,  reaching  80%   
power  at  the  0.05  significance  level.   
  
A  total  of  56  evaluable  patients  would  need  to  be  included.  In  case  that   
at  least  17  out  of  these  56  evaluable  patients  would  survive  for  at  least   
one  year,  the  conclusion  of  the  trial  would  be  that  the  higher  1-year   
survival  rate  of  35%  is  more  likely  for  the  combination  than  the   
historical  20%  survival  rate.   
  
  

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L IST  OF  A BBREVIATIONS   
 
  
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Abbreviation   
Term   
ANC   
Absolute  Neutrophil  Count   
ALC   
Absolute  Lymphocyte  Count   
APC   
Antigen-presenting  cell   
BID 
Twice  a  Day   
BMS   
Bristol-Myers  Squibb  Company   
BORR   
Best  Objective  Response  Rate   
CTLA4   
cytotoxic  T  lymphocyte  antigen  4   
CT  scan   
Computed  Axial  Tomography  scan   
CBC   
Complete  Blood  Count   
CR   
Complete  Response   
CRP   
C  Reactive  Protein   
DLT   
Dose  Limiting  Toxicity   
DSMB   
Data  Safety  Monitoring  Board   
ECOG  PS   
Eastern  Cooperative  Oncology  Group  Performance  Status   
IRAE   
Immune-related  adverse  events   
HIPAA   
Health  Insurance  Portability  and  Accountability  Act   
IMAE   
Immune-mediated  adverse  events   
IRB   
Institutional  Review  Board   
irRC   
Immune-related  response  criteria   
IRCR   
Immune-related  complete  response   
IRPD   
Immune-related  progressive  dose   
FPFV   
First  patient  first  visit   
LPFV   
Last  patient  first  visit   
MRI   
Magnetic  Resonance  Imaging   
OS   
Overall  survival   
PD   
Progressive  Disease   
PFS   
Progression  Free  Survival   
PO   
By  Mouth   
PR   
Partial  Response   
QD   
Once  Daily   
QoL   
Quality  Of  Life   
RECIST   
Response  Evaluation  Criteria  In  Solid  Tumors   
SAE   
Serious  Adverse  Event   
SPD   
Sum  of  the  products  diameters   
SD   
Stable  Disease   
TNM  Staging   
Tumor,  Node  and  Metastasis  Staging   
WBRT   
Whole  Brain  Radiotherapy   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
1
INTRODUCTION   
1.1
Research  Hypothesis  
 
Among  patients  with  melanoma  and  brain  metastases,  Ipilimumab  adds  a  clinically  relevant  benefit  to  
 
 
 
 
 
 
 
 
  
 
 
 
 
radiation  therapy.   
1.2
Product  Development  Rationale   
Ipilimumab  is  approved  for  use  in  the  US  (metastatic  melanoma)  and  in  the  EU  (for  previously  treated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic  melanoma).  The  currently  approved  dose  is  3  mg/kg  every  3  weeks  for  up  to  4  doses.  The  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
current  label  specifies  that  the  use  of  systemic  corticosteroids  at  baseline,  before  starting  Ipilimumab,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should  be  avoided  because  of  their  potential  interference  with  the  pharmacodynamics  and,  therefore,  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  efficacy  of  Ipilimumab.  However,  systemic  corticosteroids  or  other  immunosuppressants  can  be  used  
 
 
 
 
 
 
 
 
 
 
 
 
 
after  starting  Ipilimumab,  to  treat  immune-related  adverse  reactions.  The  use  of  systemic  corticosteroids  
 
 
 
 
 
 
 
 
 
 
 
 
 
after  starting  Ipilimumab  treatment  does  not  appear  to  impair  the  efficacy  of  Ipilimumab.   
Several  studies  have  been  designed  that  included  patients  with  cerebral  metastases.  However,  patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
with  active  brain  metastases  with  symptoms  or  requiring  corticosteroid  treatment,  as  well  as  those  who  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
had  to  receive  concomitant  radiation  therapy,  were  almost  universally  excluded  from  these  protocols.  An  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
open  label  phase  2  study  on  Ipilimumab  in  patients  with  brain  metastases  was  recently  published.  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
However,  although  this  trial  explored  the  activity  of  the  compound  as  a  single  agent  for  patients  with  or  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
without  concomitant  glucocorticoids,  the  completion  of  previous  radiotherapy  had  to  be  done  at  least  2  
 
 
 
 
 
 
 
 
 
 
 
  
  
weeks  before  the  start  of  Ipilimumab.   
1
The  abscopal  effect  is  a  phenomenon  in  which  local  radiotherapy  is  associated  with  the  regression  of  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
metastatic  cancer  at  a  distance  from  the  irradiated  site.  The  abscopal  effect  may  be  mediated  by  activation  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
of  the  immune  system.  In  experimental  models,  radiation  therapy  is  synergistic  to  anti-CTLA-4  strategies.   
  
1.2.1. 
Melanoma  and  brain  metastases:  clinical  relevance  of  the   
condition .  
 
Melanoma  is  the  third  most  common  cancer  causing  brain  metastases,  after  cancers  of  the  lung  and  breast, 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 which  appears  to  reflect  the  relative  propensity  of  melanoma  to  metastasize  to  the  central  nervous  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2
system  (CNS).  Brain  metastases  are  responsible  for  20  to  54  percent  of  deaths  in  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3
melanoma,  and  among  those  with  documented  brain  metastases,  these  lesions  contribute  to  death  in  up  to  
 
 
 
 
 
 
 
 
 
 
  
  
  
4
95  percent  of  cases.   
5
1   
Margolin  K,  Ernstoff  MS,  Hamid  O,  et  al.  Ipilimumab  in  patients  with  melanoma  and  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases:  an  open-label,  phase  2  trial.  Lancet  Oncol  2012;  13:  459–65   
2   
Johnson  JD,  Young  B.  Demographics  of  brain  metastasis.  Neurosurg  Clin  N  Am.  1996;7(3):337   
3   
Sawaya  R,  Bindal  RK.  Metastatic  brain  tumors.  In:  Brain  Tumors,  Kaye  AH,  Laws  ER  Jr  (Eds),  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Churchill  Livingstone,  New  York  1995.  p.923.   
4   
Skibber  JM,  Soong  SJ,  Austin  L,  Balch  CM,  Sawaya  RE.  Cranial  irradiation  after  surgical  excision  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
brain  metastases  in  melanoma  patients.  Ann  Surg  Oncol.  1996;3(2):118.   
5   
Sampson  JH,  Carter  JH  Jr,  Friedman  AH,  Seigler  HF.  Demographics,  prognosis,  and  therapy  in  702  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  with  brain  metastases  from  malignant  melanoma.  J  Neurosurg.  1998;88(1):11.   
  
14 / 93 
  

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As  with  other  primary  tumors,  patients  with  melanoma  metastatic  to  brain  typically  present  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms  of  increased  intracranial  pressure  (e.g.  headache),  focal  neurologic  deficits,  and/or  seizures.  
 
 
 
 
 
 
 
 
 
 
 
 
Brain  metastases  from  melanoma  may  have  a  particularly  high  propensity  for  spontaneous  hemorrhage.   
Melanoma  patients  with  brain  metastases  in  general  have  a  poor  prognosis.  In  a  combined  analysis  of  two  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
series  totaling  almost  1400  patients,  the  median  survival  was  four  months,  and  one  year  survival  rates  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
were  9  and  19  percent,  respectively. 5,   
6
Despite  the  general  poor  prognosis,  occasional  patients  do  well.  Favorable  prognostic  signs  include  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
presence  of  a  single  brain  metastasis  without  other  visceral  metastatic  disease,  and  an  initial  presentation  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
with  a  metastasis  to  the  brain. 5  In  contrast,  multiple  brain  lesions,  extensive  visceral  metastases,  or  a  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
primary  lesion  of  the  head  and  neck  region  carry  an  unfavorable  prognosis. 5   
In  patients  with  brain  metastases  from  other  primary  tumors,  good  performance  status  and  limited  intra-  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  extracranial  disease  are  associated  with  a  favorable  prognosis.  The  Radiation  Therapy  Oncology  
 
 
 
 
 
  
 
 
 
 
 
 
Group  (RTOG)  used  recursive  partitioning  analysis  (RPA)  to  analyze  over  1200  patients  with  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases  and  develop  a  prognostic  index  to  predict  the  outcome  following  palliative  whole  brain  
 
 
  
 
 
 
 
 
 
 
 
 
 
radiation  therapy  (WBRT)  (Table  1).  When  RPA  was  applied  to  74  patients  with  brain  metastases  from  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7
melanoma,  the  median  survival  durations  for  patients  in  RPA  classes  I,  II,  and  III  were  10.5,  5.9,  and  1.8  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
months,  respectively  (Figure  1).   
  
8
Table  1.   
Prognostic  groups  for  outcome  after  palliative  treatment  of  brain  metastases  by  recursive   
partitioning  analysis. 7   
KPS:  Karnofsky  performance  status.   
 
 
 
6   
Fife  KM,  Colman  MH,  Stevens  GN,  Firth  IC,  Moon  D,  et  al.  Determinants  of  outcome  in  melanoma  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
patients  with  cerebral  metastases.  J  Clin  Oncol.  2004;22(7):1293.   
7   
Gaspar  LE,  Scott  C,  Murray  K,  Curran  W.  Validation  of  the  RTOG  recursive  partitioning  analysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(RPA)  classification  for  brain  metastases.  Int  J  Radiat  Oncol  Biol  Phys.  2000;47(4):1001.   
8   
Buchsbaum  JC,  Suh  JH,  Lee  SY,  Chidel  MA,  Greskovich  JF,  Barnett  GH.  Survival  by  radiation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy  oncology  group  recursive  partitioning  analysis  class  and  treatment  modality  in  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
brain  metastases  from  malignant  melanoma:  a  retrospective  study.  Cancer.  2002;94(8):2265.   
  
15 / 93 
  
Class   
Prognostic  factors   
Median  survival,  months 
I   
KPS  ≥70  percent   
7.1   
Age  <65  years   
Controlled  primary  site   
No  extracranial  metastases   
III   
KPS  <70   
2.3   
II   
All  others   
4.2   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
Figure  1.   
Overall  survival  in  RPA  prognostic  groups  in  patients  with  metastatic  melanoma. 8   
  
  
More  recently,  a  diagnosis-specific  graded  prognostic  assessment  tool  has  been  developed  to  estimate  
 
  
 
 
 
 
 
 
 
 
 
 
prognosis  in  patients  with  brain  metastases.  When  a  multivariate  analysis  was  applied  to  481  patients  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
9
with  melanoma  and  brain  metastases,  the  only  statistically  significant  factors  were  the  Karnofsky  
 
 
 
 
 
 
 
 
 
 
 
 
 
performance  status  (<70,  70  to  80,  versus  90  to  100)  and  the  number  of  brain  metastases  (>3,  2  to  3,  or  1)  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
    
 
 
(Table  2).  Median  survival  based  upon  these  parameters  ranged  from  3.4  to  13.2  months. 
  
10
Table  2.   
Graded  prognostic  assessment  for  brain  metastases  from  melanoma. 10   
  
9   
Zimm  S,  Wampler  GL,  Stablein  D,  Hazra  T,  Young  HF.  Intracerebral  metastases  in  solid-tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients:  natural  history  and  results  of  treatment.  Cancer.  1981;48(2):384.   
10   Sperduto  PW,  Kased  N,  Roberge  D,  Xu  Z,  Shanley  R,  et  al.  Summary  report  on  the  graded  prognostic  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
assessment:  an  accurate  and  facile  diagnosis-specific  tool  to  estimate  survival  for  patients  with  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases.  J  Clin  Oncol.  2012  Feb  1;30(4):419-25.   
  
16 / 93 
  
Prognostic  factor   
Scoring  criteria   
Median  survival  (months)  by   
score:   
0-1.0  =  3.4   
1.5-2.0  =  4.7   
2.5-3.0  =  8.8   
3.5-4.0  =  13.2   
0   
1.0   
2.0   
Karnofsky  PS   
<7 
0   
70-8 
0   
90-10 
0   
Number  of  brain   
metastases   
>3   
2-3   
1   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
1.2.2.   
Management  of  patients  with  melanoma  metastatic  to  the  brain   
with  favorable  prognosis.  
 
In  favorable  prognosis  patients  (i.e.,  limited  or  no  extracranial  disease,  a  good  performance  status,  and  a  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
single  or  limited  number  of  brain  metastases),  aggressive  treatment  to  eradicate  metastases  in  the  brain  is  
 
 
 
 
 
 
 
 
  
 
  
 
  
associated  with  an  improved  outcome.  Surgery  traditionally  was  used  to  treat  patients  with  a  single  or  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
limited  number  of  lesions,  often  supplemented  with  WBRT.  Subsequent  advances  have  made  stereotactic  
 
 
 
 
 
 
 
 
 
 
 
 
 
radiosurgery  (SRS)  an  alternative,  particularly  when  lesions  are  not  surgically  accessible  or  when  multiple  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lesions  are  present.   
1.2.3.   
Management  of  patients  with  melanoma  metastatic  to  the  brain   
with  i ntermediate  and  poor  prognosis.  
 
Patients  with  less  favorable  prognosis  (Table  1)  are  generally  treated  with  WBRT  rather  than  surgery  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SRS.  However,  surgery  might  be  occasionally  performed  to  resect  a  large  symptomatic  or  life-threatening  
 
 
 
 
 
 
  
  
 
 
 
 
lesion.   
  
WBRT  is  widely  used  as  the  treatment  for  intermediate/poor  prognosis  patients  with  melanoma  metastatic  
  
 
 
 
 
 
 
 
 
 
 
 
 
to  the  brain.  Even  with  treatment,  the  prognosis  for  these  patients  is  poor.  In  the  Melanoma  Institute  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Australia  study,  234  patients  treated  with  WBRT  alone  had  a  median  survival  of  3.4  months,  compared  to  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
2.1  months  in  210  who  received  supportive  care  only.   
  
11
The  Radiation  Therapy  Oncology  Group  (RTOG)  conducted  a  series  of  randomized  trials  to  determine  the  
 
 
 
 
 
 
  
 
 
 
  
 
 
optimal  dose  and  fractionation  schedule  for  WBRT  in  patients  with  brain  metastases.  Patients  were  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assigned  to  40  Gy  in  four  weeks,  40  Gy  in  three  weeks,  30  Gy  in  three  weeks,  30  Gy  in  two  weeks,  or  20  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
Gy  in  one  week.  The  overall  response  rate  (75  to  80  percent  for  symptom  palliation)  and  median  survival  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
(15  to  18  weeks)  were  equivalent  in  all  arms  of  these  studies.  Patients  treated  with  larger  fractions  over  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
shorter  time  responded  more  quickly,  but  the  duration  of  the  clinical  response  and  the  time  to  progression  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
were  similar  in  all  treatment  arms.  Brain  metastases  caused  death  in  40  percent  of  patients. , , 
  
12 13 14
Subsequent  RTOG  trials  exploring  the  use  of  ultra-rapid  fractionation  schedules,  dose  escalation  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
favorable  prognosis  subgroups,  accelerated  fractionation,  and  the  use  of  radio  sensitizers, failed  to  show  
 
 
 
 
 
 
 
 
 
 
 
 
 
any  benefit  over  conventional  radiation  therapy. 
  
15
11   Fife  KM,  Colman  MH,  Stevens  GN,  et  al.  Determinants  of  outcome  in  melanoma  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cerebral  metastases.  J  Clin  Oncol.  2004;22(7):1293.   
12   Borgelt  B,  Gelber  R,  Kramer  S,  Brady  LW,  Chang  CH,  Davis  LW,  Perez  CA,  Hendrickson  FR.  The  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
palliation  of  brain  metastases:  final  results  of  the  first  two  studies  by  the  Radiation  Therapy  Oncology  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group.  Int  J  Radiat  Oncol  Biol  Phys.  1980;6(1):1.   
13   Vermeulen  SS.  Whole  brain  radiotherapy  in  the  treatment  of  metastatic  brain  tumors.  Semin  Surg  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncol.  1998;14(1):64.   
14   Berk  L.  An  overview  of  radiotherapy  trials  for  the  treatment  of  brain  metastases.  Oncology  (Williston  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Park).  1995;9(11):1205.   
15   Tsao  MN,  Lloyd  N,  Wong  RK,  Chow  E,  Rakovitch  E,  Laperriere  N,  Xu  W,  Sahgal  A.  Whole  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiotherapy  for  the  treatment  of  newly  diagnosed  multiple  brain  metastases.  Cochrane  Database  Syst  
 
 
 
 
 
 
 
 
 
 
 
 
 
Rev.  2012;4:CD003869.   
  
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1.2.4.   
Systemic  therapy  for  melanoma  patients  with  brain   
metastases.  
 
Clinical  results  from  the  development  of  immunotherapy  agents  such  as  ipilimumab and  targeted  
 
 
 
 
 
 
 
 
 
 
 
 
therapies  such  as  dabrafenib  and  vemurafenib suggest  that  systemic  therapy  may  have  a  role  in  carefully  
 
 
 
 
 
 
 
 
 
 
  
  
 
selected  patients  with  brain  metastases  not  amenable  to  surgery  and/or  radiation  therapy.   
  
Nevertheless,  more  studies  are  required  to  define  the  role  of  immunotherapy  and  targeted  therapy  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  with  melanoma  brain  metastases.   
Immunotherapy  both  with  high-dose  interleukin-2  and  the  anti-CTLA4  monoclonal  antibody  
 
 
 
 
 
 
 
 
 
 
ipilimumab have  clinically  useful  activity  in  the  treatment  of  disseminated  melanoma.  Both  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
and  IL-2  in  the  context  of  adoptive  cell  therapy  may  have  clinically  useful  activity  against  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases.  
  
In  phase  II  studies  and  case  reports,  ipilimumab ,  a  human  monoclonal  antibody  that  blocks  CTLA-4,  has  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
demonstrated  activity  against  brain  metastases  in  patients  with  advanced  melanoma.  In  the  largest  
 
 
 
 
 
 
 
 
 
 
 
 
 
experience,  12  of  51  patients  (24  percent)  with  asymptomatic  brain  metastases  not  on  steroids  had  either  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
partial  response  or  stable  disease  for  their  brain  lesions. 1, 
 In  a  cohort  of  21  patients  with  minimally  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
16
symptomatic  brain  metastases  on  a  stable  dose  of  steroids,  one  patient  had  a  complete  response  and  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
another  had  stable  disease  (overall  rate  of  disease  control  10  percent)  during  treatment.  Results  from  that  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study  and  from  other  phase  II  studies  indicate  that  the  safety  profile  and  level  of  activity  against  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases  is  similar  to  that  seen  at  non-CNS  sites.  Adoptive  cell  therapy  using  autologous  antitumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17
lymphocytes  plus  interleukin-2  following  a  lymphocyte-depleting  preparative  regimen  has  antitumor  
 
 
 
  
 
 
 
 
 
activity  in  carefully  selected  patients  with  metastatic  melanoma.  An  analysis  of  the  experience  at  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
National  Cancer  Institute  found  7  of  17  evaluable  patients  (44  percent)  with  brain  metastases  had  a  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
complete  response  in  the  brain.    
  
18
Advances  in  understanding  the  pathogenesis  of  melanoma  have  identified  the  MAPK  pathway  as  a  target  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
for  treatment  in  many  patients  with  metastatic  melanoma.  Dabrafenib  and  vemurafenib target  mutations  in  
 
  
 
 
 
 
 
 
 
 
  
BRAF.   
16   Heller  KN,  et  al.  Safety  and  survival  analysis  of  ipilimumab  therapy  in  patients  with  stable  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
asymptomatic  brain  metastases.   J  Clin  Oncol  29:  2011  (suppl;  abstr  8581).   
17   Weber  JS,  Amin  A,  Minor  D,  Siegel  J,  Berman  D,  O'Day  SJ.  Safety  and  clinical  activity  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  in  melanoma  patients  with  brain  metastases:  retrospective  analysis  of  data  from  a  phase  2  
 
 
 
 
 
 
 
 
 
 
 
  
  
trial.  Melanoma  Res.  2011;21(6):530   
18   Hong  JJ,  Rosenberg  SA,  Dudley  ME,  Yang  JC,  White  DE,  Butman  JA,  Sherry  RM.  Successful  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  of  melanoma  brain  metastases  with  adoptive  cell  therapy.  Clin  Cancer  Res. 
 
 
 
 
 
 
 
 
 
 
 
 
2010;16(19):4892.   
  
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Dabrafenib  has  activity  in  melanoma  patients  with  brain  metastases. , ,  In  a  multicenter  phase  II  study,  
 
 
 
 
 
 
 
 
 
  
 
  
 
19 20 21
172  patients  with  asymptomatic  brain  metastases  containing  either  the  V600E  or  V600K  mutation  were  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treated  with  dabrafenib.  In  the  139  patients  whose  tumor  contained  a  V600E  mutation,  objective  
 
 
 
 
 
 
 
 
 
  
 
 
 
responses  were  observed  in  29  of  74  patients  (39  percent)  in  those  whose  brain  metastases  were  treatment  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
naïve  and  20  of  65  (31  percent)  in  those  who  had  received  prior  local  treatment.  Objective  responses  were  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
observed  in  5  of  33  patients  (15  percent)  with  a  V600K  mutation.   
Case  reports  indicate  that  vemurafenib ,  another  small  molecule  inhibitor  of  BRAF,  also  has  activity  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  with  multiple  brain  metastases  who  received  prior  temozolomide and/or  whole  brain  radiation  
 
 
 
 
 
 
 
 
 
 
 
 
therapy. ,  A  phase  2  trial  with  this  molecule  in  this  setting  is  in  progress.   
22 23
Neither  vemurafenib  nor  dabrafenib  has  been  compared  directly  with  radiation  for  treatment  of  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases.   
Systemic  chemotherapy  for  patients  with  metastatic  melanoma  has  generally  had  only  limited  activity,  
 
 
 
 
 
 
 
 
 
 
 
 
 
and  this  approach  has  been  replaced  by  immunotherapy  and  targeted  therapy  for  the  initial  treatment  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic  disease.  Although  chemotherapy  agents  such  as  fotemustine and  temozolomide have  shown  
 
 
 
 
 
 
 
 
 
 
evidence  of  some  activity  against  brain  metastases, , , 
 cytotoxic  chemotherapy  does  not  have  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
24 25 26
established  role  in  the  management  of  patients  with  melanoma  brain  metastases.   
1.2.5.   
Glucocorticoids  in  brain  metastases   
  
Most  patients  with  brain  tumors  and  peritumoral  edema  can  be  adequately  managed  with  glucocorticoids.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reduction  of  intracranial  pressure  and  improvement  in  neurologic  symptoms  usually  begins  within  hours. 
 
 
 
 
 
  
 
 
 
 
 
19   Falchook  GS,  Long  GV,  Kurzrock  R,  et  al.  Dabrafenib  in  patients  with  melanoma,  untreated  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases, 
 and 
 other  solid  tumours:  a  phase  1  dose-escalation  trial.  Lancet.  2012  
 
 
 
 
 
 
 
 
 
 
 
 
May;379(9829):1893-901.   
  
20   Long  GV,  Kefford  RF,  Carr  PJ,  et  al.  Phase  1/2  study  of  GSK2118436,  a  selective  inhibitor  of  V600E  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
mutatn  BRAF  kinase:  evidence  of  activity  melanoma  brain  metastases.  Ann  Oncol.  2010;21  
 
 
 
 
 
 
 
 
 
 
 
 
(#LBA27)   
21   Long  GV,  Trefzer  U,  Davies  MA,  et  al.  Dabrafenib  in  patietns  with  VAl600Glu  or  Val600Lys  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRAF-mutant  melanoma  metastatic  to  the  brain  (BREAK-MB):  a  multicentre,  open-label,  phase  2 
 
 
 
 
 
 
  
 
 
  
trial.  Lancet  Oncol.  2012;   
22   Dummer  R,  et  al.  An  open-label  pilot  study  of  vemurafenib  in  previously  treated  metastatic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
melanoma  patients  with  brain  metastases.  J  Clin  Oncol.  2011;29:537s.   
23   Rochet  NM,  Kottschade  LA,  Markovic  SN.  Vemurafenib  for  melanoma  metastases  to  the  brain.  N  
 
 
 
 
 
 
 
 
 
 
 
 
  
Engl  J  Med.  2011  Dec;365(25):2439-41.   
24   Avril  MF,  Aamdal  S,  Grob  JJ,  et  al.  Fotemustine  compared  with  dacarbazine  in  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
disseminated  malignant  melanoma:  a  phase  III  study.  J  Clin  Oncol.  2004;22(6):1118.   
25   Agarwala  SS,  Kirkwood  JM,  Gore  M,  et  al.  Temozolomide  for  the  treatment  of  brain  metastases  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
associated  with  metastatic  melanoma:  a  phase  II  study.  J  Clin  Oncol.  2004;22(11):2101.   
26   Schadendorf  D,  Hauschild  A,  Ugurel  S,  et  al.  Dose-intensified  bi-weekly  temozolomide  in  patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
with  asymptomatic  brain  metastases  from  malignant  melanoma:  a  phase  II  DeCOG/ADO  study.  Ann  
 
 
 
 
 
 
  
  
 
 
 
Oncol.  2006;17(10):1592.   
  
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 A  decrease  in  capillary  permeability  (ie,  improvement  in  blood-brain  barrier  function)  can  be  identified  
  
 
 
 
 
 
  
 
 
 
 
 
 
27
within  six  hours,  and  changes  of  diffusion-weighted  MRI  indicating  decreased  edema  are  identifiable  
 
 
 
 
 
 
 
 
 
 
 
 
 
28
within  48  to  72  hours.  However,  adequate  reduction  in  elevated  ICP  resulting  from  peritumoral  edema  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
29
may  take  several  days  with  glucocorticoid  therapy  alone,  and  additional  treatment  may  be  required  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
initial  management  of  these  patients.   
Systemic  glucocorticoids  are  indicated  in  all  patients  who  have  symptomatic  peritumoral  edema. 
 
 
 
 
 
 
 
 
 
 
 
30
 Dexamethasone  is  the  standard  agent,  because  its  relative  lack  of  mineralocorticoid  activity  reduces  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
potential  for  fluid  retention.  In  addition,  dexamethasone  may  be  associated  with  a  lower  risk  of  infection  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
31
and  cognitive  impairment  compared  to  other  glucocorticoids.   
  
32
The  mechanism  of  action  of  glucocorticoids  for  control  of  vasogenic  edema  is  not  fully  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
understood. Dexamethasone  has  recently  been  shown  to  upregulate  Ang-1,  a  strong  BBB-stabilizing  
 
 
 
 
 
 
 
  
 
 
factor,  whereas  it  downregulates  VEGF,  a  strong  permeabilizing  factor,  in  astrocytes  and  pericytes.  
 
  
 
  
 
 
 
 
 
 
 
33
Glucocorticoids  may  also  increase  the  clearance  of  peritumoral  edema  by  facilitating  the  transport  of  fluid  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
into  the  ventricular  system,  from  which  it  is  cleared  by  cerebrospinal  fluid  (CSF)  bulk  flow. 
  
34
In  patients  with  severe  symptoms,  the  usual  dexamethasone  regimen  consists  of  a  10  mg  loading  dose,  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
followed  by  4  mg  four  times  per  day  or  8  mg  twice  daily.  There  is  some  evidence  that  lower  doses  (1  to  2  
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
   
mg  four  times  per  day)  may  be  as  effective  and  less  toxic  in  patients  without  impending  herniation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
35
Although  dexamethasone  is  typically  administered  in  four  divided  daily  doses,  its  biological  half-life  is  
 
 
 
 
 
 
 
 
 
 
 
 
  
sufficiently  long  to  allow  twice  daily  dosing  and  this  approach  is  often  used  for  maintenance  therapy.  To  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
36
27   Alberti  E,  Hartmann  A,  Schütz  HJ,  Schreckenberger  F.  The  effect  of  large  doses  of  dexamethasone  on  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
the  cerebrospinal  fluid  pressure  in  patients  with  supratentorial  tumors.  J  Neurol  1978;  217:173. 
28   Jarden  JO,  Dhawan  V,  Moeller  JR,  et  al.  The  time  course  of  steroid  action  on  blood-to-brain  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
blood-to-tumor  transport  of  82Rb:  a  positron  emission  tomographic  study.  Ann  Neurol  1989;  25:239.   
29   Sinha  S,  Bastin  ME,  Wardlaw  JM,  et  al.  Effects  of  dexamethasone  on  peritumoural  oedematous  brain:  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
a  DT-MRI  study.  J  Neurol  Neurosurg  Psychiatry  2004;  75:1632.   
30   Koehler  PJ.  Use  of  corticosteroids  in  neuro-oncology.  Anticancer  Drugs  1995;  6:19.   
31   Galicich  JH,  French  LA,  Melby  JC.  Use  of  dexamethasone  in  treatment  of  cerebral  edema  associated  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
with  brain  tumors.  J  Lancet  1961;  81:46.   
32   Batchelor  T,  DeAngelis  LM.  Medical  management  of  cerebral  metastases.  Neurosurg  Clin  N  Am  
 
 
 
 
 
 
 
 
 
 
 
 
 
1996;  7:435.   
33   Kim  H,  Lee  JM,  Park  JS,  et  al.  Dexamethasone  coordinately  regulates  angiopoietin-1  and  VEGF:  a  
 
 
 
 
 
  
 
 
 
 
 
 
  
mechanism  of  glucocorticoid-induced  stabilization  of  blood-brain  barrier.  Biochem  Biophys  Res  
 
 
 
 
 
 
 
 
 
 
Commun  2008;  372:243.   
34   Neurological  effects  of  steroid  treatment.  In:  Neurological  Complications  of  Cancer  Treatment,  
 
 
 
 
 
 
 
 
 
 
 
Butterworth-Heinemann,  Boston  p.173.   
35   Vecht  CJ,  Hovestadt  A,  Verbiest  HB,  et  al.  Dose-effect  relationship  of  dexamethasone  on  Karnofsky  
 
 
 
 
 
  
 
 
 
 
 
 
 
performance  in  metastatic  brain  tumors:  a  randomized  study  of  doses  of  4,  8,  and  16  mg  per  day.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Neurology  1994;  44:675.   
36   Use  of  glucocorticoids  in  neuro-oncology.  In:  Neurological  complications  of  cancer,  Marcel  Dekker,  
 
 
 
 
 
 
 
 
 
 
 
 
New  York  1995.  p.199.   
  
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minimize  complications,  subsequent  dosing  should  be  modified  to  use  the  lowest  possible  dose  necessary  
 
 
 
 
 
 
  
 
 
 
 
 
 
to  control  peritumoral  edema.   
Absorption  of  oral  glucocorticoids  is  excellent  and  is  complete  within  30  minutes  of  administration.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
37
Intravenous  dosing  may  be  necessary  if  oral  absorption  cannot  be  assured,  or  if  mentation  is  altered.   
Most  patients  begin  to  improve  symptomatically  within  hours  and  achieve  a  maximum  benefit  from  a  
 
 
 
 
 
 
 
 
 
  
 
 
  
given  dose  of  glucocorticoids  within  24  to  72  hours,  although  standard  neuroimaging  studies  may  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
reveal  decreased  edema  for  at  least  a  week. 36  In  general,  headaches  tend  to  respond  better  than  focal  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
deficits.  If  a dose  of  16  mg/day  of  dexamethasone  per  day  is  insufficient,  the  dose  may  be  increased  up  to  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
100  mg/day. 
  
38
Once  patients  have  responded,  glucocorticoids  should  be  gradually  withdrawn  if  possible. 
 Because  
 
 
 
 
 
 
 
 
 
 
 
 
39
dexamethasone  is  the  most  commonly  used  corticosteroid  for  brain  edema,  has  a  long  duration  of  action,  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
the  drug  should  be  tapered  about  every  four  days.  For  patients  in  good  clinical  condition,  this  may  entail  a  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
reduction  in  dose  of  up  to  50  percent  every  four  days.  However,  for  those  not  tolerating  glucocorticoid  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
withdrawal,  a  more  protracted  course  and  chronic  treatment  may  be  required.   
These  recommendations  are  consistent  with  a  systematic  review  and  evidence-based  clinical  guidelines  
 
 
 
 
  
 
 
 
 
 
 
for  the  use  of  steroids  in  brain  metastases.  Those  guidelines  recommended  a  dose  of  dexamethasone  of  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
40
16  mg  per  day  or  more  for  patients  with  severe  symptoms  due  to  increased  intracranial  pressure  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
edema  due  to  brain  metastases.  For  patients  with  milder  symptoms,  a  starting  dose  of  4  to  8  mg  of  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
dexamethasone  daily  was  recommended;  steroids  are  not  recommended  for  asymptomatic  patients.  Based  
 
 
 
 
 
 
 
 
 
 
 
 
upon  this  review  the  drug  should  be  tapered  slowly  over  two  week  time  period  or  longer  in  symptomatic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
patients.   
1.2.6.   
Abscopal  effect  of  radiation  therapy.  
 
The  abscopal  effect  is  a  phenomenon  in  which  local  radiotherapy  is  associated  with  the  regression  of  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
metastatic  cancer  at  a  distance  from  the  irradiated  site.  The  abscopal  effect  may  be  mediated  by  activation  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
of  the  immune  system.  Ipilimumab  is  a  monoclonal  antibody  that  inhibits  an  immunologic  checkpoint  on  
 
 
 
 
   
 
 
 
 
 
 
 
 
T  cells,  cytotoxic  T-lymphocyte–associated  antigen  4  (CTLA-4).  In  experimental  models,  radiation  
 
 
 
 
  
 
 
 
 
 
therapy  is  synergistic  to  anti-CTLA-4  strategies. , 
  
41 42
37   Kehlet  H,  Binder  C,  Blichert-Toft  M.  Glucocorticoid  maintenance  therapy  following  adrenalectomy:  
 
 
 
 
 
 
 
 
 
 
 
assessment  of  dosage  and  preparation.  Clin  Endocrinol  (Oxf)  1976;  5:37.   
38   Vick  NA,  Wilson  CB.  Total  care  of  the  patient  with  a  brain  tumor  with  consideration  of  some  ethical  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
issues.  Neurol  Clin  1985;  3:705.   
39   Kaal  EC,  Vecht  CJ.  The  management  of  brain  edema  in  brain  tumors.  Curr  Opin  Oncol  2004;  16:593.   
40   Ryken  TC,  McDermott  M,  Robinson  PD,  et  al.  The  role  of  steroids  in  the  management  of  brain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases:  a  systematic  review  and  evidence-based  clinical  practice  guideline.  J  Neurooncol  2010;  
  
 
 
 
 
 
 
  
 
 
96:103.   
41   
 Dewan  MZ,  et  al.  Fractionated  but  not  single-dose  radiotherapy  induces  an  immune-mediated  
 
 
 
 
 
 
 
 
 
 
 
 
abscopal  effect  when  combined  with  anti-CTLA-4  antibody.  Clin  Cancer  Res.  2009  Sep  
 
 
 
 
 
 
 
 
 
 
 
 
1;15(17):5379-88.   
42   Demaria  S,  et  al.  Immune-mediated  inhibition  of  metastases  after  treatment  with  local  radiation  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTLA-4  blockade  in  a  mouse  model  of  breast  cancer.  Clin  Cancer  Res.  2005  Jan  15;11(2  Pt  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
1):728-34.   
  
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In  the  clinical  setting  this  effect  has  been  recently  reported,  although  no  published  results  from  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
43
trials  exploring  this  interaction  between  radiation  therapy  and  ipilimumab  are  yet  available.   
  
  
1.2.7.   CTLA-4  and  T  Cell  Activation   
Figure  2 
Mechanism  of  Action   
  
Advances  in  the  understanding  of  the  mechanisms  that  regulate  T  cell  activation  have  allowed  the  rational  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
design  of  new  strategies  for  immunotherapy  of  tumors,  including  melanoma.  It  has  been  known  for  some  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
time  that  engagement  of  the  T  cell  antigen  receptor  by  itself  is  not  sufficient  for  full  T  cell  activation;  a  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
  
second  co-stimulatory  signal  is  required  for  induction  of  IL-2  production,  proliferation  and  differentiation  
 
 
  
 
 
 
 
 
 
 
 
 
to  effector  function  of  naive  T  cells.  Abundant  data  now  indicate  that  the  primary  source  of  this  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
costimulation  is  mediated  by  engagement  of  CD28  on  the  T  cell  surface  by  members  of  the  B7  family  on  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
the  antigen-presenting  cell  (APC).    (Figure  2.)   
44
Expression  of  B7  has  been  shown  to  be  limited  to  “professional”  antigen  presenting  cells;  that  is,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specialized  cells  of  the  hematopoietic  lineage,  including  dendritic  cells,  activated  macrophages,  and 
 
 
 
 
 
 
 
 
 
 
 
 
activated  B  cells.  It  has  been  suggested  that  this  sharply-defined  restriction  of  B7  expression  is  a  fail-safe  
  
  
 
 
 
 
 
 
 
 
 
   
 
mechanism  for  maintenance  of  peripheral  T  cell  tolerance,  insuring  that  T  cell  activation  can  only  be  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
43   Postow  MA,  Callahan  MK,  Barker  CA,  et  al.  Immunologic  Correlates  of  the  Abscopal  Effect  in  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Patient  with  Melanoma.  N  Engl  J  Med  2012;  366:925-93   
44   Lenschow  D.J.,  et  al.,  CD28/B7  system  of  T  cell  costimulation.  Ann  Rev  Immunol,  1996.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14:233-258.   
  
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stimulated  by  appropriate  APCs.  The  fact  that  tumor  cells  do  not  express  B7  contributes  to  their  poor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
45
capacity  to  elicit  immune  responses. , 
  
46 47
The  demonstration  that  induction  of  expression  of  B7  on  many  tumor  cells  by  transfection,  transduction,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
or  other  mechanisms  can  heighten  tumor  immunogenicity  led  to  great  interest  in  pursuing  this  as  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
approach  to  tumor  immunotherapy.  As  demonstrated  in  vivo  in  murine  tumor  models,  the  utility  of  B7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
expression  as  a  vaccination  approach  is  limited  by  the  following  factors:  (1)  B7-expressing  tumor  cell  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
vaccines  are  only  effective  when  the  tumor  cells  have  a  high  degree  of  inherent  immunogenicity;  (2)  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
while  B7-expressing  vaccines  have  been  shown  in  many  cases  to  be  effective  in  inducing  protective  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
immune  responses,  they  have  demonstrated  only  limited  utility  in  inducing  responses  to  established  
 
 
 
 
 
 
 
 
 
 
 
 
 
tumors;  and  (3)  inactivation  of  tumor  cells  by  radiation  has  been  shown  to  destroy  the  immuno-enhancing  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
activity  of  the  B7  gene  product. ,   
  
48 49
In  the  past  few  years  it  has  become  apparent  that  co-stimulation  is  even  more  complex  than  originally  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
thought.  After  activation,  T  cells  express  CTLA-4,  a  close  homologue  to  CD28.  CTLA-4  binds  members  
 
 
  
 
 
  
 
  
 
 
 
 
of  the  B7  family  with  a  much  higher  affinity  than  CD28.  Although  there  was  initially  some  controversy  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
50
as  to  the  role  of  CTLA-4  in  regulating  T  cell  activation,  it  has  become  clear  that  CTLA-4  down-regulates  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
T  cell  responses. 
  
51
This  was  initially  suggested  by  the  following  in  vitro  observations:  (1) blockade  of  CTLA-4/B7  
 
 
 
 
 
 
 
 
 
 
 
 
 
interactions  with  antibody  enhanced  T  cell  responses;  (2) cross-linking  of  CTLA-4  with  CD3  and  CD28  
 
 
 
  
 
 
 
 
 
 
 
 
 
inhibited  T  cell  responses;  and  (3) administration  of  antibodies  to  CTLA-4  in  vivo  enhanced  the  immune  
  
 
 
 
 
 
 
 
  
 
 
 
 
45 
Schwartz  R.H.  Costimulation  of  T  lymphoctyes:  the  role  of  CD28,  CTLA4,  and  B7/BB1  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
interleukin-2  production  and  immunotherapy.  Cell,  1992.  71(7):  1065-1068.   
46   Chen  L.S.,  et  al.,  Costimulation  of  antitumor  immunity  by  the  B7  counterreceptor  for  the  T  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lymphocyte  molecules  CD28  and  CTLA-4.  Cell,  1992.  71(7):1093-1102.   
47   Townsend  S.E.,  et  al.,  Tumor  rejection  after  direct  costimulation  of  CD8+  T  cells  by  B7-transfected  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
melanoma  cells.  Science,  1993.  259(5093):368-370.   
48 
Townsend  S.E.,  et  al.,  Specificity  and  longevity  of  antitumor  immune  responses  induced  by  
 
 
 
 
 
 
 
 
 
 
 
 
 
B7-transfected  tumors.  Cancer  Res,  1994.  54(24):6477-6483.   
49   Allison  J.P.,  et  al.,  Manipulation  of  costimulatory  signals  to  enhance  antitumor  t  cell  responses.  Curr  
 
  
 
 
 
 
 
 
 
  
 
 
 
Opin  Immunol,  1995.  7(5):682-686.   
50   Linsley  P.S.,  et  al.,  CTLA-4  is  a  second  receptor  for  the  B  cell  activation  antigen  B7.  J  Exp  Med,  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
1991.  174(3):561-569.   
51   Thompson  C.B.,  and  Allison  J.P.  The  emerging  role  of  CTLA-4  as  an  immune  attenuator.  Immunity,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1997.  7(4):  p.445-450.   
  
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response  to  peptide  antigens  or  superantigens  in  mice. , , , 
 Blocking  CTLA-4-B7  interaction  while  
 
 
 
 
 
 
 
 
 
 
 
 
52 53 54 55
preserving  signaling  via  CD28  resulted  in  enhanced  T  cell  responses  in  vitro 53   
Perhaps  the  most  convincing  demonstration  of  the  down-regulatory  role  of  CTLA-4  came  from 
 
 
 
 
 
 
 
 
 
 
 
 
 
examination  of  mice  with  a  null  mutation. , , 
 CTLA-4  knockout  mice  appear  to  have  spontaneously  
 
 
 
  
 
 
 
 
 
 
 
 
 
56 57 58
activated  T  cells  evident  at  approximately  1  week  after  birth,  followed  by  rampant  lymphoproliferation  
  
 
 
 
  
 
 
 
 
 
 
 
and  lymphadenopathy.  These  mice  die  at  approximately  3  weeks  of  age,  either  as  a  result  of  polyclonal  T  
 
 
 
 
  
  
 
 
 
 
  
 
 
  
cell  expansion  and  tissue  destruction  or  as  a  result  of  toxic  shock  resulting  from  lymphokine  production  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
by  the  T cells.  Since  thymocyte  differentiation  and  selection  proceed  normally  in  CTLA-4-deficient  mice,  
 
 
 
 
 
 
 
 
 
  
 
 
the  rampant  T  cell  expansion  that  occurs  in  the  mice  indicates  that  CTLA-4  plays  a  critical  role  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
down-regulating  T  cell  responses  in  the  periphery. 55   
  
1.3
Summary  of  Results  of  Investigational  Program   
1.3.1
Pharmacology  of  Ipilimumab   
Ipilimumab  is  a  human  immunoglobulin  G  (IgG1)κ  anti-CTLA-4  monoclonal  antibody  (mAb).  In  vitro  
 
  
 
 
 
 
 
 
 
 
 
 
studies  were  performed  with  ipilimumab  to  demonstrate  that  it  is  specific  for  CTLA-4,  actively  inhibits  
 
 
 
 
 
 
 
   
 
 
 
 
 
CTLA-4  interactions  with  B7.1  and  B7.2,  does  not  show  any  cross-reactivity  with  human  B7.1,  B7.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
negative  cell  lines,  and  stains  the  appropriate  cells  without  non-specific  cross-reactivity  in  normal  human  
 
 
 
 
 
 
 
 
 
 
  
 
 
tissues,  as  demonstrated  by  immunohistochemistry.  Ipilimumab  does  cross-react  with  CTLA-4  in  
 
 
 
 
 
 
 
 
 
 
 
non-human  primates  including  cynomolgus  monkeys.   
1.3.2
Animal  Toxicology  of  Ipilimumab   
The  effects  of  ipilimumab  on  prenatal  and  postnatal  development  in  monkeys  have  not  been  fully  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigated.  Preliminary  results  are  available  from  an  ongoing  study  in  cynomolgus  monkeys.  Pregnant  
 
 
 
 
 
 
 
 
 
 
 
 
 
monkeys  received  ipilimumab  every  21  days  from  the  onset  of  organogenesis  in  the  first  trimester  through  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
delivery,  at  dose  levels  either  2.6  or  7.2  times  higher  than  the  clinical  dose  of  3  mg/kg  of  ipilimumab  (by  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
AUC).  No  treatment-related  adverse  effects  on  reproduction  were  detected  during  the  first  two  trimesters  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
52   Walunas  T.L.,  et  al.,  CTLA-4  can  function  as  a  negative  regulator  of  T  cell  activation.  Immunity,  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
1994.  1(5):  p.  405-413.   
53   Kearney  E.R.,  et  al.,  Antigen-dependent  clonal  expansion  of  a  trace  population  of  antigen-specific  
 
 
 
 
 
 
 
  
 
 
 
 
CD4+  T  cells  in  vivo  is  dependent  on  CD28  costimulation  and  inhibited  by  CTLA-4.  J  Immunol,  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
1995.  155(3):  1032-1036.   
54   Krummel  M.F.  and  Allison  J.P.  CD28  and  CTLA-4  have  opposing  effects  on  the  response  of  T  cells  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
to  stimulation.  J  Exp  Med  1995;  182(2):  459-465. 
55   Krummel  M.F.,  et  al.,  Superantigen  responses  and  co-stimulation:  CD28  and  CTLA-4  have  opposing  
 
  
 
 
 
 
 
 
 
 
 
 
effects  on  T  cell  expansion  in  vitro  and  in  vivo.  Int  Immunol,  1996.  8(4):  519-523.   
56   Tivol  E.A.,  et  al.,  Loss  of  CTLA-4  leads  to  massive  lymphoproliferation  and  fatal  multiorgan  tissue  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
destruction,  revealing  a  critical  negative  regulatory  role  of  CTLA-4.  Immunity,  1995.  3(5):  541-547.   
57 
Waterhouse  P.  et  al.,  Lymphoproliferative  disorders  with  early  lethality  in  mice  deficient  in  CTLA-4.  
   
 
 
 
 
 
 
 
 
  
 
Science,  1995.  270(5238):  985-988.   
58 
Chambers  C.A.,  et  al.,  Lymphoproliferation  in  CTLA-4-deficient  mice  is  mediated  by  
 
 
 
 
 
 
 
 
 
 
 
costimulation-dependent  activation  of  CD4+  T  cells.  Immunity,  1997,  7(6):  885-895.   
  
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of  pregnancy.  Beginning  in  the  third  trimester,  the  ipilimumab  groups  experienced  higher  incidences  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
abortion,  stillbirth,  premature  delivery  (with  corresponding  lower  birth  weight),  and  higher  incidences  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
infant  mortality  in  a  dose-related  manner  compared  to  controls.   
Genetically  engineered  mice  heterozygous  for  CTLA-4  (CTLA-4+/-),  the  target  for  ipilimumab,  appeared  
 
 
 
 
 
 
 
 
 
 
 
 
healthy  and  gave  birth  to  healthy  CTLA-4+/-  heterozygous  offspring.  Mated  CTLA-4+/-  heterozygous  
 
 
 
 
 
 
 
 
 
 
 
 
mice  also  produced  offspring  deficient  in  CTLA-4  (homozygous  negative,  CTLA-4-/-).  The  CTLA-4-/-  
 
 
 
 
 
 
 
 
 
 
 
 
homozygous  negative  offspring  appeared  healthy  at  birth,  exhibited  signs  of  multiorgan  
 
 
 
 
 
 
 
 
 
 
 
lymphoproliferative  disease  by  2  weeks  of  age,  and  all  died  by  3–4  weeks  of  age  with  massive  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lymphoproliferation  and  multiorgan  tissue  destruction.   
Complete  information  on  the  pre-clinical  toxicology  studies  can  be  found  in  the  Ipilimumab  Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brochure  (IB).  Non-clinical  toxicity  assessments  included  in  vitro  evaluation  for  the  potential  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  to  mediate  complement-dependent  cellular  cytotoxicity  (CDCC)  or  antibody-dependent  
 
 
 
 
 
 
 
 
 
cellular  cytotoxicity  (ADCC),  and  toxicology  assessments  in  cynomolgus  monkeys  alone  and  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
presence  of  vaccines.   
The  in  vitro  studies  demonstrated  that  ipilimumab  did  not  mediate  CDCC  of  PHA-  or  (CD)3-activated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
human  T  cells.  However,  low  to  moderate  ADCC  activity  was  noted  at  concentrations  up  to  50  ug/mL.  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
These  data  are  consistent  with  the  requirement  of  high  levels  of  antigen  expression  on  the  surface  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
target  cells  for  efficient  ADCC  or  CDCC.  Since  ipilimumab  is  a  human  IgG1,  an  isotype  generally  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
capable  of  mediating  CDCC  and  ADCC,  the  lack  of  these  activities  is  likely  due  to  a  very  low  expression  
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
of  CTLA-4  on  activated  T  cells.  Therefore,  these  data  suggest  that  ipilimumab  treatment  would  not  result  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
in  depletion  of  activated  T  cells  in  vivo.  Indeed,  no  depletion  of  T  cells  or  T  cell  subsets  were  noted  in  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
toxicology  studies  in  cynomolgus  monkeys.   
No  mortality  or  signs  of  toxicity  were  observed  in  three  independent  14-day  intravenous  toxicology  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
studies  in  cynomolgus  monkeys  at  multiple  doses  up  to  30 mg/kg/dose.  Furthermore,  ipilimumab  was  
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluated  in  sub-chronic  and  chronic  toxicology  studies  in  cynomolgus  monkeys  with  and  without  
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis  B  (HepB)  Vaccine  and  Melanoma  Vaccine.  Ipilimumab  was  well  tolerated  alone  or  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
combination  in  all  studies.  There  were  no  significant  changes  in  clinical  signs,  body  weight  values,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  pathology  values  or  T  cell  activation  markers.  In  addition,  there  were  no  significant  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
histopathology  changes  in  the  stomach  or  colon.   
1.3.3
Clinical  Pharmacology  
 
1.3.3.a
Mechanism  of  Action   
CTLA-4  is  a  negative  regulator  of  T-cell  activation.  Ipilimumab  binds  to  CTLA-4  and  blocks  the  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
interaction  of  CTLA-4  with  its  ligands,  CD80/CD86.  Blockade  of  CTLA-4  has  been  shown  to  augment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T-cell  activation  and  proliferation.  The  mechanism  of  action  of  ipilimumab’s  effect  in  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
melanoma  is  indirect,  possibly  through  T-cell  mediated  anti-tumor  immune  responses.   
1.3.3.b
Pharmacokinetics 
The  pharmacokinetics  of  ipilimumab  was  studied  in  499  patients  with  unresectable  or  metastatic  
 
 
 
 
 
 
 
 
 
 
 
 
 
melanoma  who  received  doses  of  0.3,  3,  or  10  mg/kg  administered  once  every  3  weeks  for  four  doses.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Peak  concentration  (C  max),  trough  concentration  (Cmin),  and  area  under  the  curve  (AUC)  of  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
were  found  to  be  dose  proportional  within  the  dose  range  examined.  Upon  repeated  dosing  of  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
administered  every  3  weeks,  ipilimumab  clearance  was  found  to  be  time-invariant,  and  minimal  systemic  
 
  
 
 
 
 
  
 
 
 
 
 
accumulation  was  observed  as  evident  by  an  accumulation  index  of  1.5-fold  or  less.  Ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steady-state  concentration  was  reached  by  the  third  dose.  The  following  mean  (percent  coefficient  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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variation)  parameters  were  generated  through  population  pharmacokinetic  analysis:  terminal  half-life  of  
 
 
 
 
 
 
 
 
 
 
 
14.7  days  (30.1%);  systemic  clearance  (CL)  of  15.3  mL/h  (38.5%);  and  volume  of  distribution  at  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steady-state  (Vss)  of  7.21  L  (10.5%).  The  mean  (±SD)  ipilimumab  Cmin  achieved  at  steady-state  with  the  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
3-mg/kg  regimen  was  21.8  mcg/mL  (±11.2).   
Specific  Populations:  Cross-study  analyses  were  performed  on  data  from  patients  with  a  variety  of  
 
 
 
 
 
 
 
 
 
 
  
 
 
conditions,  including  420  patients  with  melanoma  who  received  single  or  multiple  infusions  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  at  doses  of  0.3,  3,  or  10  mg/kg.  The  effects  of  various  covariates  on  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pharmacokinetics  were  assessed  in  population  pharmacokinetic  analyses.   
Ipilimumab  CL  increased  with  increasing  body  weight;  however,  no  dose  adjustment  of  ipilimumab  is  
 
 
 
 
 
 
 
 
 
 
 
 
  
required  for  body  weight  after  administration  on  a  mg/kg  basis.  The  following  factors  had  no  clinically  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
meaningful  effect  on  the  CL  of  ipilimumab:  age  (range  26  to  86  years),  gender,  concomitant  use  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
budesonide,  performance  status,  HLA-A2*0201  status,  positive  anti-ipilimumab  antibody  status,  prior  use  
 
 
 
 
 
 
 
 
 
 
 
of  systemic  anticancer  therapy,  or  baseline  lactate  dehydrogenase  (LDH)  levels.  The  effect  of  race  was  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
examined  as  there  were  insufficient  numbers  of  patients  in  non-Caucasian  ethnic  groups.   
Renal  Impairment:  Creatinine  clearance  at  baseline  did  not  have  a  clinically  important  effect  on  
 
 
 
 
 
 
 
 
  
 
 
 
 
ipilimumab  pharmacokinetics  in  patients  with  calculated  creatinine  clearance  values  of  29  mL/min  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
greater.   
Hepatic  Impairment:  Baseline  AST,  total  bilirubin,  and  ALT  levels  did  not  have  a  clinically  important  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
effect  on  ipilimumab  pharmacokinetics  in  patients  with  various  degrees  of  hepatic  impairment.   
Pharmacokinetic  (PK)  profiles  for  ipilimumab  have  been  analyzed.  The  primary  objective  of  Protocol  
 
 
 
 
 
 
 
 
 
 
 
 
 
MDX010-015  was  to  determine  the  safety  and  PK  profile  of  single  and  multiple  doses  of  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
derived  from  a  transfectoma  or  hybridoma  cell  line.  Mean  plasma  concentrations  of  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
administered  at  doses  of  3 mg/kg  (hybridoma-derived  drug  product);  2.8 mg/kg,  5 mg/kg,  7.5 mg/kg,  
 
 
 
 
 
 
 
 
 
 
 
10 mg/kg,  15 mg/kg,  and  20 mg/kg  (transfectoma-derived  drug  product)  demonstrated  approximate  dose  
 
 
 
 
 
 
 
 
 
 
proportionality.  Equimolar  doses  of  hybridoma-derived  and  transfectoma-derived  drug  product  had  
 
 
 
 
 
 
 
 
 
 
comparable  PK  profiles.  The  range  of  mean  volume  of  distribution  at  steady  state  (Vss)  across  cohorts  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
2.8,  3,  5,  7.5,  10,  15,  and  20 mg/kg,  was  57.3  to  82.6 mL/kg,  indicating  drug  distribution  was  mostly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
limited  to  the  intravascular  space.  The  clearance  was  low  (range  0.11  to  0.29 mL/h/kg)  and  reflective  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  half-life  (range  297  to  414 h),  which  is  consistent  with  the  long  terminal  disposition  phase  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab.  There  was  moderate  variability  in  the  PK  parameters  among  subjects,  with  CV  of  11%  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
48%  in  AUC(0-21d),  20%  to  59%  in  CL,  and  17%  to  46%  in  Vss.   
Ipilimumab  was  originally  produced  and  purified  from  a  hybridoma  clone.  Ipilimumab  drug  substance  is  
 
 
 
 
 
 
  
 
 
 
 
  
currently  manufactured  using  Process  B.  A  new  drug  substance  manufacturing  process  (Process  C)  has  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
been  developed  utilizing  a  higher  producing  sub-clone  of  the  current  Master  Cell  Bank,  and  modified  cell  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
culture  and  purification  steps.  The  new  drug  substance  manufacturing  process  is  intended  to  replace  the  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
current  drug  substance  manufacturing  process.  The  biocomparability  of  Process  C  relative  to  Process  B  
 
 
 
 
 
 
 
 
  
 
 
  
was  assessed  in  Study  CA184087.   
PK  in  Phase  1  Study  CA184087  (Process  B  and  Process  C)   
  
The  PK  of  ipilimumab  was  assessed  when  manufactured  by  a  newer  process  C  relative  to  current  process  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
B  as  an  IV  infusion  (1.5-hr),  in  subjects  with  advanced  melanoma  (CA184087).  Upon  meeting  eligibility  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
criteria,  subjects  were  randomized  (1:1)  to  receive  either  ipilimumab  Process  B  (Arm  A,  reference)  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  Process  C  (Arm  B,  test)  at  a  dose  of  10  mg/kg  IV  administered  over  90  minutes  every  3  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
weeks  on  Days  1,  22,  43,  and  64  (Weeks  1,  4,  7,  and  10)  during  induction  therapy.  Randomization  was  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
26 / 93 
  

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stratified  by  baseline  body  weight  (BW)  and  LDH  values  since  both  were  identified  as  potential  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
covariates  in  a  population  PK  assessment.   
The  primary  endpoint  of  PK  data  at  week  4  demonstrated  that  the  PK  of  Process  B  and  Process  C  are  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
biocomparable  as  the  90%  CIs  for  the  ratio  of  geometric  means  of  AUC(0-21d)  and  Cmax  -  both  adjusted  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
or  not  adjusted  for  covariates  -  were  entirely  contained  with  the  pre-specified  equivalence  interval  (80  -  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
125%).   
Population  Pharmacokinetics   
The  population  pharmacokinetics  (PPK)  of  ipilimumab  was  developed  with  420  subjects  (1767  serum  
 
 
 
 
 
 
 
 
 
 
 
 
 
concentrations)  with  advanced  melanoma  in  phase  2  studies  (CA184007,  CA184008,  and  
 
 
 
 
 
 
 
 
 
 
 
CA184022). 16,17,18  Subsequently,  the  final  PPK  model  was  evaluated  by  an  external  model  validation  
 
 
 
 
 
 
 
 
 
 
 
 
 
dataset  from  CA184004  (79  subjects  with  328  serum  concentration  data).  The  PPK  analysis  demonstrated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
that  PK  of  ipilimumab  is  linear  and  exposures  are  dose  proportional  across  the  tested  dose  range  of  0.3  to  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
10  mg/kg,  and  the  model  parameters  are  time-invariant.  The  ipilimumab  CL  of  15.3  mL/h  from  PPK  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
analysis  is  consistent  with  that  determined  by  PK  analysis  as  assessed  in  MDX010-15  as  12.8  mL/h  for  a  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
dose  of  2.8  mg/kg  and  15.7  mL/h  for  a  dose  of  10  mg/kg.  The  terminal  half-life  and  Vss  of  ipilimumab  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
calculated  from  the  model  were  14.7  days,  and  7.21  L,  which  are  consistent  with  that  determined  by  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
non-compartmental  analysis  (NCA).  Volume  of  central  and  peripheral  compartment  were  found  to  be  4.16  
 
 
 
 
 
 
 
 
 
 
  
 
 
and  3.22  L,  respectively,  suggesting  that  ipilimumab  first  distributes  into  plasma  volume  and  subsequently  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
into  extracellular  fluid  space.  Clearance  of  ipilimumab  was  found  to  increase  with  increase  in  body  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weight,  supporting  dosing  of  ipilimumab  based  on  a  weight  normalized  regimen.  Other  covariates  had  
 
 
 
 
 
 
  
 
 
 
 
 
 
effects  that  were  either  not  statistically  significant  or  were  of  minimal  clinical  relevance.   
1.3.4
Clinical  Safety  with  Ipilimumab   
1.3.4.a
Overview  of  Clinical  Trials  Experience   
Because  clinical  trials  are  conducted  under  widely  varying  conditions,  the  adverse  reaction  rates  observed  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cannot  be  directly  compared  with  rates  in  other  clinical  trials  or  experience  with  therapeutics  in  the  same  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
class  and  may  not  reflect  the  rates  observed  in  clinical  practice.   
The  clinical  development  program  excluded  patients  with  active  autoimmune  disease  or  those  receiving  
 
 
 
 
 
 
 
 
 
 
 
 
 
systemic  immunosuppression  for  organ  transplantation.  Exposure  to  ipilimumab  3  mg/kg  for  four  doses  
 
 
 
 
 
 
 
  
 
 
 
 
given  by  intravenous  infusion  in  previously  treated  patients  with  unresectable  or  metastatic  melanoma  
 
 
 
 
 
 
 
 
 
 
 
 
 
was  assessed  in  a  randomized,  double-blind  clinical  study  (MDX010-20).  One  hundred  thirty-one  patients  
 
   
 
 
 
 
 
 
 
 
 
(median  age  57  years,  60%  male)  received  ipilimumab  as  a  single  agent,  380  patients  (median  age  56  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
years,  61%  male)  received  ipilimumab  with  an  investigational  gp100  peptide  vaccine  (gp100),  and  132  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  (median  age  57  years,  54%  male)  received  gp100  peptide  vaccine  alone.  Patients  in  the  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
received  a  median  of  4  doses  (range  1  to  4  doses).  Ipilimumab  was  discontinued  for  adverse  reactions  in  
  
 
  
 
  
  
 
 
 
 
 
 
  
10%  of  patients.   
The  most  common  adverse  reactions  (≥5%)  in  patients  who  received  ipilimumab  at  3  mg/kg  were  fatigue,  
 
 
 
 
 
  
 
 
 
   
 
 
 
diarrhea,  pruritus,  rash,  and  colitis. 
Table  3  presents  selected  adverse  reactions  from  MDX010-20,  which  occurred  in  at  least  5%  of  patients  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
in  the  ipilimumab-containing  arms  and  with  at  least  5%  increased  incidence  over  the  control  gp100  arm  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
for  all-grade  events  and  at  least  1%  incidence  over  the  control  group  for  Grade  3–5  events.   
Table  3: Selected  Adverse  Reactions  in  MDX010-20   
  
27 / 93 
  
  
Percentage  (%)  of  Patients a   

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a  Incidences  presented  in  this  table  are  based  on  reports  of  adverse  events  regardless  of  causality.   
Source:  Yervoy  Prescribing  Information,  Bristol-Myers  Squibb,  March  2011.   
  
Table  4  presents  the  per-patient  incidence  of  severe,  life-threatening,  or  fatal  immune-mediated  adverse  
  
 
 
 
 
 
 
 
 
 
 
 
reactions  from  MDX010-20.   
  
Table  4: Severe  to  Fatal  Immune-mediated  Adverse  Reactions  in  MDX010-20   
a   Including  fatal  outcome   
  
28 / 93 
  
  
YERVOY  3  mg/kg   
n  =  131   
YERVOY  3mg/kg   
  
+  gp100   
  
n  =  380   
gp100   
n  =  132   
System  Organ   
Class/Preferred  Term   
Any  Grade   
Grade  3-5   
Any  Grade   
Grade  3-5   
Any  Grade   
Grade  3-5   
Gastrointestinal   
Disorders   
  
  
  
  
  
  
Diarrhea   
32   
5   
37   
4   
20   
1   
Colitis   
8   
5   
5   
3   
2   
0   
Skin  and  Subcutaneous   
Tissue  Disorders   
  
  
  
  
  
  
Pruritus   
31   
0   
21   
<1   
11   
0   
Rash   
29   
2   
25   
2   
8   
0   
General  Disorders  and   
Administration  Site   
Conditions   
  
  
  
  
  
  
  
Fatigue   
41   
7   
34   
5   
31   
3   
  
Percentage  (%)  of  Patients   
  
  
YERVOY  3  mg/kg   
n  =  131   
YERVOY  3  mg/kg  +  gp100   
  
n  =  380   
Any  Immune-mediated  Adverse  Reaction   
  
15   
12   
Enterocolitis  a,b   
7   
7   
Hepatotoxicity  a   
1   
2   
Dermatitis  a   
2   
3   
Neuropathy  a   
1   
<  1   
Endocrinopathy   
4   
1   
Hypopituitarism   
4   
1   
Adrenal  insufficiency   
0   
1   
Other   
  
  
Pneumonitis   
0   
<  1   
Meningitis   
0   
<  1   
Nephritis   
1   
0   
Eosinophilia  c   
1   
0   
Pericarditis  a,c   
0   
<  1   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
b   Including  intestinal  perforation   
c   Underlying  etiology  not  established 
Source:  Yervoy  Prescribing  Information,  Bristol-Myers  Squibb,  March  2011.   
  
CA184024  evaluated  the  addition  of  10  mg/kg  ipilimumab  to  dacarbazine  in  patients  with  previously  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
untreated,  metastatic  melanoma.  A  total  of  502  patients  were  randomized  to  receive  up  to  8  cycles  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
dacarbazine  850  mg/m 2  q3w,  with  either  ipilimumab  10  mg  or  placebo  for  cycles  1-4  and  as  maintenance  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after  completion  of  chemotherapy.  Ipilimumab  AEs  were  consistent  with  previous  studies  and  
 
 
 
 
 
 
 
 
 
 
 
 
predominately  affected  skin,  I  tract,  liver,  and  the  endocrine  system.  Events  were  managed  with  
 
 
  
 
 
 
 
 
 
 
 
 
 
established  guidelines  and  were  generally  responsive  to  dose  interruption/discontinuation,  corticosteroids  
 
 
 
 
 
 
 
 
 
 
and/or  other  immunosuppresants.  Select  adverse  events  associated  with  the  mechanism  of  action  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab,  regardless  of  attribution  by  the  investigator)  are  shown  in  Table  5.   
  
 
 
 
  
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Table  5: CA184024  Select  Adverse  Events   
  
a 1  (0.4%)  hypophysitis  was  reported  on  Day  364.   
  
Safety  Profile  of  Ipilimumab  at  a  Dose  of  10  mg/kg  (Phase  2  data)   
The  safety  profile  of  ipilimumab  at  a  dose  of  10  mg/kg  was  characterized  in  a  total  of  325 subjects  who  
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
received  multiple  doses  of  10  mg/kg  ipilimumab  as  monotherapy  in  the  4  completed  melanoma  studies  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
(CA184004,  -007,  -008,  and  -022).  Overall,  the  incidence  of  Grade  3/4  AEs  attributable  to  study  drug  was  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
31%.  The  target  organ  system,  the  incidence  and  the  severity  of  the  most  commonly  observed  irAEs  are  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
displayed  in  Table 6.   
  
Table  6: Summary  of  irAE  Safety  Data  for  10  mg/kg  in  Melanoma   
  
  
30 / 93 
  
  
Ipilimumab  +  DTIC  
 
n  =  247   
Placebo  +  DTIC  
 
n  =  251   
Total   
Grade  3  -  4   
Total   
Grade  3  -  4   
%  Patients   
Dermatologic   
  
  
  
  
Pruritis   
29.6   
2.0   
8.8   
0   
Rash   
24.7   
1.2   
6.8   
0   
Gastrointestinal  (GI)   
  
  
  
  
Diarrhea   
36.4   
4.0   
24.7   
0   
Colitis   
4.5   
2.0   
0.4   
0   
GI  perforation   
0   
0   
0   
0   
Hepatic   
  
  
  
  
Increased  ALT   
33.2   
21.9   
5.6   
0.8   
Increased  AST   
29.1   
18.2   
5.6   
1.2   
Endocrine   
  
  
  
  
Hypothyroidism   
1.6   
0   
0.4   
0   
Autoimmune  thyroiditis   
0.8   
0   
0   
0   
Hyperthyroidism   
0.4   
0   
0.4   
0   
Hypophysitis a   
0   
0   
0   
0   
  
Total   
Low-grade  
 
(Grade  1  -  2)   
(%)   
High-grade  
 
(Grade  3  -  4)  (%)   
Median  Time  to   
Resolution  of  
 
Grade  2  -  4  irAEs   
(weeks)   
All  irAEs   
72.3   
46.2   
25.2   
-   
Skin  (eg,  rash,  pruritus)   
52.0   
49.2   
2.8   
6.14   
GI  (eg,  colitis,  diarrhea)   
37.2   
24.9   
12.3   
2.29   
Liver  (eg,  LFT  elevations)   
8.0   
0.9   
6.8   
4.0   
Endocrine  (eg,   
hypophysitis,  hypothyroid)   
6.2   
3.7   
2.5   
20.1   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
Overall,  the  10  mg/kg  had  an  acceptable  safety  regimen,  while  being  the  most  active  dose.  The  study  drug  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
related  deaths  across  the  program  are  inthe  SMPC.   
Across  clinical  studies  that  utilized  ipilimumab  doses  ranging  from  0.3  to  10  mg/kg,  the  following  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
adverse  reactions  were  also  reported  (incidence  less  than  1%  unless  otherwise  noted):  urticaria  (2%),  large  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
intestinal  ulcer,  esophagitis,  acute  respiratory  distress  syndrome,  renal  failure,  and  infusion  reaction.   
Based  on  the  experience  in  the  entire  clinical  program  for  melanoma,  the  incidence  and  severity  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
enterocolitis  and  hepatitis  appear  to  be  dose  dependent.   
  
1.3.4.b
Immunogenicity   
In  clinical  studies,  1.1%  of  1024  evaluable  patients  tested  positive  for  binding  antibodies  against  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  in  an  electrochemiluminescent  (ECL)  based  assay.  This  assay  has  substantial  limitations  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
detecting  anti-ipilimumab  antibodies  in  the  presence  of  ipilimumab.  Infusion-related  or  peri-infusional  
 
 
 
 
 
 
 
 
 
 
 
reactions  consistent  with  hypersensitivity  or  anaphylaxis  were  not  reported  in  these  11  patients  nor  were  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
neutralizing  antibodies  against  ipilimumab  detected.   
Because  trough  levels  of  ipilimumab  interfere  with  the  ECL  assay  results,  a  subset  analysis  was  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
performed  in  the  dose  cohort  with  the  lowest  trough  levels.  In  this  analysis,  6.9%  of  58  evaluable  patients,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
who  were  treated  with  0.3  mg/kg  dose,  tested  positive  for  binding  antibodies  against  ipilimumab.   
Immunogenicity  assay  results  are  highly  dependent  on  several  factors  including  assay  sensitivity  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
specificity,  assay  methodology,  sample  handling,  timing  of  sample  collection,  concomitant  medications,  
 
 
 
 
 
 
 
 
 
 
 
and  underlying  disease.  For  these  reasons,  comparison  of  incidence  of  antibodies  to  ipilimumab  with  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
incidences  of  antibodies  to  other  products  may  be  misleading.   
  
1.3.4.c
Pregnancy  Outcomes   
Based  on  animal  data,  ipilimumab  may  cause  fetal  harm.  The  use  of  ipilimumab  during  human  pregnancy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
has  not  been  formally  studied  in  clinical  trials.  There  have  been  7  known  pregnancies  during  ipilimumab  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
treatment:  in  3  female  subjects  and  in  the  partners  of  4  male  study  subjects.  Two  of  the  3  female  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
pregnancies  ended  with  elected  terminations.  The  third  female  subject  had  a  history  of  seizures  and  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
delivered  the  baby  at  36  weeks  gestation.  The  baby  had  respiratory  complications  that  resolved  by  birth  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
week  16.  Three  of  the  4  partners  of  male  study  subjects  had  full  term,  normal  babies.  The  fourth  baby  had  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
small  ureters,  which  are  expected  to  grow  as  the  baby  matures.  Although  these  outcomes  do  not  indicate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
that  stillbirths  or  other  severe  abnormalities  will  occur,  pregnancy  should  be  avoided  during  treatment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with  ipilimumab.   
  
1.3.4.d
Immune-mediated  Adverse  Reactions  with  Ipilimumab.   
  
Ipilimumab  can  result  in  severe  and  fatal  immune-mediated  reactions  due  to  T-cell  activation  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
proliferation.   
  
Immune-related  Gastrointestinal  Events   
The  clinical  presentation  of  GI  immune-related  AEs  included  diarrhea,  increase  in  the  frequency  of  bowel  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
movements,  abdominal  pain,  or  hematochezia,  with  or  without  fever.  Fatalities  due  to  GI  perforation  have  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
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been  reported  in  clinical  trials  of  ipilimumab.  Patients  should  be  carefully  monitored  for  GI  symptoms  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
that  may  be  indicative  of  immune-related  colitis,  diarrhea,  or  GI  perforation.  Diarrhea  or  colitis  occurring  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after  initiation  of  ipilimumab  therapy  should  be  evaluated  to  exclude  infectious  or  alternate  etiologies.  In  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  trials,  immune-related  colitis  was  associated  with  evidence  of  mucosal  inflammation,  with  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
without  ulcerations,  and  lymphocytic  infiltration.   
  
Immune-related  Hepatotoxicity   
Hepatic  immune-related  AEs  were  mostly  clinically  silent  and  manifested  as  transaminase  or  bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
 
laboratory  abnormalities.  Fatal  hepatic  failure  has  been  reported  in  clinical  trials  of  ipilimumab.  Serum  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
transaminase  and  bilirubin  levels  must  be  evaluated  before  each  dose  of  ipilimumab  as  early  laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
changes  may  be  indicative  of  emerging  immune-related  hepatitis.  Elevations  in  liver  function  tests  (LFTs)  
 
 
 
 
 
 
 
 
  
 
 
 
 
may  develop  in  the  absence  of  clinical  symptoms.  Increase  in  LFT  or  total  bilirubin  should  be  evaluated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to  exclude  other  causes  of  hepatic  injury,  including  infections,  disease  progression,  or  medications,  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
monitored  until  resolution.  Liver  biopsies  from  patients  who  had  immune-related  hepatotoxicity  showed  
 
 
 
 
 
 
 
 
 
 
 
 
evidence  of  acute  inflammation  (neutrophils,  lymphocytes,  and  macrophages).   
  
Immune-related  Skin  Toxicity   
Skin  immune-related  AEs  presented  mostly  as  a  rash  and/or  pruritus.  Some  subjects  reported  vitiligo  
 
 
 
 
 
  
 
 
 
 
 
 
 
associated  with  ipilimumab  administration.  Fatal  toxic  epidermal  necrolysis  has  been  reported  in  clinical 
 
 
 
 
 
 
 
 
 
 
  
 
trials  of  ipilimumab.   
  
  
Immune-related  Endocrinopathy   
Ipilimumab  can  cause  inflammation  of  the  endocrine  system  organs,  specifically  hypophysitis,  
 
 
 
 
 
 
 
 
 
 
 
hypopituitarism,  and  adrenal  insufficiency  and  patients  may  present  with  nonspecific  symptoms,  which  
 
 
 
 
 
 
 
 
 
 
 
 
may  resemble  other  causes  such  as  brain  metastasis  or  underlying  disease.  The  most  common  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
presentation  includes  headache  and  fatigue.  Symptoms  may  also  include  visual  field  defects,  behavioral  
 
 
 
 
 
 
 
 
 
 
 
 
 
changes,  electrolyte  disturbances,  and  hypotension.  Adrenal  crisis  as  a  cause  of  the  patient’s  symptoms  
 
 
 
 
 
 
 
  
 
 
 
 
 
should  be  excluded.  Based  on  the  available  data  with  known  outcome,  most  of  the  subjects  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptomatically  improved  with  hormone  replacement  therapy.  It  is  possible  that  long-term  hormone  
 
 
 
 
 
 
 
 
 
 
 
 
replacement  therapy  will  be  required  for  subjects  developing  hypophysitis/hypopituitarism  after  treatment  
 
 
 
 
 
 
 
 
 
 
 
with  ipilimumab.   
  
Immune-related  Neurological  Events   
Neurological  manifestations  included  muscle  weakness  and  sensory  neuropathy.  Fatal  Guillain-Barré  
 
 
 
 
 
 
 
 
 
 
syndrome  has  been  reported  in  clinical  trials  of  ipilimumab.  Patients  may  present  with  muscle  weakness.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sensory  neuropathy  may  also  occur.  Unexplained  motor  neuropathy,  muscle  weakness,  or  sensory  
 
 
 
 
 
 
 
 
 
 
 
 
neuropathy  lasting  more  than  4  days  should  be  evaluated  and  non-inflammatory  causes  such  as  disease  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
progression,  infections,  metabolic  syndromes,  and  medications  should  be  excluded. 
  
Other  Immune-related  AEs   
  
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Ocular  inflammation,  manifested  as  Grade  2  or  Grade  3  episcleritis  or  uveitis,  was  associated  with  
 
 
 
 
  
 
  
 
 
 
 
 
 
concomitant  diarrhea  in  a  few  subjects  (<  1%)  and  occasionally  occurred  in  the  absence  of  clinically  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
apparent  GI  symptoms.  Other  presumed  immune-related  AEs  reported  include,  but  were  not  limited  to,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
arthritis/arthralgias,  pneumonitis,  pancreatitis,  autoimmune  (aseptic)  meningitis,  autoimmune  nephritis,  
 
 
 
 
 
 
 
 
pure  red  cell  aplasia,  noninfective  myocarditis,  polymyositis,  and  myasthenia  gravis,  of  which  were  
 
 
 
 
 
 
 
 
 
 
 
 
 
individually  reported  for  <  1%  of  subjects.   
  
Overall,  immune-related  AEs  commonly  started  within  3  to  10  weeks  from  first  dose,  were  successfully  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
managed  in  most  instances  by  omitting  doses,  discontinuing  dosing,  and/or  through  administering  
 
 
 
 
 
 
 
 
 
 
 
 
symptomatic  or  immunosuppressive  therapy,  including  corticosteroids,  as  mentioned  above  and  detailed  
 
 
 
 
 
 
 
 
 
 
 
in  Section  7.  Immune-related  AEs  generally  resolved  within  days  to  weeks  in  the  majority  of  subjects.   
  
  
1.3.5
Clinical  Efficacy:  Melanoma  Program   
The  clinical  efficacy  of  ipilimumab  as  a  single  agent  at  a  dose  of  3  mg/kg  administered  every  3  weeks  for  
 
 
 
 
 
  
 
   
 
  
 
 
  
 
 
4  doses  has  been  established  in  MDX010-20  (a  randomized,  controlled  study  in  second  line,  locally  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
advanced/metastatic  melanoma),  which  led  to  approval  of  ipilimumab  by  the  FDA  for  the  treatment  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
unresectable  or  metastatic  melanoma.  In  study  CA184024,  the  addition  of  10  mg/kg  ipilimumab  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dacarbazine  led  to  a  prolongation  of  overall  survival  in  patients  with  previously  untreated  melanoma  and  
 
 
  
 
 
 
  
 
 
 
 
 
 
was  feasible  with  an  acceptable  safety  profile.   
  
Overall  survival  and  other  efficacy  endpoints  were  assessed  in  ipilimumab  studies.   
Overall  Survival :  Prolongs  survival  in  patients  with  metastatic  melanoma  who  have  failed  prior  
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment.   
Best  Objective  Response  Rate  (BORR) :  By  the  conventional  mWHO  criteria  confirmed  objective  
 
 
 
 
 
 
 
 
 
 
 
 
responses  have  been  observed  in  subjects  receiving  ipilimumab.  These  responses  tend  to  be  durable  with  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
the  majority  of  subjects  who  achieve  objective  responses  progression-free  at  the  end  of  long  observation  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
periods.   
Disease  Control  Rate  (DCR) :  Disease  stabilization  in  subjects  receiving  ipilimumab  is  a  key  
 
 
 
 
 
 
 
 
 
 
 
 
 
characteristic  of  anti-tumor  activity.  Stable  disease,  sometimes  of  long  duration,  or  slow  steady  decline  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tumor  lesion  size  over  long  periods  of  time,  has  been  observed.  Consequently,  SD  as  well  as  objective  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
responses  (both  captured  in  DCR)  are  important  for  completely  characterizing  anti-tumor  activity  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab   
Progression-Free  Survival  (PFS) :  Some  subjects  demonstrate  initial  tumor  volume  increase  before  
 
 
 
 
 
 
 
 
 
 
 
response,  possibly  due  to  T-cell  infiltration  as  shown  by  biopsies.  Consequently,  PFS  incompletely  
 
 
 
 
 
 
 
 
 
 
 
 
 
captures  all  patterns  of  activity  and  may  underestimate  the  clinical  activity  of  ipilimumab.   
  
1.3.5.a
Rationale  for  Using  Immune-Related  Tumor  Assessment  Criteria  (irRC)   
Ipilimumab  is  an  immuno-stimulating  antibody  with  evidence  of  anti-cancer  activity  (durable  objective  
 
 
 
 
 
 
 
 
 
 
 
 
response  and  stable  disease)  in  subjects  with  advanced  melanoma,  including  subjects  with  established  
 
 
 
 
 
 
 
 
 
 
 
 
 
brain  disease.  Observations  of  clinical  activity  defined  by  tumor  response  endpoints  defined  by  
 
 
 
 
 
 
 
 
 
 
 
 
 
conventional  criteria  (eg,  mWHO)  may  be  inadequate  to  realize  the  kinetics  and  magnitude  of  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
benefit  achieved  with  ipilimumab.   
  
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Histopathologic  evidence  has  demonstrated  ipilimumab  can  produce  an  influx  or  expansion  of  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
infiltrating  lymphocytes.  Therefore,  early  increases  in  lesion  size  detected  radiologically  or  upon  gross  
 
 
 
 
 
 
 
 
 
 
 
 
 
examination  could  be  misinterpreted  as  progressive  tumor  growth  and  precede  objective  tumor  shrinkage.  
 
 
 
 
 
 
 
 
 
 
 
 
 
In  addition  the  appearance  of  new  lesions  may  have  categorized  a  subject  to  have  progressive  disease  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
using  conventional  tumor  assessment  criteria  despite  the  concurrent  observation  of  objective  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
responses  in  pre-existing  lesions  and  a  net  reduction  in  global  tumor  burden  that  includes  the  new  lesions.   
Hence  the  appearance  of  new  lesions  in  and  of  themselves  may  not  necessarily  constitute  progressive  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
disease.  The  immune-related  response  criteria  (irRC)  were  developed  as  a  tool  to  gauge  tumor  response  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
using  the  changes  in  global  tumor  burden.  In  addition,  the  irRC  may  be  useful  to  inform  a  physician’s  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
decision  to  continue  dosing  in  subjects  who  may  receive  benefit  from  additional  ipilimumab  therapy.  The  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ir-response  assessment  is  based  solely  on  objective  measurements  (SPD)  of  index  and  new  lesions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-index  lesions  are  not  considered.   
  
1.3.5.b
MDX010-20  (Phase  3,  3  mg/kg,  previously  treated  melanoma)   
MDX010-20,  a  randomized  (3:1:1),  double-blind,  double-dummy  study  included  676 randomized  
 
 
 
 
 
 
 
 
 
subjects  with  unresectable  or  metastatic  melanoma  previously  treated  with  one  or  more  of  the  following:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aldesleukin,  dacarbazine,  temozolomide,  fotemustine,  or  carboplatin.  Of  these  676  subjects,  403  were  
 
 
 
 
 
 
 
 
 
 
 
 
randomized  to  receive  ipilimumab  at  3 mg/kg  in  combination  with  an  investigational  peptide  vaccine  with  
 
 
 
  
  
 
 
 
 
 
 
 
incomplete  Freund’s  adjuvant  (gp100),  137  were  randomized  to  receive  ipilimumab  at  3  mg/kg,  and  136  
 
 
 
 
 
 
 
 
 
   
 
 
 
were  randomized  to  receive  gp100  alone.  The  study  enrolled  only  subjects  with  HLA  A2*0201  genotype;  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
this  HLA  genotype  facilitates  the  immune  presentation  of  the  investigational  peptide  vaccine.  The  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
excluded  subjects  with  active  autoimmune  disease  or  those  receiving  systemic  immunosuppression  for  
 
 
 
 
 
 
 
 
 
 
 
 
organ  transplantation.  Ipilimumab/placebo  was  administered  at  3  mg/kg  as  an  intravenous  infusion  every  
 
 
 
 
   
 
 
 
 
 
 
3  weeks  for  4  doses.  Gp100/placebo  was  administered  at  a  dose  of  2  mg  peptide  by  deep  subcutaneous  
 
 
  
 
 
 
   
 
  
 
 
 
 
 
injection  every  3  weeks  for  four  doses.  Assessment  of  tumor  response  was  conducted  at  Weeks  12  and  24,  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
and  every  3  months  thereafter.  Subjects  with  evidence  of  objective  tumor  response  at  12  or  24  weeks  had  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
assessment  for  confirmation  of  durability  of  response  at  16  or  28  weeks,  respectively.   
The  major  efficacy  outcome  measure  was  overall  survival  (OS)  in  the  ipilimumab + gp100  arm  compared  
 
 
 
 
 
 
 
 
  
 
 
 
 
to  that  in  the  gp100  arm.  Secondary  efficacy  outcome  measures  were  OS  in  the  ipilimumab  +  gp100  arm  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
compared  to  the  ipilimumab  arm,  OS  in  the  ipilimumab  arm  compared  to  the  gp100  arm,  best  overall  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
response  rate  (BORR)  at  Week  24  between  each  of  the  study  arms,  and  duration  of  response.   
  
Of  the  randomized  subjects,  61%,  59%,  and  54%  in  the  ipilimumab  +  gp100,  ipilimumab,  and  gp100  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
arms,  respectively,  were  men.  Twenty-nine  (29%)  percent  were  ≥  65  years  of  age,  the  median  age  was  57  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
years,  71%  had  M1c  stage,  12%  had  a  history  of  previously  treated  brain  metastasis,  98%  had  ECOG  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
performance  status  of  0  and  1,  23%  had  received  aldesleukin  and  38%  had  elevated  LDH  level.  Sixty-one  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
(61%)  percent  of  subjects  randomized  to  either  ipilimumab  -containing  arm  received  all  4  planned  doses.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
The  median  duration  of  follow-up  was  8.9  months.   
The  OS  results  are  shown  in  Table  7  and  Figure  3.   
  
 
  
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Table  7: MDX010-20  Overall  Survival  Results   
a Not  adjusted  for  multiple  comparisons.   
  
Figure  3: 
MDX010-20  -  Overall  Survival  by  Treatment  (ITT  Population)   
  
  
The  best  overall  response  rate  (BORR)  as  assessed  by  the  investigator  was  5.7%  (95%  CI:  3.7%,  8.4%)  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
the  ipilimumab  +  gp100  arm,  10.9%  (95%  CI:  6.3%,  17.4%)  in  the  ipilimumab  arm,  and  1.5%  (95%  CI:  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.2%,  5.2%)  in  the  gp100  arm.  The  median  duration  of  response  was  11.5  months  in  the  ipilimumab  +  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
gp100  arm  and  has  not  been  reached  in  the  ipilimumab  or  gp100  arm.   
  
1.3.5.c
CA184024  (Phase  3,  previously  untreated  melanoma,  10  mg/kg)   
CA184024  evaluated  the  addition  of  10  mg/kg  ipilimumab  to  dacarbazine  in  patients  with  previously  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
untreated,  metastatic  melanoma.  A  total  of  502  patients  were  randomized  to  receive  up  to  8  cycles  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
dacarbazine  850  mg/m 2  q3w,  with  either  ipilimumab  10  mg/kg  or  placebo  cycles  1-4,  and  as  maintenance  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after  completion  of  chemotherapy.   
  
  
35 / 93 
  
  
Ipilimumab  
 
n  =  137   
Ipilimumab  +  gp100  
 
n  =  403   
gp100  
 
n  =  136   
Hazard  Ratio  (vs  gp100)   
(95%  CI)   
0.66   
(0.51,  0.87)   
0.68   
(0.55,  0.85)   
  
p-value   
p  =  0.0026 a   
p  =  0.0004   
  
Hazard  Ratio  (vs  ipilimumab)   
(95%  CI)   
  
1.04   
(0.83,  1.30)   
  
Median  (months)   
(95%  CI)   
10   
(8.0,  13.8)   
10   
(8.5,  11.5)   
6   
(5.5,  8.7)   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
The  two  arms  were  well  balanced  regarding  most  baseline  characteristics,  as  shown  in  Table  8.   
  
  
Table  8: CA184024  Baseline  Characteristics   
  
Patients  on  the  ipilimumab  arm  received  a  median  of  3  ipilimumab  induction  doses,  versus  4  placebo  
 
 
 
 
 
  
 
  
 
 
 
  
 
induction  doses  on  the  placebo  arm.  A  total  of  17.4%  and  21.1%  of  patients  continued  to  receive  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
maintenance  ipilimumab  or  placebo,  for  a  median  of  4  and  2 doses,  respectively.  The  number  of  patients  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
who  received  all  8  dacarbazine  doses  was  12.2%  in  the  ipilimumab  arm,  and  21.5%  in  the  placebo  arm.   
The  study  met  its  primary  end-point  of  prolonging  overall  survival  in  patients  treated  with  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(HR  0.72  (95%  CI,  0.59  –  0.87),  median  OS  11.2  vs  9.1  months,  p = 0.0009).  The  OS  Kaplan-Meier  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
curve  is  presented  in  Figure  4.   
  
36 / 93 
  
  
Ipilimumab  +  DTIC  
 
n  =  250   
Placebo  +  DTIC  
 
n  =  252   
Age  (years)   
  
  
Mean   
57.5   
56.4   
Gender  (%)   
  
  
Male   
60.8   
59.1   
Female   
39.2   
40.9   
M  Stage  (%)   
  
  
M0   
2.4   
3.2   
M1a   
14.8   
17.1   
M1b   
25.6   
24.6   
M1c   
57.2   
55.2   
ECOG  PS  (%)   
  
  
0   
70.8   
71.0   
1   
29.2   
29.0   
LDH  (%)   
  
  
≤  ULN   
  
62.8   
55.6   
>  ULN   
  
37.2   
43.7   
≤  2x  ULN   
86.4   
85.3   
>  2x  ULN   
13.6   
13.9   
Prior  adjuvant  therapy  (%)   
26.4   
26.6   
Prior  therapy  for  advanced  disease  (%)   
0   
0   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
Figure  4: 
CA184024  Kaplan-Meier  Plot  of  Overall  Survival  -  All  Randomized  Subjects   
  
  
One,  two  and  three  year  survival  rates  were  47.3%,  28.5%  and  20.8%  in  the  ipilimumab  arm,  and  36.3%,  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
17.9%  and  12.2%  in  the  placebo  arm.   
PFS,  a  secondary  end-point,  was  also  prolonged  by  the  addition  ipilimumab,  HR  0.76 (95%  CI,  0.63  -  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
0.93).  The  median  PFS  was  2.8  months  in  the  ipilimumab  and  vs  2.6 months  in  the  placebo  arm,  p  =  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
0.006.   
BORR  was  increased  from  10.3%  in  the  placebo  arm  to  15.2%  in  the  ipilimumab  arm  (Table  9).  More  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
importantly,  duration  of  response  was  more  than  twice  as  long  in  the  ipilimumab  arm  (19.3  months)  than  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
in  the  placebo  arm  (8.1  months).   
  
  
Table  9: CA184024  Tumor  Response   
  
37 / 93 
  
  
Ipilimumab  +  DTIC  
 
n  =  250   
Placebo  +  DTIC  
 
n  =  252   
Disease  Control  Rate,  n  (%)   
83  (33.2)   
76  (30.2)   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
  
1.3.5.d
10  mg/kg  Dosing  with  Ipilimumab   
In  melanoma,  Phase  3  studies  show  improved  survival  at  both  3  mg/kg  (study  MDX010-20)  as  well  as  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
with  10  mg/kg  (study  CA184024).  Several  additional  conducted  trials  studied  the  efficacy  and  safety  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10  mg/kg  dosing,  and  additional  information  gained  from  these  trials  is  listed  below:   
●
A  dose  of  10  mg/kg  is  necessary  to  ensure  a  blockade  of  the  CTLA-4  pathway:  in  vitro  a  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
concentration  of  20  μ g/mL  of  ipilimumab  was  the  minimal  concentration  able  to  fully  abrogate  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
binding  of  CTLA-4  to  B7.1  and  B7.2.  With  a  dose  of  3  mg/kg  q3w  30%  achieved  a  trough  
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
concentration  of  ipilimumab  greater  than  20  μ g/mL,  compared  to  95%  of  subjects  treated  at  10  mg/kg  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
q3w.   
●
In  addition,  in  all  ipilimumab  trials  examined  to  date,  mean  Absolute  Lymphocyte  Count  (ALC)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
increased  after  ipilimumab  treatment  throughout  the  12-week  induction-dosing  period,  in  a  
 
 
 
 
 
 
 
 
 
 
 
dose-dependent  manner.  In  an  analysis  of  ipilimumab  at  0.3,  3,  or  10  mg/kg  in  melanoma  studies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CA184007,  CA184008,  and  CA184022  combined,  the  rate  of  change  in  ALC  after  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  was  significantly  associated  with  dose  (p  =  0.0003),  with  the  largest  rate  at  10  mg/kg  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
ipilimumab.  Moreover,  the  rate  of  change  in  ALC  over  the  first  half  of  the  induction-dosing  period  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
was  significantly  associated  with  clinical  activity  in  these  studies  (p  =  0.009),  where  clinical  activity  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
was  defined  as  CR,  PR,  or  prolonged  SD  (ie,  SD  lasting  at  least  6 months  from  first  dose).  Although  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
these  analyses  alone  could  not  determine  whether  the  rate  of  change  in  ALC  was  specifically  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
associated  with  clinical  activity  in  response  to  ipilimumab  treatment,  as  opposed  to  being  generally  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prognostic,  these  results  do  suggest  a  potential  benefit  to  higher  rates  of  ALC  increase  after  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
ipilimumab  treatment.  Among  the  3  doses  evaluated,  10  mg/kg  ipilimumab  led  to  the  greatest  such  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
rates.   
●
In  the  3  primary  studies  conducted  in  advanced  melanoma  (CA184007,  CA184008,  and  CA184022),  
 
  
 
 
 
 
 
 
 
 
 
 
subjects  treated  with  10  mg/kg  during  the  induction  period  had  the  highest  response,  disease  control  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
rates,  median  OS  as  well  as  1-year  and  2-year  survival  rates  compared  to  other  doses.  The  CA184022  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
data  are  summarized  in  Table 10.   
  
Table  10: 
Summary  of  Phase  2  Response  Data  in  Melanoma  (CA184022)   
  
38 / 93 
  
BORR  (CR  +  PR),  n  (%)   
38  (15.2)   
26  (10.3)   
Complete  response   
4  (1.6)   
2  (0.8)   
Partial  response   
34  (13.6)   
24  (9.5)   
Stable  disease   
45  (18.0)   
50  (19.8)   
Progressive  disease   
111  (44.4)   
131  (52.0)   
Duration  of  response,  months   
19.3   
8.1   
  
10  mg/kg 
(n  =  72)   
3  mg/kg  
 
(n  =  72)   
0.3  mg/kg  
 
(n  =  73)   
BORR  (mWHO)  –  %   
(95%  CI)   
11.1   
(4.9  -  20.7)   
4.2   
(0.9  -  11.7)   
0   
(0.0  -  4.9)   
DCR  (mWHO)  –  %   
(95%  CI)   
29.2   
(19.0  -  41.1)   
26.4   
(16.7  -  38.1)   
13.7   
(6.8  -  23.8)   
Survival  rate  at  1  year  -  %   
%,  95%  CI   
48.64   
(36.84,  60.36)   
39.32   
(27.97,  50.87)   
39.58   
(28.20,  51.19)   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
Finally,  the  dose  and  schedule  in  study  CA184156  is  the  one  that  was  evaluated  in  the  signal  finding  study  
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
CA184041,  with  an  acceptable  safety  profile  and  improvement  of  irPFS  and  OS.   
Treatment  with  ipilimumab  has  demonstrated  clinically  important  and  durable  tumor  responses  in  several  
 
 
 
 
 
 
 
 
 
 
  
 
malignancies  including  melanoma,  prostate  cancer,  and  renal  cell  carcinoma.   
  
  
1.3.5.e
Advanced  Melanoma   
Ipilimumab  prolonged  survival  in  subjects  with  pre-treated  advanced  melanoma  are  based  on  results  from  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MDX010-20  (Phase  3)  supported  by  data  from  Phase  2  studies;  the  primary  efficacy  and  safety  studies  are  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
39 / 93 
  
Survival  rate  at  2  year  -  %   
%,  95%  CI   
29.81   
(19.13,  41.14)   
24.20   
(14.42,  34.75)   
18.43   
(9.62,  28.22)   
Overall  median  survival   
95%CI  (months)   
11.43   
(6.90,  16.10)   
8.74   
(6.87,  12.12)   
8.57   
(7.69,  12.71)   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
summarized  in  Table  11. , , , , , , , 
 The  primary  endpoint  in  MDX010-20  was  OS,  which  was  also  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
59 60 61 62 63 64 65 66
key  secondary  endpoint  in  Phase  2  studies.   
  
Table  11: 
Studies  Supporting  the  Efficacy  and  Safety  of  Ipilimumab  in  Subjects  with  Advanced   
Melanoma   
59   Randomized,  double-blind,  placebo-controlled,  Phase  2  study  comparing  the  safety  of  ipilimumab  
 
 
 
  
 
 
 
 
 
 
administered  with  or  without  prophylactic  oral  budesoride  (Entocort  EC)  in  patients  with  unresectable  
 
 
 
 
 
 
 
 
  
 
 
 
stage  III  or  IV  malignant  melanoma  (Protocol  CA184007).  Bristol-Myers  Squibb  Research  and  
 
 
 
 
 
 
 
 
 
 
 
 
Development;  2010.  Document  Control  No.  930043852.   
60   A  multicenter,  single  arm  Phase  2  study  of  MDX-010  (BMS-734016)  monotherapy  in  patients  with  
 
 
 
 
  
 
 
 
 
 
 
 
 
previously  treated  unresectable  stage  III  or  IV  melanoma  (Protocol  CA184008).  Bristol-Myers  
 
 
 
 
 
 
 
 
 
 
 
Squibb  Research  and  Development;  2010.  Document  Control  No.  930043858.   
61   A  randomized,  double-blind,  multicenter,  Phase  2,  fixed  study  of  multiple  dose  of  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
(MDX-010)  monotherapy  in  patients  with  previously  treated  unresectable  stage  III  or  IV  melanoma  
 
 
 
 
 
 
 
 
 
 
 
 
 
(Protocol  CA184022).  Bristol-Myers  Squibb  Research  and  Development;  2010.  Document  Control  
 
 
 
 
 
 
 
 
 
 
No.  9.0043860.   
62   A  randomized,  double-blind  multicenter  study  comparing  MDX010-10  monotherapy,  MDX-010  in  
 
 
 
 
 
 
 
 
 
 
combination  with  a  melanoma  peptide  vaccine  and  melanoma  vaccine  monotherapy  in  
 
 
 
 
 
 
 
 
 
 
 
HLA-A*201-postive  patients  with  previously  treated  unresectable  stage  III  or  IV  melanoma  (Protocol  
 
 
 
 
 
 
 
 
 
 
 
 
MDX0102).  Bristol-Myers  Squibb  Research  and  Development;  2010.  Document  Control  No.  
 
 
 
 
 
 
 
 
 
 
930043837.   
63   An  exploratory  study  to  determine  potential  predicitve  markers  of  response  and/or  toxicity  in  patients  
 
 
 
 
 
 
 
 
 
 
 
  
 
with  unresectable  stage  III  or  IV  malignant  melanoma  randomized  and  treated  with  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
(MDX-010/BMS-734016)  at  two  dose  levels  (Protocol  CA184004).  Bristol-Myers  Squibb  Research  
 
 
 
 
 
 
 
 
 
 
and  Development;  2010.  Document  Control  No.  930043855.   
64  A  randomized  study  comparing  MDX-010  alone  or  in  combination  with  DTIC  in  the  treatment  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  with  chemotherapy  naive  metastatic  melanoma  (Protocol  MDX01008).  Bristol-Myers  Squibb  
 
 
 
 
 
 
 
 
 
 
Research  and  Development;  3008.  Document  Control  No.  930023182.   
65   Interim  report  of  a  multicenter  Phase  2  study  to  evaluate  response  to  ipilimumab  (BMS-734016)  
 
 
  
 
  
 
 
 
 
 
 
 
monotherapy  in  subjects  with  melanoma  brain  metastases  (Protocol  CA184042).  Bristol-Myers  
 
 
 
 
 
 
 
 
 
 
Squibb  Research  and  Development.   
  
66   Collection  of  long-term  outcome  data  for  subjects  who  have  previously  participated  in  selected  
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  (MDX-010)  studies  in  metastatic  melanoma  (Protocol  MDX01028).  Bristol-Myers  
 
 
 
 
 
 
 
 
 
Squibb  Research  and  Development;  2009.  Document  Control  No.  9300038451.   
  
40 / 93 
  
  
  
  
  
#  Randomized  or  Enrolled/Treated   
Study  No.   
(Phase)   
Populations   
Primary   
Efficac 
y   
Endpoi 
nt   
Doses  Studies   
3  mg/kg   
10   
mg 
/kg   
Total   
MDX010-2 
0  (Phase  3)   
HLA-A2*0 
201-pos 
itive,   
previou 
OS   
3  mg/kg  q3  wk  x   
4  ±  gp100   
(induction)   
540/512   
--/--   
676/643 a   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
  
41 / 93 
  
sly   
treated,   
unresec 
table   
Stage   
III  or   
IV   
melano 
ma   
followed  by   
re-induction   
  
CA184022   
(Phase   
2)   
  
Previously   
treated,   
unresec 
table   
Stage   
III  or   
IV   
melano 
ma   
  
BORR   
0.3,  3,  or  10   
mg/kg  q3  wk   
x  4   
(induction)   
followed  by   
maintenance   
dosing  q12   
wk   
72/71   
72/71   
217/214   
CA184004   
(Phase   
2)   
Biomar 
ker   
Study   
Unresectabl 
e  Stage   
III  or   
IV   
melano 
ma   
  
BORR   
3  or  10  mg/kg  q3   
wk  x  4   
(induction)   
followed  by   
maintenance   
dosing  q12   
wk   
40/40   
42/42   
82/82   
CA184008   
(Phase   
2)   
Previously   
treated   
unresec 
table   
State  III   
or  IV   
melano 
ma   
BORR   
10  mg/kg  q3  wk  x   
4  (induction)   
followed  by   
maintenance   
dosing  q12   
wk   
--/--   
155/155   
155/155   
CA184007   
Unresectabl 
e  Stage   
III  or   
IV   
melano 
ma   
BORR   
10  mg/kg  q3  wk  x   
4  ±   
budesonide   
(induction)   
followed  by   
maintenance   
dosing  q12   
wk   
--/--   
115/115   
115/115   
Additional  Studies   
  
MDX010-0 
8(Phase   
2)   
Chemothera 
py-naiv 
e   
advance 
d   
melano 
ma   
ORR   
3  mg/kg  q4   
wk  x  4   
±  DTIC   
(inducti 
on)   
78/74   
--/--   
78/74   
CA184042   
(Phase   
2)   
Stage  IV   
melano 
ma  with   
DCR   
10  mg/kg  q3   
wk  x  4   
(inducti 
--/--   
28/28 b  
28/28 b  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
BORR  =  best  overall  response  rate;  DCR  =  disease  control  rate;  DTIC  =  dacarbazine;  N/A  =  not  applicable;  ORR  =  
  
 
 
 
 
  
 
 
 
  
 
  
 
 
  
overall  response  rate;  OS  =  overall  survival;  PK  =  pharmacokinetics.   
a   Total  includes  136  randomized/131  treated  subjects  in  the  gp100  treatment  group.   
b   Information  is  presented  only  for  subjects  enrolled  in  MDX010-20,  Arm  A.   
c   MDX010-15  was  primarily  a  PK  study  that  evaluated  ipilimumab  at  single  and  multiple  doses.   
  
Source:   References:  59-66   
  
  
1.4
Overall  Risk/Benefit  Assessment  
 
Ipilimumab  has  been  the  first  drug  to  demonstrate  prolonged  survival  in  subjects  with  pre-treated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
advanced  melanoma,  based  on  a  large,  multinational,  double-blind,  pivotal,  Phase 3  study   supported  by  
 
 
 
  
 
 
 
 
 
  
 
 
67
a  comprehensive  Phase  2  program.   
  
The  unique  immune-based  mechanism  of  action  is  reflected  in  the  clinical  patterns  of  anti-cancer  activity  
 
 
 
 
 
  
  
 
 
 
 
 
 
in  some  patients.  Ipilimumab  impacts  tumor  cells  indirectly,  and  measurable  clinical  effects  emerge  after  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  immunological  effects.  Tumor  infiltration  with  lymphocytes  and  the  associated  inflammation  
 
 
 
 
 
 
 
 
 
 
 
(documented  by  biopsy  in  some  subjects)  is  likely  the  cornerstone  of  the  effect  of  ipilimumab  and  can  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
manifest  in  various  patterns  of  clinical  activity  leading  to  tumor  control.  In  some  cases,  inflammation  may  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
not  be  noted  by  radiological  examination  and  objective  response  is  observed  with  the  first  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assessment  in  a  manner  seen  in  patients  receiving  other  types  of  anti-cancer  treatments.  In  other  cases,  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
response  may  be  preceded  by  an  apparent  increase  in  initial  tumor  volume  and/or  the  appearance  of  new  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lesions,  which  may  be  mistaken  for  tumor  progression  on  radiological  evaluations.  Therefore,  in  subjects  
 
 
 
 
 
 
 
 
 
 
 
  
 
who  are  not  experiencing  rapid  clinical  deterioration,  confirmation  of  progression  is  recommended,  at  the  
 
 
 
 
 
 
 
 
 
  
  
 
67  Robert  C,  Thomas  L,  Bondarenko  I,  et  al.  Ipilimumab  plus  dacarbazine  for  previously  untreated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic  melanoma.  N  Engl  J  Med.  2011  Jun  30;364(26):2517-26.   
  
  
42 / 93 
  
brain   
metasta 
ses   
on)   
followe 
d  by   
mainten 
ance   
dosing   
q12  wk   
MDX010-2 
8   
(Phase   
2)   
Surviva 
l   
Follow- 
up   
Study   
Subjects   
enrolled 
in   
earlier   
Medare 
x   
studies,   
includin 
g   
MDX0 
10-08   
and   
MDX0 
10-15 c   
OS   
N/A 
--/N/A   
--/NA   
--/N/A   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
investigator’s  discretion,  to  better  understand  the  prognosis  as  well  as  to  avoid  unnecessarily  initiating  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
potentially  toxic  alternative  therapies  in  subjects  who  might  be  benefitting  from  treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
Immune-related  (ir)  response  criteria  were  developed  based  on  these  observations  to  systematically  
 
 
 
 
 
 
 
 
 
 
 
 
categorize  novel  patterns  of  clinical  activity  and  are  currently  being  prospectively  evaluated  in  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
studies.   
In  metastatic  diseases,  stabilization  is  more  common  than  response,  and  in  some  instances  is  associated  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
with  slow,  steady  decline  in  tumor  burden  over  many  months,  sometimes  improving  to  partial  and/or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
complete  responses.  Thus,  the  immune-based  mechanism  of  action  of  ipilimumab  results  in  durable  
 
 
 
 
 
 
 
 
 
 
 
 
 
disease  control,  sometimes  with  novel  patterns  of  response,  which  contribute  to  its  improvement  in  OS.   
The  immune-based  mechanism  of  action  is  also  reflected  in  the  safety  profile.  The  most  common  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
drug-related  AEs  are  immune-mediated,  consistent  with  the  mechanism  of  action  of  the  drug  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
generally  medically  manageable  with  topical  and/or  systemic  immunosuppressants.  As  previously  
 
 
 
 
 
 
 
 
 
 
discussed,  the  immune-mediated  adverse  reactions  primarily  involve  the  GI  tract,  skin,  liver,  endocrine  
 
 
 
 
 
 
 
 
 
 
 
 
 
glands,  and  nervous  system.   
The  early  diagnosis  of  immune-mediated  adverse  reactions  is  important  to  initiate  therapy  and  minimize  
 
 
 
 
 
 
  
 
 
 
 
 
 
complications.  Immune-mediated  adverse  reactions  are  generally  manageable  using  symptomatic  or  
 
 
 
 
 
 
 
 
 
 
immunosuppressive  therapy  as  recommended  through  detailed  diagnosis  and  management  guidelines,  as  
 
 
 
 
 
 
 
 
 
 
 
described  fully  in  the  current  IB.  The  management  guidelines  for  general  immune-mediated  adverse  
 
 
 
 
 
 
 
 
 
 
 
 
 
reactions  and  ipilimumab-related  GI  toxicities,  hepatotoxicity,  endocrinopathy,  and  neuropathy  are  
 
 
 
 
 
 
 
 
 
 
provided  in  the  appendices  of  the  current  IB.   
  
In  summary,  ipilimumab  offers  clinically  meaningful  and  statistically  significant  survival  benefit  to  
 
 
 
 
 
 
 
 
 
 
 
 
patients  with  pre-treated  advanced  melanoma  and  evidence  of  clinical  activity  in  randomized  studies  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
other  tumor  types.  These  findings,  together  with  evidence  of  a  safety  profile  that  is  manageable  with  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
careful  monitoring  and  appropriate  intervention  for  treatment  of  immune-mediated  toxicities,  suggest  an  
 
 
 
 
 
 
 
 
 
 
 
 
acceptable  benefit  to  risk  ratio.   
This  clinical  study  will  focus  on  patients  with  melanoma  and  brain  metastases  of  intermediate  prognosis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(RPA  class  2).  As  described  earlier,  the  estimated  prognosis  of  these  patients  is  dismal.  All  patients  are  to  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
receive  the  standard  therapy  for  this  condition,  that  is,  WBRT.  Ipilimumab  as  a  single  agent  has  shown  to  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
be  active  in  these  patients.  There  are  biological  grounds  for  potential  synergistic  efficacy.  The  safety  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  proposed  dose  of  Ipilimumab  is  well  known,  and  there  is  no  major  concern  on  its  use  in  this  patient  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
population.  The  safety  of  the  combination  of  ipilimumab  and  WBRT  has  not  been  described.  Given  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
fact  that  a  safety  data  monitoring  group  will  be  defined  for  this  study,  and  that  the  patients  have  a  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
condition  which  clearly  represents  an  unmet  medical  need,  the  overall  risk-benefit  ratio  for  patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
entering  this  protocol  is  therefore  at  least  comparable  to  and  potentially  better  than  alternative  options.   
  
1.5
Study  Rationale   
• 
Melanoma  is  the  third  most  common  cancer  causing  brain  metastases,  after  cancers  of  the  lung  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  breast,  which  appears  to  reflect  the  relative  propensity  of  melanoma  to  metastasize  to  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
central  nervous  system  (CNS).  Brain  metastases  are  responsible  for  20  to  54  percent  of  deaths  in  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
patients  with  melanoma,  and  among  those  with  documented  brain  metastases,  these  lesions  
 
 
 
 
 
 
 
 
 
 
 
 
contribute  to  death  in  up  to  95  percent  of  cases,  with  an  estimated  median  overall  survival  ranging  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
between  1.8  and  10.5  months,  depending  upon  other  prognostic  factors.  2,3,5,6,7,8,9,11   
  
43 / 93 
  

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• 
Ipilimumab  is  an  anti-CTLA4  monoclonal  antibody  that  has  demonstrated  a  clinically  relevant  
 
 
 
 
 
 
 
 
  
 
 
and  statistically  significant  improvement  in  overall  survival,  either  alone  (second  line) 67  or  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
combination  with  DTIC  (1st  line). 
  
68
• 
Ipilimumab  has  shown  activity  against  brain  metastases. 1,16,17   
• 
According  to  the  EMA-approved  label  for  Yervoy ® ,  the  use  of  glucocorticoids  at  baseline  
 
 
 
 
 
 
 
 
 
 
 
 
 
(commonly  prescribed  when  brain  metastases  are  diagnosed)  should  be  avoided  before  the  
 
 
 
 
 
 
 
 
 
 
 
 
administration  of  ipilimumab.  Data  show  that  the  use  of  even  high  doses  of  glucocorticoids  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  management  of  immune-related  adverse  events  do  not  decrease  the  efficacy  of  Yervoy ® .  There  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
is  no  documented  experience  on  the  efficacy  of  Yervoy ®  when  given  concomitantly  with  radiation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy  and  glucocorticoids. 
  
69
• 
In  experimental  models,  radiation  therapy  is  synergistic  to  anti-CTLA-4  strategies  (abscopal  
 
 
 
 
 
 
 
 
 
 
 
effect). 41,42,43   
• 
There  are  no  published  results  from  clinical  trials  on  the  interaction  between  radiation  therapy  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab.   
  
  
2
STUDY  OBJECTIVES   
2.1
Primary  Objective.   
●
Efficacy  -  Primary  endpoint:  1-year  survival  rate   
  
2.2
Secondary  Objectives   
●
Efficacy  –  Endpoints:   
  
o
Progression-Free  survival-PFS  (median,  6-month  PFS  rate)   
▪
Intracranial  PFS  (median,  6-month  PFS  rate)   
▪
Extracranial  PFS  (median,  6-month  PFS  rate)   
o
Overall  survival  (median)   
o
Response  rate:  (global,  intracranial,  extracranial)  (“Immune-related  response  criteria”)   
●
Safety:  Adverse  Event  rates   
●
Feasibility:  dose  delays/reductions,  treatment  exposure   
  
2.3. Exploratory  Objectives.   
o
Potential  baseline  predictors  of  efficacy  (in  tumour  tissue  and  peripheral  blood  –  see  6.4.3.)   
o
Potential  early  surrogates  for  response:  intrapatient  variation  of  quantitative  apparent  diffusion  
 
 
 
 
 
 
 
 
 
 
 
coefficients  of  serial  diffussion-weighted  magnetic  resonance  imaging   
  
68  Hodi  FS,  O'Day  SJ,  McDermott  DF,  et  al.  Improved  survival  with  ipilimumab  in  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic  melanoma.  N  Engl  J  Med.  2010  Aug  19;363(8):711-23.   
  
69    http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/   
002213/WC500109299.pdf   
  
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3
STUDY  DESIGN   
This  is  a  non-controlled,  single  stage,  multicenter  phase  2  clinical  study.  A  total  of  56  evaluable  patients  
   
 
 
 
 
  
 
  
 
 
 
 
 
will  be  treated  in  this  study.   
●
Main  elegibility  criteria  are:  patients  with  melanoma  and  brain  metastases,  adequately  fit  (ECOG  PS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0  to  1;  Barthel  Index  >  10/20)  and  of  intermediate  prognosis  according  to  the  RPA  classification  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
(Table  1).These  patients  must  not  have  cerebral  metastases  for  which  local  therapy  (neurosurgery, 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiosurgery)  might  achieve  a  disease-free  status;  they  must  not  be  experiencing  a  rapid  clinical  
 
 
  
 
 
 
 
 
 
  
 
 
deterioration,  risk  of  herniation;  patients  must  not  require  unstable  ascending  dosing  of  supportive  
 
 
 
 
 
 
 
 
 
 
 
 
 
medication  in  the  last  week  -including  anti-convulsivants,  steroids  and  analgesics-,  or  dexamethasone  
 
 
 
 
 
 
 
 
 
 
 
 
>  16  mg/day  (or  other  glucocorticoid  at  an  equivalent  dose);  patients  must  not  have  a  high  LDH  (>  2  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
x  ULN),  they  must  not  have  an  uncontrolled  diabetes  mellitus(HbA1c  >  9%)  and  must  be  suitable  for  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
receiving  an  anti  CTLA4  (i.e.  not  having  any  autoimmune-mediated  co-morbidities).  Patients  must  
 
 
 
 
 
 
 
 
 
 
 
 
have  not  received  prior  therapy  for  brain  metastases.  Screening  stage:Once  the  ICF  is  signed  by  the  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
patient  and  investigator,  patients  will  be  sequentially  registered  at  the  Spanish  Melanoma  Group  
 
 
 
 
 
 
 
 
 
 
 
 
 
Datacenter  or  delegated  CRO,  by  submitting  a  “registration  form”.  A  Patient  Identification  Number  
 
 
 
 
 
  
 
  
 
 
 
will  be  provided  by  the  Sponsor.  A  second  form,  the  “eligibility  checklist”,  will  be  sent  by  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigational  site  once  the  screening  phase  has  been  completed,  either  if  the  patient  becomes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
elegible  or  if  he/she  results  in  a  screening  failure.  No  protocol  exceptions  will  be  permitted  by  the  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
sponsor.   
Patient  inclusion:   
After  confirming  that  a  patient  is  a  candidate  for  inclusion  in  this  study  (inclusion  /  exclusion),  the  subject  
 
 
  
   
 
 
  
 
 
  
 
 
 
will  be  assigned  a  code  of  patient  centralized  (registration  or  inclusion  of  patients).   
  
The  process  of  enrolling  patients  described  below:   
  
1.  Complete  and  sign  the  inclusion  of  the  patient  (the  registration  form  must  be  signed  by  a  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Principal  Investigator  or  designated  appropriately  identified  in  the  list  of  signatures  and  recording  
 
 
 
 
 
 
 
 
 
 
 
 
 
studio  delegation  of  responsibilities).   
  
  
2.  Send  the  completed  and  signed  form  to:  
  
  
MARKETING  RESEARCH  &  CLINICAL  PHARMACIST,  SL   
  
FAX  (+  34  93  253  11  68)  or  e-mail  to  investigacion@mfar.net   
  
  
3.  MFAR,  SL  will  register  the  patient  and   
  
4.  will  send  the  inclusion  confirmation  form  to  the  site,  both  by  fax  and  email.  Confirmation  of  patient  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
inclusion  will  contain  the  patient  number,  which  identifies  subjects  in  the  trial.   
  
5.  Once  the  site  has  received  the  confirmation  of  inclusion  for  the  patient,  the  patient  can  begin  receiving  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
protocol  treatment.   
●
The  trial  schema  is  represented  in  the  following  figure:   
  
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All  individual  patient  registered  into  the  trial  should  undergo  the  screening  phase  of  the  study.  Patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consenting,  registered  and  eligible  will  subsequently  proceed  through  the  treatment  and  follow  up  phases  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of  the  trial.   
  
●
Screening  Phase   
−
It  initiates  after  the  written  informed  consent  is  obtained  and  the  patients  is  registered.  In  this  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
phase  the  assessment  of  the  subject’s  eligibility  to  participate  will  be  done,  as  determined  by  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
inclusion/exclusion  criteria.   
●
Treatment  Phase   
−
Treatment  will  consist  in  the  administration  of  ipilimumab  and  WBRT.  The  dose  of  ipilimumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will  be  3 mg/kg,  administered  intravenously  over  a  90-minute  period  every  3 weeks,  for  a  total  of  
 
 
 
 
 
  
 
 
 
 
  
 
 
four  doses.  Standard  WBRT  should  be  initiated  between  the  first  and  second  dose  of  ipilimumab.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The  dose  of  radiation  therapy  will  be  30  Gy  over  10  fractions.  Radiobiologically  equivalent  doses  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
might  be  acceptable,  but  require  discussion  and  approval  of  the  Sponsor.   
−
Laboratory  evaluations  should  be  performed  and  the  results  examined  before  administration  of  
 
 
 
 
 
 
 
 
 
 
 
 
each  ipilimumab  dose,  with  the  exception  of  hormone  results.  For  these  latter  parameters  it  is  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
required  that  at  least  the  results  of  the  tests  performed  within  the  last  3  weeks  are  available  and  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
normal.   
−
As  durable  disease  stabilization  and/or  objective  tumor  response  can  be  seen  after  early  
 
 
 
 
 
 
 
 
 
 
 
 
 
progression  before  Week 12,  it  is  recommended  that,  in  the  absence  of  dose-limiting  toxicities  
 
 
  
 
 
 
 
 
 
 
 
 
  
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(eg,  serious  immune-mediated  adverse  reactions),  all  four  doses  of  ipilimumab  be  administered  
 
 
 
 
 
 
 
 
 
 
 
 
over  the  initial  12 weeks  even  in  the  setting  of  apparent  clinical  progression,  providing  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subject’s  performance  status  remains  stable.   
−
All  subjects  who  enter  the  treatment  period,  including  those  who  may  have  discontinued  
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  for  drug-related  AEs  and/or  who  have  evidence  of  clinical  progression  during  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
induction  period,  should  obtain  a  12-week  tumor  assessment.   
−
Based  on  clinical  experience  in  the  ongoing  and  completed  melanoma  studies,  the  following  
 
 
 
 
 
 
 
 
 
 
 
 
 
recommendations  apply  for  subject  management  in  light  of  the  Week 12  or  later  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
assessments:   
●
The  appearance  of  new  lesions  in  subjects  with  other  stable  or  shrinking  baseline  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
burden  may  be  experiencing  clinical  benefit  and  should  continue  in  follow-up  and/or  
 
 
 
 
 
 
 
 
 
 
 
 
maintenance  therapy  before  alternative  anti-cancer  agents  are  considered.  These  subjects  can  
 
 
 
 
 
 
 
 
 
 
 
be  seen  to  have  continued  tumor  shrinkage  in  follow-up  scans.   
●
As  long  as  overall  tumor  burden  is  stable  or  decreasing,  subjects  should  remain  in  follow-up,  
 
 
 
 
 
  
 
 
 
 
 
  
 
even  in  the  presence  of  new  lesions.   
●
Clinical  progression  warranting  alternative  anti-cancer  treatment  should  be  considered  only  in  
 
 
 
 
 
 
 
 
 
  
subjects  whose  overall  tumor  burden  appears  to  be  substantially  increased  and/or  in  subjects  
 
 
 
 
 
 
 
 
 
 
 
 
 
whose  performance  status  is  decreased.   
  
●
Follow-up  (duration  of  study).   
−
Subjects  who  are  no  longer  receiving  ipilimumab  because  of  unacceptable  toxicity  (refractory  
 
 
 
 
 
 
 
 
 
 
 
 
Grade > 3  immune-mediated  adverse  reactions)  or  due  to  investigator  judgment  are  managed  in  
 
 
 
 
 
 
 
 
 
 
 
 
follow-up.  Efficacy  assessments  for  these  subjects  during  follow-up  are  as  per  the  standard  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
care.  Date  of  death  is  recorded.   
−
Subjects  who  discontinue  ipilimumab  treatments  should  be  followed  until  death  or  the  closure  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  study  (whichever  is  first).   
−
Subjects  who  are  no  longer  receiving  ipilimumab  because  of  clinical  progression  and  who  have  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
switched  to  alternative  treatment  are  not  followed  formally  except  to  record  the  date  of  death.   
  
Study  duration:   
●
For  each  individual  patient,  the  maximal  duration  of  the  treatment  period  is  4  cycles  of  ipilimumab.  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
Patients  will  be  followed  up  until  death  or  trial  termination  (whatever  comes  first),  for  a  maximum  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
36  months.  The  study  will  be  terminated  18  months  after  the  last  patient  received  the  first  dose  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab.   
  
  
4
S UBJECT  SELECTION  CRITERIA   
For  entry  into  the  study,  the  following  criteria  MUST  be  met.  No  exceptions  from  the  protocol-specific  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
selection  criteria  will  be  approved.   
  
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4.1
Inclusion  Criteria   
1)
Willing  and  able  to  give  written  informed  consent.   
2)
Histologic  diagnosis  of  melanoma.   
3)
First  episode  of  radiological  evidence  of  brain  metastases   
4)
Age>18  years.   
5)
RTOG-RPA  class  2  (Table  1)   
6)
Karnofsky  performance  status  (PS)  >  70%.(Appendix  1)   
7)
Barthel  Index  of  Activities  of  Daily  Living  >  10  (Appendix  2)   
8)
Measurable  disease  (mWHO  criteria).   
9)
Adequate  organ  function  as  determine  by  the  following  criteria:   
a.
WBC  ≥  2000/uL   
b.
Absolute  neutrophil  count  (ANC)  >1.5  x  10 9 /L.   
c.
Platelet  count  >75  x  10 9 /L.   
d.
Hemoglobin  >9  g/dL.  If  the  patient  received  a  RBC  transfusion,  the  required  value  of  
 
 
 
 
 
 
  
 
 
 
 
 
 
hemoglobin  should  be  met  at  least  1  week  after  the  most  recent  transfusion.   
  
e.
Serum  creatinine  ≤  2.0  x  ULN.   
f.
Serum  aspartate  aminotransferase  (AST)  and  serum  alanine  aminotransferase  (ALT)  ≤  2.5  x  
 
 
 
 
 
 
 
 
  
  
ULN  for  patients  without  liver  metastasis,  or  ≤  5  times  for  liver  metastases.   
g.
Total  bilirubin  ≤  2.0  x  ULN,  (except  patients  with  Gilbert’s  Syndrome,  who  must  have  a  
 
  
  
 
 
 
 
 
 
 
 
  
total  bilirubin  less  than  3.0  mg/dL)   
h.
Albumin  >  2.5  g/dL   
  
10) Persons  of  reproductive  potential  must  agree  to  use  an  adequate  method  of  contraception  throughout  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  and  for  at  least  26  weeks  after  ipilimumab  is  stopped:   
  
a.
WOCBP  include  any  female  who  has  experienced  menarche  and  who  has  not  undergone  
 
 
 
 
 
 
 
 
 
 
 
 
 
successful  surgical  sterilization  (hysterectomy,  bilateral  tubal  ligation,  or  bilateral  
 
 
 
 
 
 
 
 
 
oophorectomy)  or  is  not  post-menopausal.  WOCBP  must  have  a  negative  serum  or  urine  
 
 
 
 
 
 
 
  
 
 
 
 
pregnancy  test  (minimum  sensitivity  25 IU/L  or  equivalent  units  of  HCG)  within  72 hours  
 
 
 
 
 
 
 
 
 
 
 
 
before  the  start  of  ipilimumab.  If  the  pregnancy  test  is  positive,  the  patient  must  not  receive  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
ipilimumab  and  must  not  be  enrolled  in  the  study.  Before  study  enrollment,  women  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
childbearing  potential  (WOCBP)  must  be  advised  of  the  importance  of  avoiding  pregnancy  
 
 
 
 
 
 
 
 
 
 
 
 
during  study  participation  and  the  potential  risk  factors  for  an  unintentional  pregnancy.  
 
 
 
 
 
 
 
 
 
 
 
 
WOCBP  must  be  using  an  adequate  method  of  contraception  to  avoid  pregnancy  throughout  
 
 
 
 
 
 
 
 
  
 
 
 
the  study  and  for  up  to  26 weeks  after  the  last  dose  of  investigational  product,  in  such  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
manner  that  the  risk  of  pregnancy  is  minimized.  In  general,  the  decision  for  appropriate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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methods  to  prevent  pregnancy  should  be  determined  by  discussions  between  the  investigator  
 
 
 
 
 
 
 
 
 
 
 
 
and  the  study  subject.   
●
Post-menopause  is  defined  as:   
  
i.
Amenorrhea  ≥ 12  consecutive  months  without  another  cause,  or   
  
ii.
For  women  with  irregular  menstrual  periods  and  taking  hormone  replacement  
 
 
 
 
 
 
 
 
 
 
therapy  (HRT),  a  documented  serum  follicle  stimulating  hormone  (FSH)  level  ≥  
 
  
 
 
 
 
 
 
  
35  mIU/mL.   
●
Women  who  are  using  oral  contraceptives,  other  hormonal  contraceptives  (vaginal  
 
 
 
 
 
 
 
 
 
 
products,  skin  patches,  or  implanted  or  injectable  products),  or  mechanical  products  such  
 
 
 
 
 
 
 
 
 
 
 
 
as  an  intrauterine  device  or  barrier  methods  (diaphragm,  condoms,  spermicides)  to  
 
 
 
 
 
 
 
 
 
 
 
prevent  pregnancy,  or  are  practicing  abstinence  or  where  their  partner  is  sterile  (eg,  
 
 
 
 
 
 
 
 
 
 
 
 
 
vasectomy)  should  be  considered  to  be  of  childbearing  potential.   
b.
Men  of  fathering  potential  must  be  using  an  adequate  method  of  contraception  to  avoid  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
conception  throughout  the  study,  and  for  up  to  26  weeks  after  the  last  dose  of  investigational  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
product  in  such  a  manner  that  the  risk  of  pregnancy  is  minimized.   
4.2
Exclusion  Criteria   
1)  Patients  with  melanoma  and  brain  metastases  with  any  of  the  following  disease-specific  characteristics:   
a. 
Documented  evidence  of  prior  progression  of  melanoma  to  an  ipilimumab-containing  
 
 
 
 
 
 
 
 
 
 
regimen  (i.e.  received  at  least  2  doses  of  ipilimumab  for  either  advanced  disease  or  in  the  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
adjuvant  setting  and  the  disease  progressed/relapsed  -according  to  mWHO  criteria-  within  
 
 
 
 
 
 
 
 
 
 
 
24  weeks  since  the  first  dose  of  ipilimumab)   
b. 
Prior  radiation  therapy  to  the  brain   
c. 
Other  prior  antineoplastic  therapies  for  brain  metastases.   
d. 
Patients  with  cerebral  metastases  as  the  only  location  of  the  disease,  for  which  local  therapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(neurosurgery,  radiosurgery)  could  achieve  a  disease-free  status   
e. 
Patients  with  a  rapid  clinical  deterioration,  or  with  risk  of  herniation,  or  who  require  
 
  
 
 
 
 
 
 
 
 
 
 
 
unstable  ascending  dosing  of  supportive  medication  in  the  last  week  -including  
 
 
 
 
 
 
 
 
 
 
 
anti-convulsivants,  steroids  and  analgesics-,  or  who  require  dexamethasone  >  16  mg/d  (or  
 
 
 
 
 
 
 
  
 
 
 
other  glucocorticoid  at  an  equipotent  dose),  or  with  a  high  LDH  (>  2  x  ULN).   
  
2) Any  other  malignancy  form  which  the  patient  has  been  disease-free  for  less  than  5  years,  with  the  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
exception  of  adequately  treated  and  cured  basal  or  squamous  cell  skin  cancer,  superficial  bladder  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cancer  or  carcinoma  in  situ  of  the  cervix,  or  incidental  prostate  cancer.   
3) Uncontrolled  diabetes  mellitus  (HbA1c  >  9%)   
  
4) Autoimmune  disease  other  than  vitiligo  or  past  thyroiditis  under  substitutive  hormone  therapy:  
 
 
 
 
 
 
 
 
 
 
 
 
Patients  with  a  history  of  inflammatory  bowel  disease,  including  ulcerative  colitis  and  Crohn’s  
 
  
 
 
 
 
 
 
 
 
 
 
Disease,  are  excluded  from  this  study,  as  are  patients  with  a  history  of  symptomatic  disease  (eg,  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
rheumatoid  arthritis,  systemic  progressive  sclerosis  [scleroderma],  systemic  lupus  erythematosus,  
 
 
 
 
 
 
 
 
 
autoimmune  vasculitis  [eg,  Wegener’s  Granulomatosis]);  motor  neuropathy  considered  of  
 
 
 
 
 
 
 
 
 
autoimmune  origin  (e.g.  Guillain-Barre  Syndrome  and  Myasthenia  Gravis).   
  
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5) Other  chronic  intestinal  diseases  associated  with  diarrhea.   
6) Active  infection  or  other  serious  illness  or  medical  condition.   
7) Known  active  or  chronic  infection  with  HIV,  Hepatitis  B,  or  Hepatitis  C.   
8) Therapy  with  any  of  the  following:  IL-2,  interferon,  or  other  non-study  immunotherapy  regimens;  
 
 
 
 
 
 
 
 
 
 
 
 
 
cytotoxic  chemotherapy;  immunosuppressive  agents;  target  molecular  inhibitors  (BRAF,  MEK,  KIT);  
 
 
 
 
 
 
 
 
 
 
or  chronic  use  of  systemic  corticosteroids  (used  for  the  management  of  non-cancer  related  illnesses),  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
either  concomitantly  or  during  the  last  3  weeks  prior  to  the  beginning  of  the  treatment.   
9) Any  experimental  therapy  administered  in  the  past  30  days  prior  to  the  beginning  of  the  treatment.   
10) Any  non-oncology  vaccine  therapy  used  for  the  prevention  of  infectious  diseases  (for  up  to  4  weeks  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
prior  to  or  after  any  dose  of  blinded  study  drug)   
  
11) Women  of  childbearing  potential  (WOCBP),  as  defined  above  in  “Inclusion  criteria”,  who:   
a.
are  unwilling  or  unable  to  use  an  acceptable  method  of  contraception  to  avoid  pregnancy  for  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
their  entire  study  period  and  for  at  least  26  weeks  after  cessation  of  study  drug,  or   
b.
have  a  positive  pregnancy  test  at  baseline,  or   
c.
are  pregnant  or  breastfeeding.   
12) Prisoners  or  subjects  who  are  compulsorily  detained  (involuntarily  incarcerated)  for  treatment  of  
 
 
 
 
 
 
 
 
 
 
 
 
either  a  psychiatric  or  physical  (eg,  infectious)  illness.   
  
13) Any  other  general,  medical  or  psychological  conditions  which  in  the  opinion  of  the  investigator  will  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
make  the  administration  of  ipilimumab  hazardous,  or  that  would  preclude  appropriate  informed  
 
 
 
 
 
 
 
 
 
 
 
 
consent  or  compliance  with  the  protocol,  or  obscure  the  interpretation  of  eventual  AEs.   
  
4.3
Data  Safety  Monitoring  Plan   
A  Data  Safety  Monitoring  Committee  (DSMC)  will  be  designated  prior  to  the  initiation  of  the  study,  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
chaired  by  the  coordinating  principal  investigator.  The  DSMC  will  meet  approximately  every  4  months  to  
 
 
 
 
 
 
 
 
 
 
 
  
  
ensure  that  subject  safety  is  carefully  monitored.  The  DSMC  might  also  be  consulted  on  an  ad-hoc  basis  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
should  a  safety  signal  emerge,  and  may  also  convene  an  ad-hoc  meeting  on  its  own  initiative.  Following  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  review,  the  DSMC  will  recommend  continuation,  modification,  or  discontinuation  of  the  study  based  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
on  observed  toxicities.   
  
The  DSMC  will  have  access  to  reports  of  study  data  including  analyses  addressing  population  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
characteristics,  dosing,  safety,  and  efficacy  updated  as  available  prior  to  each  of  its  meetings.   
  
  
5. 
STUDY  THERAPY   
5.1. 
Ipilimumab  
 
5.1.1. Dose  Calculations  
 
Each  patient  will  receive  ipilimumab  3  mg/Kg  every  3  weeks,  for  a  total  of  4  administration.  Infusions  
 
 
 
 
  
 
  
 
  
 
  
 
 
should  be  given  over  90  minutes  (not  bolus  or  IV  push).   
  
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Calculate  Total  Dose  as  follows:   
             Patient  body  weight  in  kg  x  (x)  mg  =  total  dose  in  mg   
Calculate  Total  Infusion  Volume  as  follows:   
             Total  dose  in  mg  ÷  5  mg/mL  =  infusion  volume  in  mL   
Calculate  Rate  of  Infusion  as  follows:   
             Infusion  volume  in  mL  ÷  90  minutes  =  rate  of  infusion  in  mL/min.   
For  example,  a  patient  weighing  75  kg  would  be  administered  225  mg  of  ipilimumab  (75  kg  x  3  mg/kg  =  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
  
225  mg)  with  an  infusion  volume  of  45  mL  (225  mg  ÷  5  mg/mL  =  45  mL)  at  a  rate  of  approximately  0.5  
 
 
 
 
 
 
 
 
 
 
   
  
 
   
 
 
 
 
mL/min  (45  mL  ÷  90  minutes)  in  90  minutes.   
The  total  dose  must  be  calculated  using  the  most  recent  subject  weight  (obtained  within  3  days  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
dosing  visit,  and  prior  to  the  infusion).   
  
The  maximum  dose  of  ipilimumab  per  cycle  is  400  mg.  Therefore,  patients  ≥  133  kg  should  not  receive  a  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
dose  >  400  mg  per  cycle.   
  
5.1.2. 
Storage,  Preparation,  and  Administration   
Ipilimumab  injection  must  not  be  administered  as  an  IV  push  or  bolus  injection.  Care  must  be  taken  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assure  sterility  of  the  prepared  solutions,  since  the  drug  product  does  not  contain  any  antimicrobial  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
preservatives  or  bacteriostatic  agents.   
●
Do  not  shake  product.   
●
Inspect  parenteral  drug  products  visually  for  particulate  matter  and  discoloration  prior  to  
 
 
 
 
 
 
 
 
 
 
 
 
administration.  Discard  vial  if  solution  is  cloudy,  there  is  pronounced  discoloration  (solution  may  
 
 
 
 
 
 
 
 
 
 
 
 
 
have  pale  yellow  color),  or  there  is  foreign  particulate  matter  other  than  translucent-to-white,  
 
 
 
 
 
 
 
 
 
 
 
 
 
amorphous  particles.   
  
Preparation  of  Solution   
●
Allow  the  vials  to  stand  at  room  temperature  for  approximately  5  minutes  prior  to  preparation  of  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
infusion.   
●
Withdraw  the  required  volume  of  ipilimumab  and  transfer  into  an  intravenous  bag.   
●
Dilute  with  0.9%  Sodium  Chloride  Injection,  USP  or  5%  Dextrose  Injection,  USP  to  prepare  a  diluted  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
solution  with  a  final  concentration  ranging  from  1  mg/mL  to  2  mg/mL.  Mix  diluted  solution  by  gentle  
 
  
 
 
 
  
   
 
 
 
 
 
 
inversion.   
●
Store  the  diluted  solution  for  no  more  than  24  hours  under  refrigeration  (2°C  to  8°C,  36°F  to  46°F)  or  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
at  room  temperature  (20°C  to  25°C,  68°F  to  77°F).   
●
Discard  partially  used  vials  or  empty  vials  of  ipilimumab.   
  
Administration  Instructions   
●
Do  not  mix  ipilimumab  with,  or  administer  as  an  infusion  with,  other  medicinal  products.   
  
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●
Flush  the  intravenous  line  with  0.9%  Sodium  Chloride  Injection,  USP  or  0.5%  Dextrose  Injection,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USP  after  each  dose.   
●
Administer  diluted  solution  over  90  minutes  through  an  intravenous  line  containing  a  sterile,  
 
 
 
 
 
 
 
 
 
 
  
 
non-pyrogenic,  low-protein-binding  in-line  filter.   
See  the  current  Summary  of  product  characteristics  (SMPC)Brochure  for  additional  information  on  
 
 
 
 
 
 
 
 
 
 
 
 
allowable  filter  types.  The  infusion  must  be  completed  in  90  minutes  with  an  10  ml  normal  saline  flush  at  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
the  end.   
Ipilimumab  should  be  administered  under  the  supervision  of  a  physician  experienced  in  the  use  of  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
intravenous  (IV)  agents.  Ipilimumab  is  administered  as  an  IV  infusion  only.   
  
5.1.3. Dose  Modification   
Ipilimumab  Dose  Skipping  Rule   
Decisions  to  skip  an  ipilimumab  dose  must  be  made  on  specified  safety  criteria.  Treatment  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  will  be  skipped  or  discontinued  if  the  subject  experiences  at  least  one  adverse  event,  specified  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
below,  considered  by  the  investigator  to  be  “possibly,”  probably,”  or  “certainly”  related  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  treatment.  The  investigator  should  contact  the  Sponsor  for  any  adverse  event  that  will  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prompt  a  skipped  dose  or  discontinuation  of  ipilimumab.   
The  following  criteria  will  be  used  to  determine  dose  skipping,  restarting  doses,  or  discontinuing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab.   
It  may  be  necessary  to  skip  study  drug  dosing  for  the  following  related  adverse  event(s):   
●
Any  ≥  Grade  2  non-skin  related  adverse  event  (including  immune-mediated  adverse  reactions),  
  
  
 
 
 
 
 
 
 
 
except  for  laboratory  abnormalities   
●
Any  ≥  Grade  3  laboratory  abnormality   
●
Any  adverse  event,  laboratory  abnormality  or  intercurrent  illness  that,  in  the  judgment  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator,  presents  a  substantial  clinical  risk  to  the  subject  with  continued  dosing.   
  
It  is  necessary  to  skip  study  drug  dosing  for  the  following  adverse  events:   
●
Any  ≥  Grade  3  skin  related  adverse  event  regardless  of  causality.   
  
Restart  ipilimumab  dosing  if/when  the  adverse  event(s)  resolve(s)  to  ≤ Grade 1 severity  or  returns  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
baseline  within  2  weeks  of  initial  dose  administration:   
●
If  the  adverse  event  has  resolved,  restart  ipilimumab  dosing  at  the  next  scheduled  timepoint  per  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
protocol.   
  
●
If  the  adverse  event  has  not  resolved  in  the  protocol-specified  dosing  window  (3  weeks  [ ± 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
days]),  the  next  scheduled  dose  will  be  skipped  and  dosing  will  be  resumed  at  the  subsequently  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
scheduled  dose.   
●
If  >  1  dose  is  expected  to  be  skipped,  the  dosing  schedule  modifications  must  be  discussed  with  
   
  
 
 
 
 
 
 
 
 
 
 
 
 
the  principal  investigator  prior  to  implementation.   
  
  
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5.1.4. Discontinuation  of  Study  Therapy  
 
Subjects  MUST  be  discontinued  from  study  therapy  AND  withdrawn  from  the  study  for  the  following  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
reasons:   
●
Withdrawal  of  informed  consent  (subject’s  decision  to  withdraw  for  any  reason)   
●
Any  clinical  adverse  event,  laboratory  abnormality  or  intercurrent  illness  which,  in  the  opinion  of  the  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
investigator,  indicates  that  continued  treatment  with  study  therapy  is  not  in  the  best  interest  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subject   
●
Pregnancy   
−
All  WOCBP  should  be  instructed  to  contact  the  investigator  immediately  if  they  suspect  they  
 
 
 
 
 
 
 
 
 
  
 
 
 
might  be  pregnant  (e.g.,  missed  or  late  menstrual  period)  at  any  time  during  study  participation.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Institutional  policy  and  local  regulations  should  determine  the  frequency  of  on  study  pregnancy  
 
 
 
 
 
 
 
 
 
 
 
 
 
tests  for  WOCBP  enrolled  in  the  study.   
−
The  investigator  must  immediately  notify  the  Sponsor  in  the  event  of  a  confirmed  pregnancy  in  a  
 
 
 
 
 
 
 
 
 
 
  
 
   
patient  participating  in  the  study.   
●
Termination  of  the  study  by  the  Sponsor.   
●
Imprisonment  or  the  compulsory  detention  for  treatment  of  either  a  psychiatric  or  physical  (e.g.,  
 
 
 
 
 
 
 
 
  
 
 
 
 
infectious  disease)  illness.   
  
5.1.5. Permanent  Discontinuation  of  Ipilimumab   
5.1.5.a Permanent  Discontinuation  for  Related  Adverse  Events   
  
Permanently  discontinue  ipilimumab  for  any  of  the  following:   
●
Persistent  moderate  adverse  reactions  or  inability  to  reduce  corticosteroid  dose  to  7.5  mg  prednisone  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
or  equivalent  per  day  (due  to  an  AE).   
●
Failure  to  complete  full  treatment  course  within  18  weeks  from  administration  of  first  dose.   
●
Severe  or  life-threatening  adverse  reactions,  including  any  of  the  following:   
−
Colitis  with  abdominal  pain,  fever,  ileus,  or  peritoneal  signs;  increase  in  stool  frequency  (7  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
more  over  baseline),  stool  incontinence,  need  for  intravenous  hydration  for  more  than  24  hours,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gastrointestinal  hemorrhage,  and  gastrointestinal  perforation   
−
Aspartate  aminotransferase  (AST)  or  alanine  aminotransferase  (ALT)  >5  times  the  upper  limit  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
normal  or  total  bilirubin  >3  times  the  upper  limit  of  normal   
−
Stevens-Johnson  syndrome,  toxic  epidermal  necrolysis,  or  rash  complicated  by  full  thickness  
 
 
 
 
 
 
 
 
 
 
 
dermal  ulceration,  or  necrotic,  bullous,  or  hemorrhagic  manifestations   
−
Severe  motor  or  sensory  neuropathy,  Guillain-Barré  syndrome,  or  myasthenia  gravis   
−
Severe  immune-mediated  reactions  involving  any  organ  system  (eg,  nephritis,  pneumonitis,  
 
 
 
 
 
 
 
 
 
 
pancreatitis,  non-infectious  myocarditis)   
−
Immune-mediated  ocular  disease  that  is  unresponsive  to  topical  immunosuppressive  therapy   
  
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−
Any  adverse  event,  laboratory  abnormality  or  intercurrent  illness  which,  in  the  judgment  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator,  presents  a  substantial  clinical  risk  to  the  patient  with  continued  dosing.   
  
−
The  development  of  progression  (irPD)  in  the  global  tumor  burden  confirmed  by  serial  imaging  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4-6  weeks  later  and/or  clinical  deterioration  of  subject’s  condition  such  that  further  benefit  from  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  dosing  is  unlikely  or  requires  a  change  of  therapy.   
Please  refer  to  the  IB  for  specific  treatment  algorithms.   
The  following  neurological  adverse  event  requires  permanent  discontinuation  of  ipilimumab  and  defines  
 
 
 
 
 
 
 
 
 
 
 
 
unacceptable  neurotoxicity:   
−
Any  motor  neurologic  toxicity  >/=  Grade  3  regardless  of  causality   
−
Any  >/=  Grade  3  treatment  related  sensory  neurologic  toxicity   
  
Please  refer  to  the  IB  for  specific  treatment  algorithms.   
  
5.1.5.b Exceptions  to  Permanent  Discontinuation  
 
●
Potentially  reversible  inflammation  (< Grade 4),  attributable  to  a  local  anti-tumor  reaction  and  a  
 
 
 
 
 
  
 
 
 
  
potential  therapeutic  response.  This  includes  inflammatory  reactions  at  sites  of  tumor  resections  or  in  
 
 
 
 
 
 
  
 
 
 
 
  
draining  lymph  nodes,  or  at  sites  suspicious  for,  but  not  diagnostic  of  metastasis.   
●
Hospitalization  for  ≤ Grade  2  adverse  events  where  the  primary  reason  for  hospitalization  is  to  
 
 
  
 
 
 
 
 
 
 
 
 
 
expedite  the  clinical  work-up.   
●
Patients  with  the  following  conditions  where  in  the  investigator’s  opinion  continuing  study  drug  
 
 
 
 
 
 
 
 
 
 
 
 
 
administration  is  justified:   
−
Ocular  toxicity  that  has  responded  to  topical  therapy.   
−
Endocrinopathies  where  clinical  symptoms  are  controlled  with  appropriate  hormone  replacement  
 
 
 
 
 
 
 
 
 
 
therapy.  Note:  Ipilimumab  may  not  be  restarted  while  the  patient  is  being  treated  for  this  toxicity  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
with  systemic  corticosteroids,  except  for  patients  on  stable  doses  of  hormone  replacement  therapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
such  as  hydrocortisone.   
  
5.1.6. 
Immune-Related  Adverse  Events  (irAEs)Reactions  and   
Immune-mediated  Adverse  Reactions:  Definition,  Monitoring,  and  Treatment   
Blocking  CTLA-4  function  may  permit  the  emergence  of  auto-reactive  T cells  and  resultant  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
autoimmunity.  Rash/vitiligo,  diarrhea/colitis,  uveitis/episcleritis,  hepatitis,  and  hypopituitarism  were  
 
 
 
 
 
 
 
 
drug-related,  presumptive  autoimmune  events,  now  termed  immune-mediated  adverse  reactions,  noted  in  
 
 
 
 
 
 
 
 
 
  
previous  ipilimumab  studies.   
For  the  purposes  of  this  study,  an  immune-related  adverse  reaction  is  defined  as  an  adverse  reaction  of  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
unknown  etiology  associated  with  drug  exposure  and  consistent  with  an  immune  phenomenon.  Efforts  
 
 
 
 
 
 
 
 
 
 
 
 
 
should  be  made  to  rule  out  neoplastic,  infectious,  metabolic,  toxin  or  other  etiologic  causes  prior  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
labeling  an  event  an  immune-related  adverse  reactions.  Serologic,  immunologic,  and  histologic  (biopsy)  
 
 
 
 
 
 
 
 
 
 
 
 
data  should  be  used  to  support  the  diagnosis  of  an  immune-related  toxicity.  Suspected  immune-related  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
adverse  reactions  must  be  documented  on  an  AE  or  SAE  form.  Another  term  for  an  irAE  is  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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immune-mediate  adverse  reaction,  as  it  is  termed  in  both  FDA  and  EMA  approved  Prescribing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information.  Both  terms  may  be  used  in  this  protocol  document.   
  
Patients  should  be  informed  of  and  carefully  monitored  for  evidence  of  clinically  significant  systemic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
immune-mediated  adverse  reactions  (e.g.,  systemic  lupus  erythematosus-like  diseases)  or  organ-specific  
 
 
 
 
 
 
 
 
 
 
immune-mediated  adverse  reaction  (e.g.,  rash,  colitis,  uveitis,  hepatitis  or  thyroid  disease).  If  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
immune-mediated  adverse  reaction  is  noted,  appropriate  work-up  (including  biopsy  if  possible)  should  be  
 
 
  
 
 
 
 
  
 
 
 
performed,  and  steroid  therapy  may  be  considered  if  clinically  necessary.   
  
It  is  unknown  if  systemic  corticosteroid  therapy  has  an  attenuating  effect  on  ipilimumab  activity.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
However,  clinical  anti-tumor  responses  have  been  maintained  in  patients  treated  with  corticosteroids  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinued  from  ipilimumab.  If  utilized,  corticosteroid  therapy  should  be  individualized  for  each  
 
 
 
 
 
 
 
 
 
 
 
 
patient.  Prior  experience  suggests  that  colitis  manifested  as  ≥ Grade  3  diarrhea  requires  corticosteroid  
 
 
 
 
 
 
 
 
  
 
 
 
treatment.   
Specific  treatment  algorithms  for  immune-mediated  adverse  reactions  adverse  events  are  included  as  
 
 
 
 
 
 
 
 
 
 
 
 
appendices  in  the  IB.   
5.1.7. 
Other  Guidance   
In  patients  experiencing  neurological  deterioration  due  to  an  increase  of  either  the  tumor  mass  or  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
peritumoral  edema,  the  decision  to  maintain  or  not  ipilimumab  will  be  done  case  by  case  on  the  basis  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  judgement  and  discussion  with  the  Sponsor.   
  
5.1.8. Treatment  of  Infusion  Reactions  Associated  with  Ipilimumab  
 
Since  ipilimumab  contains  only  human  protein  sequences,  it  is  less  likely  that  any  allergic  reaction  will  be  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
seen  in  patients.  However,  it  is  possible  that  infusion  of  ipilimumab  will  induce  a  cytokine  release  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
syndrome  that  could  be  evidenced  by  fever,  chills,  rigors,  rash,  pruritus,  hypotension,  hypertension,  
 
 
 
 
 
 
 
 
 
 
 
 
 
bronchospasm,  or  other  symptoms.  No  prophylactic  pre-medication  will  be  given  unless  indicated  by  
 
 
 
 
 
 
 
 
 
 
 
 
 
previous  experience  in  an  individual  patient.  Reactions  should  be  treated  based  upon  the  following  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
recommendations.   
●
For  mild  symptoms  (e.g.,  localized  cutaneous  reactions  such  as  mild  pruritus,  flushing,  rash):   
−
Decrease  the  rate  of  infusion  until  recovery  from  symptoms,  remain  at  bedside  and  monitor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patient.   
−
Complete  the  ipilimumab  infusion  at  the  initial  planned  rate.   
−
Diphenhydramine  50 mg  IV,  Dexchlorpheniramine  maleate  5  mg  IV,  or  an  equivalent  
 
 
 
 
 
 
 
 
 
 
 
antihistaminic  agent  may  be  administered  at  the  discretion  of  the  treating  physician;  patients  may  
 
 
 
 
  
 
 
 
 
 
 
 
 
receive  additional  doses  with  close  monitoring.   
−
Premedication  with  diphenhydramine  or  dexchlorpheniramine  maleate  may  be  given  at  the  
 
 
 
 
 
 
 
 
 
 
 
discretion  of  the  investigator  for  subsequent  doses  of  ipilimumab.   
●
For  moderate  symptoms  (any  symptom  not  listed  above  [mild  symptoms]  or  below  [severe  
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms]  such  as  generalized  pruritus,  flushing,  rash,  dyspnea,  hypotension  with  systolic  BP  
 
 
 
 
 
 
 
 
 
 
 
 
>80 mmHg):   
  
−
Interrupt  ipilimumab.   
−
Administer  diphenhydramine  50 mg  IV,  dexchlorpheniramine  maleate  5  mg  IV,  or  an  equivalent  
 
 
 
 
 
  
 
 
 
 
 
antihistaminic  agent   
  
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−
Monitor  patient  closely  until  resolution  of  symptoms.   
−
Corticosteroids  may  abrogate  any  beneficial  immunologic  effect,  but  may  be  administered  at  the  
 
 
 
 
 
 
 
 
 
 
  
 
discretion  of  the  treating  physician.   
−
Resume  ipilimumab  infusion  after  recovery  of  symptoms.   
−
At  the  discretion  of  the  treating  physician,  ipilimumab  infusion  may  be  resumed  at  one  half  the  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
initial  infusion  rate,  then  increased  incrementally  to  the  initial  infusion  rate.   
−
If  symptoms  develop  after  resumption  of  the  infusion,  the  infusion  should  be  discontinued  and  no  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
additional  ipilimumab  should  be  administered  that  day.   
−
The  next  dose  of  ipilimumab  will  be  administered  at  its  next  scheduled  time  and  may  be  given  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
with  pre-medication  (diphenhydramine  and  acetaminophen)  and  careful  monitoring,  following  the  
 
 
 
 
 
 
 
 
 
 
same  treatment  guidelines  outlined  above.   
−
At  the  discretion  of  the  treating  physician  additional  oral  or  IV  antihistamine  may  be  administered  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prior  to  dosing  with  ipilimumab.   
●
For  severe  symptoms  (e.g.,  any  reaction  such  as  bronchospasm,  generalized  urticaria,  systolic  blood  
 
 
 
 
 
 
 
 
 
 
 
 
 
pressure  • 80 mm  Hg,  or  angioedema):   
−
Immediately  discontinue  infusion  of  ipilimumab,  and  disconnect  infusion  tubing  from  the  subject.   
−
Consider  bronchodilators,  epinephrine  1 mg  IV  or  subcutaneously,  and/or  diphenhydramine  
 
 
 
 
 
 
 
 
 
50 mg  IV  (or  dexchlorpheniramine  maleate  5  mg,  or  an  equivalent  antihistaminic  agent),  with  
 
 
 
 
  
 
 
 
 
 
 
 
methylprednisolone  100 mg  IV,  as  needed.   
−
Patients  should  be  monitored  until  the  investigator  is  comfortable  that  the  symptoms  will  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
recur.   
−
No  further  ipilimumab  will  be  administered.   
●
In  case  of  late-occurring  hypersensitivity  symptoms  (e.g.,  appearance  within  one  week  after  treatment  
 
 
 
 
 
 
 
 
 
 
 
 
 
of  a  localized  or  generalized  pruritus),  symptomatic  treatment  may  be  given  (e.g.,  oral  antihistamine,  
  
 
 
 
 
 
 
 
 
 
 
 
 
or  corticosteroids).   
5.1.9. Treatment  of  Ipilimumab-Related  Isolated  Drug  Fever   
In  the  event  of  isolated  drug  fever,  the  investigator  must  use  clinical  judgment  to  determine  if  the  fever  is  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
related  to  the  ipilimumab  or  to  an  infectious  etiology.  If  a  patient  experiences  isolated  drug  fever,  for  the  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
next  dose,  pre-treatment  with  acetaminophen  or  non-steroidal  anti-inflammatory  agent  (investigator  
 
 
 
 
 
 
 
 
 
 
discretion)  should  be  instituted  and  a  repeated  antipyretic  dose  at  6  and  12  hours  after  ipilimumab  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
infusion,  should  be  administered.  The  infusion  rate  will  remain  unchanged  for  future  doses.  If  a  patient  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
experiences  recurrent  isolated  drug  fever  following  premedication  and  post  dosing  with  an  appropriate  
 
 
 
 
 
 
 
 
 
 
 
 
 
antipyretic,  the  infusion  rate  for  subsequent  dosing  should  be  decreased  to  50%  of  the  previous  rate.  If  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
fever  recurs  following  infusion  rate  change,  the  investigator  should  assess  the  patient’s  level  of  discomfort  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with  the  event  and  use  clinical  judgment  to  determine  if  the  patient  should  receive  further  ipilimumab.   
5.1.10. Monitoring  and  Management  of  Immune-mediated  Adverse  Reactions   
Immune-mediated  Enterocolitis  
 
Monitor  patients  for  signs  and  symptoms  of  enterocolitis  (such  as  diarrhea,  abdominal  pain,  mucus  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
blood  in  stool,  with  or  without  fever)  and  of  bowel  perforation  (such  as  peritoneal  signs  and  ileus).  In  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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symptomatic  patients,  rule  out  infectious  etiologies  and  consider  endoscopic  evaluation  for  persistent  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
severe  symptoms.   
Permanently  discontinue  ipilimumab  in  patients  with  severe  enterocolitis  and  initiate  systemic  
 
 
 
 
 
 
 
 
 
 
 
corticosteroids  at  a  dose  of  1  to  2  mg/kg/day  of  prednisone  or  equivalent.  Upon  improvement  to  Grade  1  
   
 
  
  
 
 
 
 
 
 
  
  
or  less,  initiate  corticosteroid  taper  and  continue  to  taper  over  at  least  one  month.  In  clinical  trials,  rapid  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
corticosteroid  tapering  resulted  in  recurrence  or  worsening  symptoms  of  enterocolitis  in  some  patients.   
Withhold  ipilimumab  dosing  for  moderate  enterocolitis;  administer  anti-diarrheal  treatment  and,  if  
 
 
 
 
 
 
 
 
 
 
 
persistent  for  more  than  one  week,  initiate  systemic  corticosteroids  at  a  dose  of  0.5  mg/kg/day  prednisone  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
or  equivalent.   
Immune-mediated  Hepatitis  
 
Monitor  liver  function  tests  (hepatic  transaminase  and  bilirubin  levels)  and  assess  patients  for  signs  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms  of  hepatotoxicity  before  each  dose  of  ipilimumab.  In  patients  with  hepatotoxicity,  rule  out  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
infectious  or  malignant  causes  and  increase  frequency  of  liver  function  test  monitoring  until  resolution.   
Permanently  discontinue  ipilimumab  in  patients  with  Grade  3–5  hepatotoxicity  and  administer  systemic  
 
 
 
 
 
 
 
 
 
 
 
 
corticosteroids  at  a  dose  of  1  to  2  mg/kg/day  of  prednisone  or  equivalent.  When  liver  function  tests  show  
   
 
  
  
 
 
 
 
 
 
 
 
 
 
sustained  improvement  or  return  to  baseline,  initiate  corticosteroid  tapering  and  continue  to  taper  over  1  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
month.  Across  the  clinical  development  program  for  ipilimumab,  mycophenolate  treatment  has  been  
 
 
 
 
 
 
 
 
 
 
 
 
administered  in  patients  who  have  persistent  severe  hepatitis  despite  high-dose  corticosteroids.  Withhold  
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  in  patients  with  Grade  2  hepatotoxicity. 
Immune-mediated  Dermatitis  
 
Monitor  patients  for  signs  and  symptoms  of  dermatitis  such  as  rash  and  pruritus.  Unless  an  alternate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
etiology  has  been  identified,  signs  or  symptoms  of  dermatitis  should  be  considered  immune-mediated.   
  
Permanently  discontinue  ipilimumab  in  patients  with  Stevens-Johnson  syndrome,  toxic  epidermal  
 
 
 
 
 
 
 
 
 
 
necrolysis,  or  rash  complicated  by  full  thickness  dermal  ulceration,  or  necrotic,  bullous,  or  hemorrhagic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
manifestations.  Administer  systemic  corticosteroids  at  a  dose  of  1  to  2  mg/kg/day  of  prednisone  or  
 
 
 
 
  
 
  
  
 
 
 
 
equivalent.  When  dermatitis  is  controlled,  corticosteroid  tapering  should  occur  over  a  period  of  at  least  1  
 
 
  
 
 
 
 
 
  
 
  
  
month.  Withhold  ipilimumab  dosing  in  patients  with  moderate  to  severe  signs  and  symptoms.   
  
For  mild  to  moderate  dermatitis,  such  as  localized  rash  and  pruritus,  treat  symptomatically.  Administer  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
topical  or  systemic  corticosteroids  if  there  is  no  improvement  of  symptoms  within  1  week.   
Immune-mediated  Neuropathies  
 
Monitor  for  symptoms  of  motor  or  sensory  neuropathy  such  as  unilateral  or  bilateral  weakness,  sensory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alterations,  or  paresthesia.  Permanently  discontinue  ipilimumab  in  patients  with  severe  neuropathy  
 
 
 
 
 
 
 
 
 
 
 
(interfering  with  daily  activities)  such  as  Guillain-Barré-like  syndromes.  Institute  medical  intervention  as  
 
 
 
 
 
 
 
 
 
 
 
 
appropriate  for  management  of  severe  neuropathy.  Consider  initiation  of  systemic  corticosteroids  at  a  
 
 
 
 
 
 
 
 
 
 
 
  
dose  of  1  to  2  mg/kg/day  prednisone  or  equivalent  for  severe  neuropathies.  Withhold  ipilimumab  dosing  
 
  
  
 
 
 
 
 
 
 
 
 
 
in  patients  with  moderate  neuropathy  (not  interfering  with  daily  activities).   
Immune-mediated  Endocrinopathies  
 
Monitor  patients  for  clinical  signs  and  symptoms  of  hypophysitis,  adrenal  insufficiency  (including  adrenal  
 
 
 
 
 
 
 
 
 
 
 
 
 
crisis),  and  hyper-  or  hypothyroidism.  Patients  may  present  with  fatigue,  headache,  mental  status  changes,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
abdominal  pain,  unusual  bowel  habits,  and  hypotension,  or  nonspecific  symptoms  which  may  resemble  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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other  causes  such  as  brain  metastasis  or  underlying  disease.  Unless  an  alternate  etiology  has  been  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
identified,  signs  or  symptoms  of  endocrinopathies  should  be  considered  immune-mediated.   
Monitor  thyroid  function  tests  and  clinical  chemistries  at  the  start  of  treatment,  before  each  dose,  and  as  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
clinically  indicated  based  on  symptoms.  In  a  limited  number  of  patients,  hypophysitis  was  diagnosed  by  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
imaging  studies  through  enlargement  of  the  pituitary  gland.  Withhold  ipilimumab  dosing  in  symptomatic  
 
 
 
 
 
 
 
 
 
 
  
 
patients.  Initiate  systemic  corticosteroids  at  a  dose  of  1  to  2  mg/kg/day  of  prednisone  or  equivalent,  and 
 
 
 
   
 
  
  
 
 
 
 
 
 
initiate  appropriate  hormone  replacement  therapy.   
Other  Immune-mediated  Adverse  Reactions,  Including  Ocular   
Manifestations  
 
The  following  clinically  significant  immune-mediated  adverse  reactions  were  seen  in  less  than  1%  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab-treated  patients  in  Study  1:  nephritis,  pneumonitis,  meningitis,  pericarditis,  uveitis,  iritis,  and  
 
 
 
 
 
 
 
 
 
 
 
 
hemolytic  anemia.   
Across  the  clinical  development  program  for  ipilimumab,  the  following  likely  immune-mediated  adverse  
 
 
 
 
 
 
 
 
 
 
 
 
reactions  were  also  reported  with  less  than  1%  incidence:  myocarditis,  angiopathy,  temporal  arteritis,  
 
 
 
 
 
 
 
 
 
 
 
 
 
vasculitis,  polymyalgia  rheumatica,  conjunctivitis,  blepharitis,  episcleritis,  scleritis,  leukocytoclastic  
 
 
 
 
 
 
 
 
vasculitis,  erythema  multiforme,  psoriasis,  pancreatitis,  arthritis,  and  autoimmune  thyroiditis.   
Permanently  discontinue  ipilimumab  for  clinically  significant  or  severe  immune-mediated  adverse  
 
 
 
 
 
 
 
 
 
 
reactions.  Initiate  systemic  corticosteroids  at  a  dose  of  1  to  2  mg/kg/day  prednisone  or  equivalent  for  
 
 
 
 
  
 
  
  
 
 
 
 
 
severe  immune-mediated  adverse  reactions.   
Administer  corticosteroid  eye  drops  to  patients  who  develop  uveitis,  iritis,  or  episcleritis.  Permanently  
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinue  ipilimumab  for  immune-mediated  ocular  disease  that  is  unresponsive  to  local  
 
 
 
 
 
 
 
 
 
 
 
immunosuppressive  therapy.   
5.1.11. Liver  Function  Test  (LFT)  Assessments  Required  Before   
Administration  of  Ipilimumab   
Liver  function  tests  (AST,  ALT,  T.  bilirubin)  will  be  evaluated  for  every  subject  prior  to  administration  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
ipilimumab.  Blood  samples  must  be  collected  and  analyzed  at  local  or  central  labs  within  3  days  prior  to  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
dosing.  LFT  results  must  be  reviewed  by  the  principal  investigator  (or  designee)  to  meet  dosing  criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specifications:  ≤  2.5  x  ULN  for  AST,  ALT  and  ≤  1.5  x  ULN  for  T.  bilirubin  unless  liver  metastases  are  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
present  in  which  case  LFT  ≤  5  x  ULN  for  AST,  ALT  and  T.  bilirubin  ≤  3.0  x  ULN)  prior  to  dosing.   
  
If,  during  the  course  of  treatment  abnormal  LFT  values  are  detected,  the  subject  must  be  managed  using  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  hepatotoxicity  algorithm  section  of  the  ipilimumab  Investigators.   
  
5.2. Radiation  therapy   
The  selected  dose  and  regimen  for  WBRT  is  a  total  dose  of  30  Gy  in  10  daily  fractions  of  3  Gy.  Radio  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
biologically  equivalent  doses  might  be  discussed,  but  require  the  approval  of  the  sponsor.   
  
  
5.3. Glucocorticoid  therapy   
The  following  guidelines  are  consistent  with  a  systematic  review  and  evidence-based  clinical  guidelines  
 
 
 
 
 
  
 
 
 
 
 
 
for  the  use  of  steroids  in  brain  metastases. 40   
  
  
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Those  guidelines  recommended  a  dose  of  dexamethasone  of  16  mg  per  day  or  more  for  patients  with  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
severe  symptoms  due  to  increased  intracranial  pressure  and  edema  due  to  brain  metastases.  However,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
these  patients  are  formally  excluded  from  the  protocol.   
  
For  patients  with  milder  symptoms,  a  starting  dose  of  4  to  8  mg  of  dexamethasone  daily  is  recommended;  
 
 
 
 
  
 
 
    
 
 
 
  
 
steroids  are  not  recommended  for  asymptomatic  patients.   
  
Based  upon  this  review  the  drug  should  be  tapered  slowly  over  two  week  time  period  or  longer  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptomatic  patients.   
  
5.4. Prohibited  and  Restricted  Therapies  During  the  Study   
5.4.1. Prohibited  Therapies   
Patients  in  this  study  may  not  use  vaccines  for  the  treatment  or  prevention  of  cancer  for  up  to  one  month  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
pre  and  post  dosing  with  ipilimumab.   
  
Concomitant  systemic  or  local  anti-cancer  medications  or  treatments  are  prohibited  in  this  study  while  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
receiving  ipilimumab  treatments,  with  the  exception  of  WBRT.   
  
Patients  may  not  use  any  of  the  following  therapies  during  the  study:   
●
Any  non-study  anti-cancer  agent  (investigational  or  non-investigational)   
●
Any  other  investigational  agents   
●
Any  other  CTLA-4  inhibitors  or  agonists   
●
CD137  agonists   
●
Anti-PD1  agents   
●
Immunosuppressive  agents   
●
Chronic  systemic  corticosteroids  for  other  conditions  not  related  to  the  disease  or  to  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
managements  of  ipilimumab  adverse  events.   
●
Any  non-oncology  vaccine  therapies  used  for  the  prevention  of  infectious  diseases  (for  up  to  30  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
days  prior  to  or  after  any  dose  of  study  drug).   
  
5.4.2. Restricted  Therapies   
Not  applicable   
.   
 
 
 
  
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6. 
STUDY  PROCEDURES  AND  OBSERVATIONS   
6.1. Time  and  Events  Schedule  (Table  12)   
  
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Visit   
  
Visit  1   
Registration   
(Day  -28  to   
day  -1)   
Visit  2   
Eligibility   
(Day  -7  to   
day  -1)   
Visit   
3.   
C1D 
1   
Visits  R.1   
to  R.x   
Starting   
Between   
C1D2  and   
C2D1   
Visit   
4   
C2D 
1   
Visit   
5   
C3D 
1   
Visit   
6   
C4D 
1   
End  of   
treatment   
C4D30( + 2)   
Follow-up   
Tumor   
Assesment   
(every  9   
weeks  +/-  1)   
Follow  up   
visits   
Months  6,  9,   
12,  15,  18,   
21,  24,  27,  30   
(+/-  1  week)   
Informed  Consent  Form   
X   
  
  
  
  
  
  
  
  
  
Central  registration   
X   
  
  
  
  
  
  
  
  
  
Medical  History   
  
X(1)   
  
  
  
  
  
  
  
  
Concomitant  diseases   
  
X(1)   
X   
X   
X   
X   
X   
X   
  
X   
Symptoms   
  
X   
X   
X   
X   
X   
X   
X   
  
X   
Karnofsky  PS,Barthel  Index,  
 
 
 
Physical 
 exam, 
 vital  
 
 
 
constants,  body  weight   
  
X   
X   
X   
X   
X   
X   
X   
  
X   
Neurological  exam   
  
X   
X   
X   
X   
X   
X   
X   
  
X   
Concomitant  medications   
  
X   
X   
X   
X   
X   
X   
X   
  
X   
RPA  class   
  
X   
  
  
  
  
  
  
  
  
Inclusion/Exclusion  checklist   
  
X   
  
  
  
  
  
  
  
  
Eligibility  communication   
  
X   
  
  
  
  
  
  
  
  
Blood  Workup   
  
  
  
  
  
  
  
  
  
  
Hematology   
  
X   
  
X   
X   
X   
X   
X   
  
X   
Biochemistry   
  
X   
  
X   
X   
X   
X   
X   
  
X   
Pregnancy  test   
  
X(2)   
  
  
X   
X   
X   
X   
  
  
Auto-immunity  panel   
  
X(1)   
  
  
  
  
  
  
  
  
Hormones  (morning  cortisol  
 
 
 
and  ACTH,  free  T4,  T3,  
 
 
 
 
 
TSH,  prolactin)   
  
X(1)   
  
  
X   
X   
X   
X   
  
X   
Efficacy  evaluation   
  
  
  
  
  
  
  
  
  
  

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(1)  Can  be  performed  between  d-28  and  d-1.   
(2)  All  WOCBP  MUST  have  a  negative  pregnancy  test  within  72  hours  before  receiving  ipilimumab.  The  minimum  sensitivity  of  the  pregnancy  test  must  be  25   
IU/L  or  equivalent  units  of  HCG.  If  the  pregnancy  test  is  positive,  the  subject  must  not  receive  ipilimumab  and  must  not  be  enrolled  in  the  study.   
(3)  If  done,  it  should  be  performed  up  to  2  weeks  prior  to  C1D1   
(4)  If  applicable,  4  weeks  ( +  1)  after  the  end  of  WBRT 
  (5)  Should  be  done  on  week  12 +1   
 
 
 
  
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Chest-Abdomen-pelvis 
 CT  
 
 
scan   
  
X(1)   
  
  
  
  
  
X(5)   
X   
X   
Craneal  CT  scan/MRI   
  
X(1)   
  
  
  
  
  
X(5)   
X   
X   
Safety  evaluation   
  
  
  
  
  
  
  
  
  
  
Adverse  events  /SAEs   
Throughout  the  study   
Dose  reductions   
  
  
  
  
Throughout  the  study,  when  applicable   
Throughout  the  study,  when  applicable   
Dose  delays   
  
  
  
  
Biomarker 
 evaluation  
 
 
(optional)   
  
  
  
  
  
  
  
  
  
  
Archived  tumour  tissue   
  
X(1)   
  
  
  
  
  
  
  
  
Peripheral  blood  (serum  +  
 
 
 
 
whole  blood)   
  
  
X   
  
X   
X   
X    
X   
  
  
DW-MRI  (optional)   
  
X(3)   
  
  
  
X(4)   
  
X   
  
  
Intervention   
  
  
  
  
  
  
  
  
  
  
Ipilimumab  infusion   
  
  
C1   
  
C2   
C3   
C4   
  
  
  
Initiation  of  radiation  therapy   
  
  
  
X   
  
  
  
  
  
  

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6.2. Procedures  by  Visit   
The  Time  and  Events  Schedule  summarizes  the  frequency  and  timing  of  various  measurements.  (Table  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12)   
  
6.2.1. Study  Procedures  by  Visit  and  Treatment  Cycle  
 
Note  that  results  of  all  safety  laboratory  tests  (that  is,  all  chemistry  and  all  hematology  results)  must  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
obtained  and  reviewed  before  ipilimumab  administration,  as  applicable.  All  laboratory  results  must  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
within  the  established  range  before  ipilimumab  is  administered.  All  treatment-period  laboratory  samples  
 
 
 
 
 
  
 
 
 
 
 
must  be  collected  within  a  window  of  up  to  1 days  before  administration  of  ipilimumab.  Laboratory  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
evaluations  using  a  local  laboratory  must  be  performed  and  the  result  examined  by  the  investigator  before  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
administration  of  each  dose  of  ipilimumab.  The  only  exception  might  be  the  hormonal  tests,  for  which  is  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
acceptable  a  delay  of  up  to  3  weeks  in  reporting  the  results.   
  
6.2.1.a 
Registration  visit.  
 
Explanation  of  the  study  to  the  patient.  Completion  and  signature  of  the  informed  consent  form.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submission  of  the  registration  form  to  the  Sponsor.  Assignation  of  a  patient  number.   
 
  
6.2.1.b 
Screening/Baseline  Visit  
 
Initiation  of  study  specific  procedures  to  assess  eligibility:  medical  history,  concomitant  medications,  rule  
 
 
 
 
  
 
 
 
 
 
 
 
out  forbidden  therapies,  record  baseline  symptoms,  physical  exam  (including  basic  neurologic  exam),  lab  
 
 
 
 
 
 
 
 
 
 
 
 
 
workout,  assessment  of  the  disease.  Cathegorization  of  RPA  class  (table  1),  and  Karnofsky  and  Barthel  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
scales.   
  
  
6.2.1.c 
Treatment  Visits  
 
Patients  will  be  assessed  at  least  once  before  each  administration  of  ipilimumab.  Patients  will  also  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluated  before  the  first  dose  of  WBRT,  and  at  least  weekly  during  the  administration  of  WBRT.  These  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
assessments  will  record  patient’s  symptoms,  performance  status,  Barthel  index,  vital  constants,  physical  
 
 
 
 
 
 
 
 
 
 
 
 
examination  (including  basic  neurological  examination),  lab  tests  and  concomitant  medications.  Once  
 
 
 
 
 
 
 
 
 
 
 
treatment  has  started,  evaluation  of  eventual  adverse  events  and  deviations  from  dosing  regimen  will  also  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  documented,  with  mention  of  their  potential  relation  with  the  study  therapy.  The  disease  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluated  morphologically  as  detailed  in  section  6.4.2.   
Patient’s  weight  will  be  measured  at  each  treatment  visit  (or  the  day  before).  The  dose  of  ipilimumab  will  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
be  based  on  that  measurement.   
6.2.1.d 
End  of  Treatment  visit.  
 
End  of  treatment  visit  (EOT)  will  take  place  30  +  2  days  after  the  last  dose  of  ipilimumab.  This  visit  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
will  require  a  complete  evaluation  of  patient’s  symptoms,  Karnofsky/Barthel  scores,  physical  exam  
 
  
 
 
 
 
 
 
 
 
 
(including  weight,  vital  constants  and  neurological  exam),  lab  tests,  collection  of  AEs  and  of  concomitant  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
medication.  If  the  disease  was  not  evaluated  before,  EOT  visit  should  include  a  body  and  craneal  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
CTscan/MRI.   
  
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6.2.1.e 
Follow-up  visits.  
 
Per  protocol,  the  disease  should  be  evaluated  until  death  or  confirmed  progression  (mWHO/immune  
 
 
 
 
 
 
 
 
 
 
 
 
 
response  criteria).  Tumor  assessment  will  be  performed  with  CT/MRI  of  brain,  chest,  abdomen  and  pelvis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
at  baseline,  at  weeks  12  and  17  +  1  and  then,  every  9  +  1  weeks.  The  same  method  of  assessment  (CT  or  
 
  
 
 
 
   
 
 
    
 
 
 
 
 
 
 
 
MRI)  should  be  used  throughout  the  patient’s  time  on  study  for  consistent  evaluation  of  response.   
After  EOT  visit,  the  occurrence  of  new  SAEs  and  irAEs  will  be  reported  up  to  90  days  after  last  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  administration.  Ongoing  SAEs/irAEs  will  be  followed  up  until  recovery.   
Survival  status  will  be  checked  at  week  12,  16-18  and  then,  every  8-10  weeks.   
  
6.2.2. Study  Completion  or  Early  Discontinuation  Visit   
At  the  time  of  study  early  withdrawal,  the  reason  for  early  withdrawal  and  any  new  or  continuing  adverse  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
events  should  be  documented.   
  
6.2.3. Study  Drug  Discontinuation   
If  study  drug  administration  is  discontinued,  the  reason  for  discontinuation  will  be  recorded.   
  
6.3. Details  of  Procedures   
6.3.1. Study  Materials   
The  Sponsor  will  provide  ipilimumab  at  no  cost  for  this  study.   
In-line  infusion  filters  will  be  obtained  locally  by  the  site.   
The  sponsor  (or  designee)  will  also  supply:   
●
Study  document  file  binder   
●
SMPC   
●
Drug  Preparation  Guidelines   
●
Laboratory  Manuals   
●
CRFs   
  
●
NCI  Common  Terminology  Criteria  for  Adverse  Events  (CTCAE)  version  4.0   
  
6.3.2. Safety  Assessments   
All  patients  who  receive  at  least  one  dose  of  ipilimumab  will  be  considered  evaluable  for  safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
parameters.  Additionally,  any  occurrence  of  non-SAE  or  SAE  from  time  of  consent  forward,  up  to  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
including  follow-up  visits,  will  be  reported.  See  Section  8:  Adverse  Event  Reporting.   
Safety  will  be  evaluated  for  all  treated  patients  using  the  National  Cancer  Institute  (NCI)  Common  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Terminology  Criteria  for  Adverse  Events  (CTCAE),  Version  4.0  (http://ctep.cancer.gov).  Safety  
 
 
 
 
 
 
 
 
 
 
assessments  will  be  based  on  medical  review  of  adverse  event  reports  and  the  results  of  vital  sign  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
measurements,  physical  examinations,  and  clinical  laboratory  tests.   
  
  
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6.4. Criteria  for  Evaluation   
6.4.1. Safety  Evaluation   
6.4.1.a 
Medical  History,  Physical  Exam,  Physical  Measurements  
 
Medical  history  will  be  obtained  at  the  Elegibility  Visit.  Medical  history  must  include  date  of  diagnosis  of  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
melanoma,  including  histological  documentation  of  malignancy  and  current  staging.  B-Raf  mutation  
 
 
 
 
 
 
 
 
 
 
 
status  will  be  recorded.   
Pre-treatment  events  present  within  2  weeks  of  starting  study  therapy,  whether  or  not  related  to  current  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
disease,  will  be  captured  prior  to  study  start.  Any  changes  from  baseline  will  be  documented  as  an  AE  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
the  CRF.   
The  Screening  Visit  Physical  Examination  should  include  weight,  height,  Karnofsky  PS  (Appendix  1),  
 
 
 
 
 
 
 
 
 
 
 
 
 
Barthel  Index  (Appendix  2),  RPA  class  of  brain  metastases  (Table  1),  blood  pressure,  heart  rate  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
temperature  and  should  be  performed  within  7  days  of  starting  study  therapy.   
Subsequent  targeted  physical  examinations,  including  weight,  will  be  performed  at  each  dosing  visit  and  
 
 
 
 
 
 
 
 
  
 
 
 
 
at  the  End  of  Treatment  Visit.  Targeted  physical  examinations  are  a  focused  assessment  of  body  areas  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
relevant  at  the  time  of  the  visit.  Only  physical  examination  findings  that  qualify  as  an  AE  or  SAE  will  be  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
documented  on  the  appropriate  CRF  pages.   
  
6.4.1.b 
Vital  Signs  
 
Vital  signs  to  include:  blood  pressure  (BP),  heart  rate,  and  temperature.  During  study  drug  infusions,  vital  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sign  measurements  must  be  collected  prior  to  dosing  and  every  30  minutes  for  the  duration  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
infusion.  Vital  signs  are  to  be  captured  in  the  subject  record.  Findings  should  be  reported  only  if  they  meet 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
AE/SAE  criteria.   
6.4.1.c 
Pregnancy  Testing  
 
WOCBP  are  required  to  have  pregnancy  tests  performed.  A  negative  pregnancy  test  must  be  documented  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
at  the  eligibility  visit.  Additionally,  WOCBP  must  exhibit  a  negative  serum  or  urine  pregnancy (minimum  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
sensitivity  25  IU/L  or  equivalent  units  of  HCG)  within  72  hours  prior  to  the  start  of  study  drug .  The  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening  pregnancy  test  may  need  to  be  repeated  prior  to  the  start  of  study  drug  dosing.   
A  urine  pregnancy  test  must  be  performed  prior  to  dosing  at  every  study  drug  administration  visit.   
  
6.4.1.d 
Performance  Status  and  Barthel  Index  
 
Karnofsky  Performance  Status  and  Barthel  Index  will  be  evaluated  and  documented  at  Screening,  at  each  
 
 
 
 
 
 
 
 
 
 
  
  
 
dosing  visit,  and  at  the  End  of  Treatment  visit.  See  Appendix  1  and  2  for  description  of  the  respective  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
scoring  systems.   
  
  
6.4.1.e 
Laboratory  Testing  
 
Laboratory  tests  are  obtained  as  part  of  screening  and  to  determine  eligibility.  Results  of  safety  laboratory  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
collections  (ie,  Chemistry  and  Hematology)  must  be  obtained  and  reviewed  in  advance  of  study  drug  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dosing.   
•  The  following  lab  parameters  must  be  collected  within  a  window  of  up  to  1  day  prior  to  dosing:  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
CBC/diff  (includes  ANC  and  ALC),  AST,  ALT,  total  bilirubin,  CRP,  sodium,  chloride,  bicarbonate,  BUN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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or  urea,  creatinine,  and  glucose.  Baseline  values  up  to  7  days  before  the  first  dose  are  acceptable  prior  to  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
C1.These  lab  tests  will  also  be  performed  at  week  12,  EOT,  and  90  days  after  last  dose  administration  of  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  (+/-1  week).   
•  CBC/diff,  AST,  ALT,  total  bilirubin,  sodium,  chloride,  BUN  or  urea,  creatinine,  and  glucose  will  also  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
collected  weekly  during  WBRT   
  
All  protocol-specified  laboratory  tests  will  be  analyzed  and  reported  by  a  local  lab.   
Importantly,  LFT  results  (AST,  ALT,  and  total  bilirubin)  must  be  reviewed  within  24  h  prior  to  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
dosing .  If  abnormal  LFTs  are  detected,  the  subject  must  be  managed  using  the  hepatoxicity  algorithm  in  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
the  SMPC.  (Additional  draws  must  be  incorporated  when  monitoring  recovery  from  any  non-hematologic  
 
 
 
 
 
 
 
 
 
 
 
 
 
AE  (eg,  elevations  in  ALT,  AST).   
  
6.4.1.f 
Endocrine  Tests  
 
The  following  endocrine  tests  should  be  performed  at  Screening  and  prior  to  each  dosing  visit:  TSH,  free  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
T4  and  T3,  morning  ACTH  and  cortisol,  and  prolactin.   
  
Other  hormones  might  be  tested  as  well  as  clinically  indicated.   
  
  
During  treatment,  if  patient  is  asymptomatic,  it  will  be  adequate  to  confirm  at  least  the  normality  of  the  
 
  
  
  
 
 
 
 
  
 
 
 
 
 
results  of  the  tests  performed  within  the  last  3  weeks.  If  the  patient  is  symptomatic  (e.g.  asthenia,  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
cephalea)  it  will  be  mandatory  to  check  the  results  of  the  pre-dose  testing  (at  least  72  h  prior  to  dose  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
administration)   
  
6.4.1.g 
HIV  and  Hepatitis  Panel  
 
At  screening,  testing  for  HIV,  hepatitis  C  antibody,  and  hepatitis  B  surface  antigen  (HBsAg)  should  be  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
performed  for  clinically  suspected  HIV,  HBV,  and  HCV.  If  positive  results  at  Screening  are  not  indicative  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
of  true  active  or  chronic  infection,  the  subject  may  enter  the  study  after  discussion  and  agreement  between  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  Investigator  and  the  Medical  Monitor.  These  tests  will  be  repeated  during  the  course  of  the  study  if  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
clinically  indicated.   
  
6.4.2. Efficacy  Evaluation   
The  primary  endpoint  will  be  1-year  survival.  Secondary  endpoints  require  the  assessment  of  disease  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression  or  response  to  therapy.   
  
Secondary  response-based  endpoints  (PFS,  BORR,  DCR,  and  duration  of  response)  will  be  captured  
 
 
 
 
 
 
 
 
 
 
 
 
 
using  two  distinct  but  related  criteria:   
●
Modified  WHO  (mWHO)  criteria.   
●
Immune-related  Response  Criteria  (irRC)   
The  mWHO  criteria  will  be  used  to  define  response-based  secondary  endpoints.  The  irRC  will  be  used  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
a)  define  exploratory  endpoints  and  to  b)  define  confirmed  disease  progression  for  the  purpose  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinuing  ipilimumab  treatment  in  order  to  permit  physicians  to  continue  treating  with  ipilimumab  in  
 
 
 
 
 
 
 
  
 
 
 
  
spite  of  the  appearance  of  small  new  lesions  and/or  transient  increases  in  tumor  burden  that  may  signal  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
anti-cancer  inflammation.  The  irRC  criteria  will  be  used  for  exploratory  analyses.  Tumor  response  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
based  on  investigator  assessment.   
  
  
65 / 93 
  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
Tumor  assessment  of  the  disease  will  be  performed  with  CT/MRI  of  brain,  chest,  abdomen  and  pelvis  at  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
baseline,  at  weeks  12  and  16-18  and  then,  every  8-10  weeks.  The  same  method  of  assessment  (CT  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI)  should  be  used  throughout  the  patient’s  time  on  study  for  consistent  evaluation  of  response.   
6.4.2.a 
Radiological  Assessment  of  Tumor  Lesions  
 
CT/MRI  imaging  of  the  brain,  chest  and  abdomen-pelvis  is  required  at  Screening  (ie,  Baseline)  and  at  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
each  tumor  assessment  visit,  regardless  of  the  location  of  known  metastases.  In  addition,  CT/MRI  scans  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
must  be  obtained  of  anatomic  regions  not  covered  by  the  chest  and  abdomen  scans,  in  subjects  where  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
there  is  clinical  suspicion  for  deep  soft  tissue  metastases  (eg,  lesions  in  the  thigh).  Such  additional  CT/  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRIs  will  be  required  at  Screening  only  when  deep  soft  tissue  disease  is  suspected  during  Screening  and  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
must  be  consistently  repeated  at  all  tumor  assessment  visits  if  a  deep  soft  tissue  lesion  is  identified  during  
 
 
 
  
 
 
 
   
 
 
 
  
 
 
Screening.  In  cases  without  suspicion  for  deep  soft  tissue  disease,  no  such  CT/MRIs  are  required.   
Obviously,  brain  scans  are  required  at  Screening  and  at  each  disease  evaluation  visit.  MRIs  are  preferred,  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
contrast-enhanced  CTs  are  a  second  choice.   
Similar  methods  of  tumor  assessment  and  similar  techniques  must  be  used  to  characterize  each  identified  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
and  reported  lesion  at  Screening  during  the  treatment  evaluation  phases.  Imaging-based  evaluation  is  
 
 
 
 
 
 
 
 
 
 
 
 
 
preferred  to  clinical  examination.  Helical  (spiral)  CT  scans  of  chest  and  abdomen  are  preferred.  If  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
available,  conventional  (nonhelical,  non-spiral  CT)  should  be  used.  If  not  contraindicated,  IV  contrast  
 
 
 
 
 
 
 
 
 
 
 
 
 
should  be  used  for  all  studies.  If  IV  contrast  is  contraindicated,  MRI  should  be  used  at  the  Screening  exam  
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
and  at  all  tumor  assessment  time  points.  Oral  contrast  should  be  used  for  all  applicable  imaging  unless  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
contraindicated.   
A  reference  measurement  ruler  must  be  printed  on  every  image  for  scale  determination.  Sections  should  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  contiguous,  similarly  sized  and  consistent  from  visit-to-visit.  Section  thickness  must  be  based  on  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
institutional  standards  (eg,  from  5  to  8  mm,  10  mm  cuts  are  not  recommended).  Chest  x-rays  and  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
ultrasound  are  not  acceptable  methods  to  measure  disease.   
  
Response  and  progression  of  disease  must  be  documented  by  CT  or  MRI  similar  to  the  methods  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
used  at  Screening.   
Screening  bone  scans  are  not  mandatory,  and  should  be  performed  as  clinically  indicated.  Abnormal  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
findings  on  Screening  bone  scans,  consistent  with  malignant  disease,  require  follow-up  bone  scans  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specified  intervals.  Normal  bone  scans  at  Screening  do  not  require  follow-up  bone  scans,  except  when  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinically  indicated.  Abnormal  bone  scans  should  be  confirmed  with  radiographic  plain  films,  CT  or  MRI.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Similarly,  progressive  disease  based  only  on  new  lesion(s)  found  on  bone  scans  must  be  supported  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
plain  films,  CT  or  MRI  imaging  studies  of  the  bone  lesion(s)  to  confirm  their  malignant  nature.  Increased  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
intensity  of  uptake  in  previously  abnormal  areas  on  bone  scans  is  not  considered  progressive  disease,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
unless  the  lesions  seen  on  the  correlative  imaging  studies  confirm  the  finding  of  disease  progression.  New  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
areas  of  abnormal  uptake  on  a  bone  scan  represent  disease  progression.   
Any  subject  who  develops  an  objective  tumor  response  (CR  or  PR)  is  required  to  undergo  confirmatory  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
scans  no  less  than  4  weeks  since  the  prior  scan  in  order  to  verify  the  reliability  of  the  radiologic  finding.   
  
6.4.2.b 
Non-radiographic  Assessments  
 
Visible  cutaneous  lesions  must  be  measured  clinically.  Digital  and  standardized  photographic  images  
 
 
 
 
 
 
 
 
 
 
 
 
including  a  ruler  for  scale  as  part  of  the  image  are  recommended  for  documentation.  All  clinical 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assessments  must  be  performed  within  close  proximity  (±  7  days)  of  any  protocol  specified  radiographic  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
assessments   
  
66 / 93 
  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
  
6.4.2.c 
Definition  of  Measurable/Non-measurable  Lesions  
 
Definitions  of  lesions  are  based  on  modified  WHO  criteria  in  this  study.   
●
Measurable  lesions  are  lesions  that  can  be  accurately  measured  in  2  perpendicular  diameters,  with  
 
 
 
 
 
 
 
 
   
 
 
 
at  least  one  diameter  ≥  20  mm  and  the  other  dimension  ≥  10  mm  (10  mm  x  10  mm  for  spiral  CT).  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
The  area  will  be  defined  as  the  product  of  the  largest  diameter  with  its  perpendicular.  Skin  lesions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
can  be  considered  measurable.   
●
Non-measurable  (evaluable)  lesions  are  all  other  lesions,  including  unidimensionally  measurable 
 
 
 
 
 
 
 
 
 
 
disease  and  small  lesions  (lesions  without  at  least  one  diameter  ≥  20  mm).   
●
The  definition  of  measurable  and  non-measurable  lesions  also  applies  to  new  lesions  to  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
included  in  the  assessments  for  irRC   
Lesions  occurring  in  a  previously  irradiated  area  (unless  they  are  documented  as  new  lesions  since  the  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
completion  of  radiation  therapy),  bone  lesions,  leptomeningeal  disease,  ascites,  pleural  or  pericardial  
 
 
 
 
 
 
 
 
 
 
 
 
effusion,  lymphangitis  cutis/pulmonis,  abdominal  masses  that  are  not  pathologically/cytologically  
 
 
 
 
 
 
 
 
 
confirmed  and  followed  by  imaging  techniques  and  cystic  lesions.   
All  measurable  and  non-measurable  lesions  should  be  assessed  at  Screening  and  at  the  defined  time  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
points.  Extra  assessments  may  be  performed,  as  clinically  indicated,  if  there  is  a  suspicion  of  progression.  
 
 
 
 
 
 
 
 
  
   
 
 
 
The  Investigator  will  base  tumor  evaluations  on  the  modified  form  of  the  WHO  criteria  or  irRC  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specified  in  the  subsequent  sections.   
  
6.4.2.d 
Definition  of  Index/Non-index  Lesions 
All  measurable  lesions,  up  to  a  maximum  of  five  lesions  per  organ  and  fifteen  lesions  in  total ,  should  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
be  identified  as  index  lesions  to  be  measured  and  recorded  on  the  CRF  at  Screening.  The  index  lesions  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
should  be  representative  of  all  involved  organs.  No  more  than  five  index  lesions  can  be  identified  among  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
skin  lesions.  No  more  than  ten  index  lesions  can  be  identified  among  all  sites  other  than  skin.  In  addition,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
index  lesions  should  be  selected  based  on  their  size  (lesions  with  the  longest  diameters),  their  suitability  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for  accurate  repeat  assessment  by  imaging  techniques,  and  how  representative  they  are  of  the  subject’s  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tumor  burden.  At  Screening,  a  sum  of  the  products  of  diameters  for  all  index  lesions  will  be  calculated  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
and  considered  the  baseline  sum  of  the  products  of  diameters.  The  baseline  sum  will  be  used  as  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
reference  point  to  determine  the  objective  tumor  response  of  the  index  lesions.   
Measurable  lesions,  other  than  index  lesions,  and  all  sites  of  non-measurable  disease,  will  be  identified  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
non-index  lesions.  Non-index  lesions  will  be  recorded  on  the  CRF  and  should  be  evaluated  at  the  same  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
assessment  time  points  as  the  index  lesions.  In  subsequent  assessments,  non-index  lesions  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
recorded  as  “stable  or  decreased  disease”,  “absent”,  or  “progression”.   
  
6.4.2.e 
Definition  of  Tumor  Response  per  mWHO  
 
mWHO  tumor  response  will  be  based  on  the  following  criteria:  Index  Lesions   
  
●
Complete  Response  (CR):  Complete  disappearance  of  all  index  lesions.   
●
Partial  Response  (PR):  Decrease,  relative  to  baseline,  of  50%  or  greater  in  the  sum  of  the  products  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
of  the  two  largest  perpendicular  diameters  of  all  index  lesions.   
  
67 / 93 
  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
●
Stable  Disease  (SD):  Does  not  meet  criteria  for  complete  or  partial  response,  in  the  absence  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progressive  disease.   
●
Progressive  Disease  (PD):  At  least  25%  increase  in  the  sum  of  the  products  of  all  index  lesions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(taking  as  reference  the  smallest  sum  recorded  at  or  following  baseline)  and/or  the  appearance  of  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
any  new  lesion(s).   
  
Non-Index  Lesions   
●
Complete  Response  (CR):  Complete  disappearance  of  all  non-index  lesions.   
●
Incomplete  Response  (IR)  /  Stable  Disease  (SD):  No  change  or  any  change  with  persistence  of  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
one  or  more  non-index  lesions.   
●
Progressive  Disease  (PD):  Appearance  of  any  new  lesion(s)  and/or  unequivocal  progression  of  
 
 
 
 
 
 
 
 
 
 
 
 
non-index  lesion(s)  (eg,  an  increase  in  pleural  effusions,  or  other  fluid  collections  defined  as  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
approximate  doubling  of  the  volume  which  was  present  at  baseline  or  nadir,  unless  there  is  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiographic  evidence  of  a  benign  cause  for  the  fluid  collection  or  the  effusion  is  cytologically  
 
 
  
 
 
 
 
 
 
 
 
  
 
negative  for  malignant  cells).   
  
6.4.2.f 
Response  per  Time  Point  
 
OR  is  determined  as  the  combination  of  assessments  of  index  and  non-index  lesions  using  the  following   
criteria  presented  in  Table  13   
  
Table  13: 
Overall  Response  per  mWHO   
  
  
6.4.2.g Best  Overall  Response  (BOR)per  Subject  (Including  all  TimePoints)  
 
BOR  is  the  best  confirmed  response  designation  over  the  study  as  a  whole,  recorded  between  the  date  of  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
first  dose  until  the  last  tumor  assessment  prior  to  subsequent  therapy  (except  for  local  palliative  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiotherapy  for  painful  bone  lesions)  for  the  individual  subject  in  the  study.  The  assessment  of  response  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
at  12  weeks  has  particular  emphasis  due  to  the  mechanism  of  action  of  ipilimumab  inducing  immune  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
responses  as  basis  for  clinical  responses.  For  the  assessment  of  BOR,  all  available  assessments  per  subject  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
are  considered.  CR  or  PR  determinations  included  in  the  BOR  assessment  must  be  confirmed  by  a  second  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
(confirmatory)  evaluation  meeting  the  criteria  for  response  and  performed  no  less  than  4  weeks  after  the  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
criteria  for  response  are  first  met.   
Consistent  with  the  definition  of  BOR  in  this  study,  the  date  of  disease  progression  is  defined  for  each  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
subject  based  on  post-Week  12  time  points,  in  cases  where  a  subject  had  an  OR  of  CR,  PR  or  SD  at  Week  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
12.  BOR  assessment  of  SD  requires  an  OR  of  SD  (or  unconfirmed  PR  or  CR)  at  Week  12,  in  the  absence  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
of  BOR  of  CR,  PR  or  PD.   
  
68 / 93 
  
Index  Lesions   
Non-index  Lesions   
New  Lesions   
Overall  Response   
CR   
CR   
PR   
SD   
PD   
Any 
Any 
CR   
IR/SD   
CR  or  IR/SD   
CR  or  IR/SD   
Any 
PD   
Any 
No   
No   
No   
No   
Yes  or  No   
Yes  or  No   
Yes   
CR   
PR   
PR   
SD   
PD   
PD   
PD   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
The  following  criteria  (Table  14)  summarize  the  combination  of  assessments  of  OR  at  different  time  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
points  throughout  the  study  to  establish  BOR  for  the  individual  subject  with  emphasis  on  the  12  week  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
time  point  due  to  the  mechanism  of  action  of  ipilimumab:   
  
Table  14. 
Assessment  of  Best  Overall  Response   
  
*  Initial  OR  of  PR  or  CR  confirmed  by  a  second  (confirmatory)  evaluation  meeting  the  criteria  for  response  and   
performed  no  less  than  4  weeks  after  the  criteria  for  response  are  first  met.   
**  OR  of  PR  or  CR  not  confirmed  by  a  second  (confirmatory)  evaluation  meeting  the  criteria  for  response  and   
performed  no  less  than  4  weeks  after  the  criteria  for  response  are  first  met.   
  
6.4.2.h Local  Radiotherapy  for  Symptomatic  Bone  Lesions  
 
Local  radiation  treatment  to  the  site  of  bone  metastasis  will  be  permitted  for  palliative  pain  management  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
at  any  time  during  the  study  but  it  is  encouraged  that  the  Investigator  perform  this  local  radiotherapy  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
following  consultation  with  the  Medical  Monitor  and  the  Week  12  following  re-staging  assessments  (ie,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week  16,  confirmatory  assessments).   
  
6.4.2.i Response  Kinetics  and  Immune-related  Endpoints  
 
Ipilimumab  is  expected  to  trigger  immune-mediated  responses,  which  require  activation  of  the  immune  
 
 
 
 
 
 
 
 
 
 
 
 
 
system  prior  to  the  observation  of  clinical  responses.  Such  immune  activation  may  take  weeks  to  months  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
to  become  evident.  Some  subjects  with  advanced  melanoma  may  have  objective  volume  increase  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tumor  lesions  within  12  weeks  following  start  of  ipilimumab  dosing.  These  subjects  may  not  have  had  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sufficient  time  to  develop  the  required  immune  activation  or,  in  some  subjects,  tumor  volume  increases  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
may  represent  infiltration  of  lymphocytes  into  the  original  tumor.  In  conventional  studies,  such  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
volume  increases  during  the  first  12  weeks  of  the  study  would  constitute  PD  and  lead  to  discontinuation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
of  imaging  to  detect  response,  thus  disregarding  the  potential  for  subsequent  immune-mediated  clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
response.  Therefore,  in  this  study,  subjects  with  tumor  volume  increase  detected  prior  to  Week  12  but  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
without  rapid  clinical  deterioration  will  continue  to  be  treated  with  ipilimumab  and  clinically  observed  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with  a  stringent  imaging  schedule  to  allow  detection  of  a  subsequent  tumor  response  until  progression  is  
  
 
 
 
 
 
 
  
 
 
 
 
  
confirmed  at  the  subsequent  timepoint.  Such  assessments  will  be  using  identical  criteria,  considering  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
69 / 93 
  
Overall  Response  At  Time 
Points  Before  Week  12   
Overall  Response   
At   
  
Week  12   
Overall  Response  At  Time 
Points  After  Week  12   
Best  Overall  Response    
For  All  Time  Points   
CR*  or  PR*   
Any 
Any 
CR  or  PR   
  
(at  time  point  before    
Week  12)   
PD,  SD,  or  no  data   
CR*  or  PR*   
Any 
CR  or  PR  (at  12   
weeks)   
PD,  SD,  CR**,  PR**   
  
or  no  data   
SD,  CR**,  PR**   
CR*  or  PR*   
CR  or  PR   
  
(at  time  point  after   
  
Week  12)   
PD,  SD,  PR**,  CR**   
  
or  no  data   
SD,  PR**,  CR**   
PD,  SD,  PR**,  CR**   
  
or  no  data   
SD   
SD,  PR**,  CR**   
  
or  no  data   
PD   
Any 
PD  (at  Week  12)   
PD   
PD   
Any 
PD  (at  time  point   
  
before  Week  12)   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
index  and  non-index  lesions.  Best  overall  response  assessments  will  therefore  include  responses  occurring  
 
 
 
 
 
 
 
 
 
 
 
 
 
at  any  time  before  disease  progression  and  after  early  progression  within  the  first  twelve  weeks  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study.  This  will  improve  the  overall  assessment  of  the  clinical  activity  of  ipilimumab  and  more  likely  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
capture  its  true  potential  to  induce  clinical  responses.   
In  this  study,  disease  progression  using  irRC  as  determined  by  the  investigator  will  serve  to  determine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinuation  from  study  treatment.  New  lesions  will  be  measured  and  incorporated  into  the  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assessment.  Tumor  volume  will  be  treated  as  a  continuous  variable  and  new  lesion  volume  will  be  added  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
to  the  volume  of  existing  index  lesions.  Response  as  well  as  progression  will  require  confirmation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
through  a  subsequent  scan  at  least  4  weeks  apart.   
  
 
 
 
  
70 / 93 
  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
6.4.2.j Definition  of  Tumor  Response  Using  irRC  
 
  
Calculation  of  Immune-Related  Sum  of  Products  of  Diameters  (irSPD) 
The  immune-related  sum  of  products  of  diameters  (irSPD)  incorporates  measurable  new  lesions  that  may  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
have  developed  on-study,  providing  an  assessment  that  includes  both  index  and  new  lesions.  The  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assessment  performed  during  Screening  will  serve  as  the  baseline  for  determination  of  tumor  response  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
using  irRC.   
irSPD  at  Baseline :  The  sum  of  the  product  of  the  diameters  for  all  index  lesions  identified  prior  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
randomization.  At  baseline,  irSPD  and  SPD  are  the  same.   
irSPD  at  Tumor  Assessment  (TA) :  For  every  post-treatment  TA  collected,  per  protocol  or  as  clinically  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
indicated,  the  irSPD  at  TA  will  be  calculated  using  tumor  imaging  scans.  Both  index  lesions  and  any  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
measurable  new  lesions  that  have  developed  on  study  will  be  included.   
irSPD  Nadir :  For  tumors  that  are  assessed  more  than  one  time  after  baseline,  the  lowest  value  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
irSPD  (irSPD  Baseline  or  irSPD  at  TA)  is  used  to  classify  subsequent  TAs  for  each  subject.  Because 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab  treatment  may  result  in  complex  tumor  dynamics  in  which  index  lesions  may  shrink  while  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
new  lesions  appear,  the  irSPD  nadir  may  be  different  from  the  SPD  nadir,  and  may  occur  either  before  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after  the  SPD  nadir.   
At  baseline,  the  irSPD  is  measured  and  recorded.   
At  each  subsequent  assessment  timepoint,  a  separate  assessment  of  timepoint  overall  response  will  be  
 
 
 
 
  
 
 
 
 
 
 
 
 
obtained  for  that  timepoint.  The  sum  of  products  of  perpendicular  diameters  calculated  and  recorded  at  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
each  post-baseline  timepoint  for  immune-related  response  purposes  (irSPD)  include  measurements  of  
 
 
 
 
 
 
 
 
 
 
 
index  lesions  and  also  include  measurable  new  lesions  which  are  not  too  small  to  measure  at  this  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
timepoint.  A  value  of  25  mm2  (5  mm  x  5  mm)  is  imputed  for  each  index  and  previously  measurable  new  
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
lesion  which  is  present  but  too  small  to  measure.   
  
Timepoint  Overall  Response  using  irRC   
The  overall  assessment  of  immune-related  response  reported  at  each  timepoint  will  be  based  on  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
following  criteria:   
●
Immune-related  Complete  Response  (irCR) :  Complete  disappearance  of  all  tumor  lesions  
 
 
 
 
 
 
 
 
 
 
(index  and  non-index  together  with  no  new  measurable/unmeasurable  lesions).   
●
Immune-related  Partial  Response  (irPR):  A  decrease,  relative  to  baseline  of  the  irSPD  (as  
 
 
 
 
 
 
 
 
 
 
 
 
 
defined  above)  of  50%  or  greater  is  considered  an  irPR.   
●
Immune-related  Stable  Disease  (irSD):  irSD  is  defined  as  an  evaluable  response  that  fails  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
meet  criteria  for  immune-related  complete  response  or  immune-related  partial  response,  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
absence  of  immune-related  progressive  disease.   
●
Immune-related  Progressive  Disease  (irPD):  At  least  a  25%  increase  in  the  irSPD  (based  on  
 
 
 
 
 
  
 
 
 
 
 
 
 
irSPD  of  all  index  lesions  and  any  measurable  new  lesions,  as  defined  above)  over  the  nadir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
irSPD,  or  the  occurrence  of  any  new  measurable  lesions  if  the  SPD  nadir  is  “0”.   
  
71 / 93 
  

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
●
Immune-related  Unknown  Response  (irUN):  Tumor  assessments  which  cannot  be  evaluated  
 
 
 
 
 
 
 
 
 
 
(eg,  due  to  image  quality,  inability  to  assess  all  relevant  lesions,  etc)  will  be  reported  as  irUN.   
Immune-related  Response  Criteria  Definitions  are  summarized  in  Table  15.   
  
  
Table  15. 
Immune-related  Response  Criteria  Definitions   
  
  
Note:  Both  immune-related  response  and  progression  require  confirmation  through  a  subsequent   
scan  at  least  4  weeks  apart  from  first  detection.   
  
6.4.2.k Immune-Related  Best  Overall  Response  Using  irRC  (irBOR)   
  
irBOR  is  the  best  confirmed  irRC  overall  response  over  the  study  as  a  whole,  recorded  between  the  date  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
of  first  dose  until  the  last  tumor  assessment  before  subsequent  therapy  (except  for  local  palliative  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiotherapy  for  painful  bone  lesions)  for  the  individual  subject  in  the  study.  For  the  assessment  of  irBOR, 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
all  available  assessments  per  subject  are  considered.   
irCR  or  irPR  determinations  included  in  the  irBOR  assessment  must  be  confirmed  by  a  second  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
(confirmatory)  evaluation  meeting  the  criteria  for  response  and  performed  no  less  than  4  weeks  after  the  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
criteria  for  response  are  first  met.   
  
6.4.3. Exploratory  endpoints:  predictive  biomarkers   
6.4.3.a Background  for  Biomarker  Research  in  Melanoma   
Despite  advances  in  our  knowledge  of  the  disease,  malignant  melanoma  remains  an  unpredictable  entity.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers  are  playing  an  increasing  role  in  the  development  of  new  cancer  treatments.  Predictive  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarkers  can  be  used  to  improve  response  rate,  by  subject  stratification  and  support  treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinuation  decision  in  case  of  severe  adverse  events.  Biomarkers  also  add  to  the  knowledge  on  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mechanism  of  action  of  drugs,  supporting  rationale  for  different  combination  therapies  and  dosing  
 
 
 
 
 
 
 
 
 
 
 
 
 
schedules.   
  
An  area  of  unmet  need  in  melanoma  drug  development  is  the  identification  of  biomarkers  that  can  be  used  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
to  reliably  predict  or  assess  whether  systemic  therapies  would  provide  benefit  to  subjects.  The  revolution  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
in  molecular  biological  techniques,  such  as  DNA  sequencing  and  gene-expression  profiling,  has  
 
 
 
 
 
 
 
 
 
 
 
 
  
72 / 93 
  
Index  Lesions 
Non-inde 
x   
  
Lesions   
New   
Lesions   
%  Change  in  Tumor  Burden 
(including  new  lesions)   
Overall   
irRC   
  
Response   
CR   
CR   
No   
-  100%   
irCR   
CR   
Any 
Any 
>-100%  to  ≤  -50%   
irPR   
>  -50%  to  <  +25%   
irSD   
≥  +25%   
irPD   
PR   
Any 
Any 
>  -100%  to  ≤  -50%   
irPR   
>  -50%  to  <  +25%   
irSD   
≥  +25%   
irPD   
SD   
Any 
Any 
>  -50%  to  <  +25%   
irSD   
≥  +25%   
irPD   
PD   
Any 
Any 
≥  +25%   
irPD   
U   
Any 
Any 
U   
irUN   

GRAY-B  Study  (GEM  1202).  V1.0  (28  Nov  2013)   
  
uncovered  many  potential  protein  targets  and  biomarkers  relevant  to  melanoma  progression.  The  
 
 
 
 
 
 
 
 
 
 
 
 
elucidation  of  biomarkers  in  melanoma,  both  diagnostic  and  prognostic,  is  an  important  area  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigation.   
  
Previous  Ipilimumab  studies  have  explored  a  variety  of  predictive  and  pharmacodynamic  biomarkers  in  
 
 
 
 
  
 
 
 
 
 
 
 
melanoma  subjects  and  resulted  in  the  identification  of  a  number  of  potential  biomarker  candidates  that  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
might  be  used  to  better  understand  the  mechanism  of  action  of  Ipilimumab  and  to  predict  or  early  predict  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
(by  measuring  changes  within  few  weeks  after  the  start  of  the  treatment)  response  to  this  agent.  These  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
include  peripheral  blood  biomarkers  such  as  Absolute  Lymphocyte  Count  (ALC),  activated  and  memory  
 
 
 
 
 
 
 
 
 
 
 
 
 
T  cells,  and  some  serum  biomarkers  such  as  C-reactive  protein  (CRP).  An  apparent  association  was  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
detected  between  low  baseline  serum  levels  of  CRP  and  longer  overall  survival  in  metastatic  melanoma  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects  treated  with  10  mg/kg  ipilimumab  in  CA184007  Phase  2  trial.  Gene  polymorphisms  of  CD86  and  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
CTLA-4  have  been  associated  with  a  number  of  autoimmune  diseases.  Previously,  the  association  of  some  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
of  these  genetic  markers  with  efficacy  or  safety  of  ipilimumab  has  been  explored.  However,  data  from  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
limited  number  of  subjects  from  Phase  2  trials  with  ipilimumab  have  not  yet  resulted  in  the  discovery  of  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
any  genetic  biomarkers  that  might  predict  efficacy  or  immune-mediated  adverse  events  caused  by  this  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
agent.   
The  aim  of  this  optional  study  is  to  determine  whether  a  correlation  between  the  proposed  biomarkers  and  
 
 
 
 
 
   
 
  
 
 
 
 
 
 
disease  behavior  (progression,  overall  survival,  treatment  response)  exist  in  patients  with  melanoma  
 
 
 
 
 
 
 
 
 
 
 
 
metastatic  to  the  brain,  that  have  specifically  consented  for  the  participation  in  this  part  of  the  study .   
The  present  biomarker  plan  proposes  assessment  of  such  biomarkers  to  investigate  their  associations  with  
 
 
 
 
 
 
 
 
  
 
 
 
 
immune-mediated  adverse  events  when  ipilimumab  is  administered  with  radiation  therapy:   
●
To  evaluate  tumor  biomarkers  pathways  by  IHC  and  their  correlation  with  prognosis  as  well  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
their  role  as  predictive  factors  to  treatment  with  ipilimumab+radiotherapy  in  29  patients  
 
 
 
 
 
 
 
 
 
 
 
 
participating  on  GEM  12-02  clinical  trial.   
●
To  evaluate  serum  levels  of  several  cytoquines  (by  means  of  cytoquines  panel)  at  baseline,  and  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
before  each  ipilimumab  administration  (expected  4-5  samples  per  patient,  29  patients).   
●
To  evaluate  Peripheral  Blood  Mononuclear  Cells  (PBMCs),  with  true  counts  for  absolute  
 
 
 
 
 
 
 
 
 
 
 
 
numbers  and  percentage  at  baseline,  and  before  each  ipilimumab  administration  (expected  4-5  
 
 
 
 
 
 
 
 
 
 
 
 
samples  per  patient,  29  patients).   
  
6.4.3.b Biomarker  Measures  
 
●
ALC  will  be  assessed  as  a  part  of  standard  hematology  panel.   
●
CRP  will  be  obtained  as  a  component  of  the  serum  chemistry  lab  test.   
●
Tumor  Samples:  at  least  29  tumor  samples  (biopsies)  will  be  collected  and  histology  and  IHC  will  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
be  carried  out  to  evaluate  a  panel  of  biomarkers  that  includes:  CD3,  CD4,  CD8,  CD31,  PD-1,  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
PD-L1,  CD45RO,  CD68,  NK,  DC,  CD80,  CD86,  ICAM,  VCAM,  HLA-A,B,C,  HLA-DR,  PTEN.   
  
●
Serum  Samples  will  be  evaluated  in  at  least  29  patients  at  4-5  timepoints  (116  refrigerated  serum  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
samples).  For  each  sample,  10  ml  of  serum  will  be  collected  and  a  cytokine  panel  will  be  carried  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
out,  including:   
  
  
73 / 93 
  
Cytokines   
IFN- γ   
TNF- α   
IL-1 β   
IL-2   
IL-4   
IL-6   
IL-7   
IL-8   

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●
Peripheral  Blood  immune  cells  will  be  evaluated  in  at  least  29  patients  at  4-5  timepoints  (116  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
refrigerated  periferal  blood  samples).  For  each  sample,  10  ml  of  heparin  blood  will  be  collected  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for  flow  citometry  to  evaluate  a  panel  of  cells  that  include:   
If  consented  by  the  patient,  the  remaining  biological  materials  (tissue  blocks  or  its  derivatives,  serum  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alliquots  and  frozen  pellets)  will  be  stored  for  future  studies.   
Biological  samples  for  the  these  exploratory  studies  will  be  collected  by   
MARKETING  FARMACÉUTICO  &  INVESTIGACIÓN  CLÍNICA,  S.L.   
Secretari  Coloma,  64-68,  esc.  B,  entlo.  5ª   
08024  Barcelona   
Tel:  +34  93  434  44  12   
Fax:  +34  93  253  11  68   
e-mail:  investigacion@mfar.net   
The  molecular  substudy  coordinator  is  Dr.  Ignacio  Melero  from  CIMA  (Navarra)   
Samples  will  be  analyzed  and  stored  in   
Centro  de  investigación  Médica  Aplicada  (CIMA)  –  Navarra   
La.  Inmunología  terapia  génica   
Avda.  Pío  XII,  55  Lab.  404   
E-31008-Pamplona-España   
An  additional  document  will  be  provided  in  the  Investigator  Site  File  with  detailed  instructions  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biological  sample  collection  and  shipment.   
  
74 / 93 
  
IL-10   
IL-12   
IL-15   
IL-17   
Adhesion  molecules   
sICAM-1   
sVCAM-1   
sCD25   
  
T  cells   
CD3   
CD4   
CD8   
CD56   
CD45RA   
CD45RO   
CD62L   
LFA-1 
 (activated  
 
 
conformation)   
NK  cells   
NKp46   
CD16   
CD56   
  
T  reg   
CD4   
CD25   
FoxP3   
  
MDSC   
CD14   
CD15   
CD33   
HLA-DR   
DC   
BDCA-1   
BDCA-2   
BDCA-3   
  
T  cell  activation  (with  PMA  +  ionomycin)   
CD69   
CD25   
IFN-   
IL-4   
IL-17   
LFA-1(active   
conformation)   
  
  

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6.4.3.c. Blood/Lab  Biomarkers  timepoints  
 
Except  for  ALC  and  RCP,  which  will  be  determined  with  every  routine  blood  tests  as  per  section  6.4.1.e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  Table  12,  the  other  biomarkers  will  be  sampled  at  baseline  (i.e.  up  to  28  days  prior  to  C1D1),  at  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1D21,  C2D21,  C3D21  (+/-  3  days),and  at  the  EOT  visit.   
  
  
6.4.3.d Archival  Tumor  Tissue  
 
When  available,  paraffin-embedded  tumor  tissue  will  be  submitted  for  each  subject  for  immunoscoring.  
 
 
 
 
 
 
 
 
 
 
 
 
 
The  tumor  tissue  does  not  have  to  be  submitted  prior  to  the  start  of  treatment  and  is  not  required  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eligibility.  Separate  instructions  for  submission  of  archival  tumor  samples  will  be  provided.   
  
6.4.4. D IFUSSION -W EIGHTED  MRI  (DW-MRI). 
  
70
DW  Imaging  (DWI)  explores  the  random  motion  of  water  molecules  in  the  body.  Water  molecules  held  in  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
a  container  outside  the  body  are  in  constant  random  brownian  motion.  This  uninhibited  motion  of  water  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
molecules  is  free  diffusion.  By  contrast,  the  movement  of  water  molecules  in  biologic  tissues  is  restricted  
  
 
 
 
 
 
 
 
 
  
 
  
 
because  their  motion  is  modified  and  limited  by  interactions  with  cell  membranes  and  macromolecules.   
In  biologic  tissue,  the  DWI  signal  is  derived  from  the  motion  of  water  molecules  in  the  extracellular 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
space,  the  intracellular  space,  and  the  intravascular  space.  Not  surprisingly,  given  a  unit  time,  water  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
molecules  in  the  intravascular  space  will  have  a  greater  diffusion  distance  because  of  blood  flow  than  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
those  in  the  extracellular  and  intracellular  spaces.  Clearly,  the  contribution  of  intravascular  water  diffusion  
  
 
 
 
 
 
 
 
 
 
 
 
 
to  the  measured  DWI  signal  can  vary  among  tissues.  In  tumors  showing  increased  vascularity,  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
contribution  of  intravascular  water  diffusion  to  the  MR  signal  may  account  for  a  significant  proportion.   
The  degree  of  restriction  to  water  diffusion  in  biologic  tissue  is  inversely  correlated  to  the  tissue  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cellularity  and  the  integrity  of  cell  membranes.  The  motion  of  water  molecules  is  more  restricted  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tissues  with  a  high  cellular  density  associated  with  numerous  intact  cell  membranes  (e.g.,  tumor  tissue).  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
The  lipophilic  cell  membranes  act  as  barriers  to  motion  of  water  molecules  in  both  the  extracellular  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
intracellular  spaces.  By  contrast,  in  areas  of  low  cellularity  or  where  the  cellular  membrane  has  been  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
breached,  the  motion  of  water  molecules  is  less  restricted.  A  less  cellular  environment  provides  a  larger  
 
 
 
 
 
  
 
  
 
 
 
  
 
extracellular  space  for  diffusion  of  water  molecules,  and  these  molecules  may  also  freely  transgress  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
defective  cell  membranes  to  move  from  the  extracellular  into  the  intracellular  compartment.   
DWI  yields  qualitative  and  quantitative  information  that  provides  unique  insight  into  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
characteristics,  and  there  is  growing  evidence  for  its  use  in  the  assessment  of  the  patient  with  cancer.   
Tumors  are  frequently  more  cellular  than  the  tissue  from  which  they  originate  and  thus  appear  to  be  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
relatively  high  signal  intensity  (restricted  diffusion)  at  DWI.  Tumors  differ  in  their  cellularity,  and  this  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
difference  may  reflect  their  histologic  composition  and  biologic  aggressiveness.  The  use  of  DWI  for 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tumor  characterization  was  first  shown  in  brain  tumors.   
70   Provenzale  JM,  Mukundan  S,P.  Barboriak  DP.  Diffusion-weighted  and  Perfusion  MR  Imaging  for  
 
 
 
 
 
 
 
 
 
 
 
 
Brain  Tumor  Characterization  and  Assessment  of  Treatment  Response.  Radiology  2006;  239:  
 
 
 
 
 
 
 
 
 
 
 
632-649   
  
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Perhaps  one  of  the  most  exciting  potential  applications  of  DW  MRI  imaging  has  been  in  measurement  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
the  response  of  solid  tumors  to  therapy.  The  results  of  several  studies,  usually  of  animal  models,  have  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
suggested  that  substantial  changes  in  water  diffusion  evolving  in  the  first  few  weeks  after  initiation  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  may  be  helpful  in  predicting  response  to  therapy.  If  this  application  is  validated  in  human  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
studies,  it  could  lead  to  important  changes  in  clinical  practice  by  allowing  much  earlier  changes  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy.   
Studies  of  patients  with  brain  tumors  have  shown  that  increases  in  water  diffusion  generally  indicate  a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
positive  response  to  therapy.  It  appears  likely,  at  least  for  some  antineoplastic  agents,  that  measurement  of  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
tumoral  ADC  shortly  after  the  start  of  therapy  might  be  an  early  marker  of  good  response  to  therapy.   
DW-MRI  will  be  optional  and  will  be  done  in  two  timepoints:  at  baseline  (up  to  2  weeks  prior  to  therapy)  
 
 
 
 
 
 
 
  
 
  
 
   
 
  
 
and  1  month  after  the  end  of  WBRT.   
  
  
7. 
IN VESTIGATIONAL  P RODUCT :  IPILIMUMAB   
The  investigational  product  is  defined  as  a  pharmaceutical  form  of  an  active  ingredient  being  tested  as  a  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
reference  in  the  study,  whether  blinded  or  unblinded.  In  this  study,  the  investigational  product  is  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ipilimumab.   
Other  medications  used  in  the  study  as  support  or  escape  medication  for  preventative,  diagnostic,  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapeutic  reasons,  as  components  of  the  standard  of  care  for  a  given  diagnosis,  are  considered  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
noninvestigational  products.  In  this  protocol,  a  noninvestigational  product  is  dexamethasone  or  equivalent  
 
 
 
 
  
 
  
 
 
 
glucocorticoid.   
7.1. Identification   
Ipilimumab  is  available  in  concentrations  of  5 mg/mL  (50 mg/10 mL  and  200 mg/40 mL).  The  sterile  
 
 
 
 
 
 
 
 
 
 
 
 
solution  in  the  vial  is  clear  and  colorless.  Ipilimumab  is  administered  via  intravenous  infusion  only.   
7.2. Packaging  and  Labeling   
The  Sponsor  will  provide  ipilimumab  at  no  cost  for  this  study.  Ipilimumab  will  be  provided  in  open-label  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
containers.  The  labels  will  contain  the  protocol  prefix,  batch  number,  content,  storage  conditions,  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dispensing  instructions  along  with  the  Investigational  New  Drug  (IND)  caution  statement.   
7.3. Storage,  Handling,  and  Dispensing   
7.3.1. Storage   
Ipilimumab  must  be  stored  in  a  secure  area  according  to  local  regulations.  The  investigator  must  ensure  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
that  it  is  stored  at  a  temperature  ≥  2°C  and  ≤ 8°C.   
7.3.2. Handling  and  Disposal   
As  with  all  injectable  drugs,  care  should  be  taken  when  handling  and  preparing  ipilimumab.  Whenever  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
possible,  ipilimumab  should  be  prepared  in  a  laminar  flow  hood  or  safety  cabinet  using  standard  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
precautions  for  the  safe  handling  of  intravenous  agents  applying  aseptic  technique.  Latex  gloves  are  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
required.  If  ipilimumab  concentrate  or  solution  comes  in  contact  with  skin  or  mucosa,  immediately  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
thoroughly  wash  with  soap  and  water.  After  final  drug  reconciliation,  unused  ipilimumab  solution  should  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  disposed  at  the  site  following  procedures  for  the  disposal  of  anticancer  drugs.   
  
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7.3.3. Dispensing   
It  is  the  responsibility  of  the  investigator  to  ensure  that  ipilimumab  is  only  dispensed  to  study  subjects.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
The  ipilimumab  must  be  dispensed  only  from  official  study  sites  by  authorized  personnel  according  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
local  regulations.   
7.4. Drug  Ordering  and  Accountability   
7.4.1. Initial  Orders   
Following  submission  and  approval  of  the  required  regulatory  documents,  a  supply  of  ipilimumab  may  be  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
ordered  from  the  site’s  Pharmacy  by  completing  a  Drug  Request  Form.  The  first  request  may  take  place  at  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
site  opening.   
Ipilimumab  vials  (40  mL)  are  shipped  in  quantities  of  five.  The  initial  order  should  be  limited  to  25  vials  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
(5  cartons  of  5  vials  each).  Allow  5  business  days  for  shipment  of  drug  from  the  receipt  of  the  Drug  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Request  Form  by  the  Sponsor  (or  designated  third  party  vendor).  Drug  is  protocol  specific,  but  not  patient  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
specific.  All  product  will  be  shipped  by  courier  in  a  temperature-controlled  container.  Shipments  will  be  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
made  from  a  third  party  vendor.  There  will  be  no  weekend  or  holiday  delivery  of  drugs.   
It  is  possible  that  sites  may  have  more  than  one  ipilimumab  clinical  study  ongoing  at  the  same  time.  It  is  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
imperative  that  only  product  designated  for  this  protocol  number  be  used  for  this  study.   
  
  
7.4.2. Re-Supply   
Drug  re-supply  request  form  should  be  submitted  electronically  or  by  fax  to  a  Sponsor-designated  third  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
party  vendor,  at  least  5  business  days  before  the  expected  delivery  date.  Deliveries  will  be  made  Tuesday  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
through  Friday.   
When  assessing  need  for  resupply,  institutions  should  keep  in  mind  the  number  of  vials  used  per  treatment  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
dose,  and  that  shipments  may  take  5  business  days  from  the  Sponsor  designated  third  party  vendor  receipt  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
of  request.  Drug  is  not  patient  specific.  Be  sure  to  check  with  your  pharmacy  regarding  existing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigational  stock  to  assure  optimal  use  of  drug  on  hand.   
  
7.5. Ipilimumab  Accountability   
It  is  the  responsibility  of  the  investigator  to  ensure  that  a  current  record  of  ipilimumab  disposition  is  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
maintained  at  each  study  site  where  ipilimumab  is  inventoried  and  disposed.  Records  or  logs  must  comply  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
with  applicable  regulations  and  guidelines,  and  should  include:  Amount  received  and  placed  in  storage  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
area.   
●
Amount  currently  in  storage  area.   
●
Label  ID  number  or  batch  number  and  use  date  or  expiry  date.   
●
Dates  and  initials  of  person  responsible  for  each  ipilimumab  inventory  entry/movement.   
●
Amount  dispensed  to  and  returned  by  each  subject,  including  unique  subject  identifiers.   
●
Amount  transferred  to  another  area/site  for  dispensing  or  storage.   
●
Non-study  disposition  (e.g.,  lost,  wasted,  broken).   
●
Amount  destroyed  at  study  site.   
  
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7.6. Ipilimumab  Destruction   
If  ipilimumab  is  to  be  destroyed  on  site,  it  is  the  investigator’s  responsibility  to  ensure  that  arrangements   
have  been  made  for  disposal  and  that  procedures  for  proper  disposal  have  been  established  according  to   
applicable  regulations,  guidelines,  and  institutional  procedures.  Appropriate  records  of  the  disposal  must   
be  maintained.   Provide  a  certificate  of  destruction  to  the  Sponsor  upon  disposal.   
  
8. 
ADVERSE  EVENT  REPORTING  
 
8.1. Collection  of  Safety  Information  
 
An  Adverse  Event  (AE)  is  defined  as  any  new  untoward  medical  occurrence  or  worsening  of  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
pre-existing  medical  condition  in  a  patient  or  clinical  investigation  subject  administered  an  investigational  
 
 
   
 
 
 
 
 
 
 
 
(medicinal)  product  and  that  does  not  necessarily  have  a  causal  relationship  with  this  treatment.  An  AE  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
can  therefore  be  any  unfavorable  and  unintended  sign  (including  an  abnormal  laboratory  finding,  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
example),  symptom,  or  disease  temporally  associated  with  the  use  of  investigational  product,  whether  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
not  considered  related  to  the  investigational  product.   
Adverse  events  can  be  spontaneously  reported  or  elicited  during  open-ended  questioning,  examination,  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluation  of  a  subject.  (In  order  to  prevent  reporting  bias,  subjects  should  not  be  questioned  regarding  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
the  specific  occurrence  of  one  or  more  AEs.)   
8.1.1. Serious  Adverse  Events  
 
A  serious  AE  (SAE)  is  any  untoward  medical  occurrence  that  at  any  dose:   
  
●
results  in  death   
●
is  life-threatening  (defined  as  an  event  in  which  the  subject  was  at  risk  of  death  at  the  time  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
event;  it  does  not  refer  to  an  event  which  hypothetically  might  have  caused  death  if  it  were  more  
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
severe)   
●
requires  inpatient  hospitalization  or  causes  prolongation  of  existing  hospitalization  (see  NOTE  
 
 
 
 
 
 
 
 
 
 
 
below) 
  
 
 
●
results  in  persistent  or  significant  disability/incapacity   
●
is  a  congenital  anomaly/birth  defect   
  
●
is  an  important  medical  event  (defined  as  a  medical  event(s)  that  may  not  be  immediately  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
life-threatening  or  result  in  death  or  hospitalization  but,  based  upon  appropriate  medical  and  scientific  
 
 
  
 
 
 
 
 
 
 
 
 
 
judgment,  may  jeopardize  the  subject  or  may  require  intervention  [eg,  medical,  surgical]  to  prevent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
one  of  the  other  serious  outcomes  listed  in  the  definition  above.)  Examples  of  such  events  include,  but  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
are  not  limited  to,  intensive  treatment  in  an  emergency  room  or  at  home  for  allergic  bronchospasm;  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
blood  dyscrasias  or  convulsions  that  do  not  result  in  hospitalization.)   
  
●
Suspected  transmission  of  an  infectious  agent  (eg,  any  organism,  virus  or  infectious  particle,  
 
 
 
 
 
 
 
 
 
 
 
 
 
pathogenic  or  non-pathogenic)  via  the  study  drug  is  an  SAE.   
Although  pregnancy,  overdose,  cancer  are  not  always  serious  by  regulatory  definition,  these  events  must  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  handled  as  SAEs.   (See  Section  8.4  for  reporting  pregnancies.)   
  
NOTE :  The  following  hospitalizations  are  not  considered  SAEs:   
●
a  visit  to  the  emergency  room  or  other  hospital  department  lasting  less  than  24  hours  that  does  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
result  in  admission  (unless  considered  an  “important  medical  event”  or  a  life-threatening  event)   
  
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●
elective  surgery  planned  before  signing  consent   
●
admissions  as  per  protocol  for  a  planned  medical/surgical  procedure   
●
routine  health  assessment  requiring  admission  for  baseline/trending  of  health  status  (eg,  routine  
 
 
 
 
 
 
 
 
 
 
 
 
colonoscopy)   
●
medical/surgical  admission  for  purpose  other  than  remedying  ill  health  state  that  was  planned  before  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study  entry.  Appropriate  documentation  is  required  in  these  cases.   
●
Admission  encountered  for  another  life  circumstance  that  carries  no  bearing  on  health  status  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
requires  no  medical/surgical  intervention  (eg,  lack  of  housing,  economic  inadequacy,  caregiver  
 
 
 
 
 
 
 
 
 
 
 
respite,  family  circumstances,  administrative).   
  
8.1.2. Nonserious  Adverse  Events   
A  nonserious  adverse  event  is  an  AE  not  classified  as  serious.   
  
8.2. Assignment  of  Adverse  Event  Intensity  and  Relationship  to   
Investigational  Product  
 
All  adverse  events,  including  those  that  are  serious,  will  be  graded  according  to  the  National  Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institute  Common  Terminology  Criteria  for  Adverse  Events  (NCI CTCAE),  Version 4.0.   
The  following  categories  and  definitions  of  causal  relationship  to  investigational  product  as  determined  
 
 
 
 
 
 
 
 
 
 
 
 
 
by  a  physician  should  be  used:   
●
Related:  There  is  a  reasonable  causal  relationship  to  investigational  product  administration  and  the  
 
 
  
 
 
 
 
 
 
 
 
 
adverse  event.   
●
Not  Related:  There  is  not  a  reasonable  causal  relationship  to  investigational  product  administration  
 
 
 
 
  
 
 
 
 
 
 
 
and  the  adverse  event.   
The  expression  “reasonable  causal  relationship”  is  meant  to  convey  in  general  that  there  are  facts  (eg,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evidence  such  as  de-challenge/re-challenge)  or  other  arguments  to  suggest  a  positive  causal  relationship.   
  
8.3. Collection  and  Reporting  
 
Adverse  events  can  be  spontaneously  reported  or  elicited  during  open-ended  questioning,  examination,  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluation  of  a  subject.  (In  order  to  prevent  reporting  bias,  subjects  should  not  be  questioned  regarding  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
the  specific  occurrence  of  one  or  more  AEs.)   
If  known,  the  diagnosis  of  the  underlying  illness  or  disorder  should  be  recorded,  rather  than  its  individual  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms.  The  following  information  should  be  captured  for  all  AEs:  onset,  duration,  intensity,  
 
 
 
 
 
 
 
 
 
 
 
 
 
seriousness,  relationship  to  investigational  product,  action  taken,  and  treatment  required.  If  treatment  for  
 
 
 
 
 
 
 
 
 
  
 
 
the  AE  was  administered,  it  should  be  recorded  in  the  medical  record.   
The  investigator  shall  supply  the  sponsor  and  Ethics  Committee  with  any  additional  requested  
 
 
 
 
 
 
 
 
 
 
 
 
 
information,  notably  for  reported  deaths  of  subjects.   
8.3.1. Serious  Adverse  Events  
 
The  following  information  is  provided  to  investigators  for  either  inclusion  in  protocol  documents  or  other  
 
 
  
  
 
 
 
  
 
 
 
 
related  study  documents.  It  will  also  be  contained  in  the  Study  Agreement:   
Following  the  subject’s  written  consent  to  participate  in  the  study,  all  SAEs  must  be  collected,  including  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
those  thought  to  be  associated  with  protocol-specified  procedures.  All  SAEs  must  be  collected  that  occur  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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within  90  days  of  discontinuation  of  dosing  of  the  investigational  product.  If  applicable,  SAEs  must  be  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
collected  that  relate  to  any  later  protocol-specified  procedure  (eg,  a  follow-up  skin  biopsy).  The  
 
 
 
 
 
 
 
 
  
 
 
 
 
investigator  should  notify  the  Sponsor  of  any  SAE  occurring  after  this  time  period  that  is  believed  to  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
related  to  the  investigational  product  or  protocol-specified  procedure.   
All  SAEs  whether  related  or  unrelated  to  the  ipilimumab,  must  be  immediately  reported  to  the  Sponsor  or  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
delegated  CRO  (by  the  investigator  or  designee)  within  24  hours  of  becoming  aware  of  the  event.  If  only  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
limited  information  is  initially  available,  follow-up  reports  are  required.  The  original  SAE  form  must  be  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
kept  on  file  at  the  study  site.   
All  SAEs  should  be  immediately  reported  to  CRO:   
MARKETING  FARMACÉUTICO  &  INVESTIGACIÓN  CLÍNICA,  S.L.   
Secretari  Coloma,  64-68,  esc.  B,  entlo.  5ª   
08024  Barcelona   
Tel:  +34  93  434  44  12   
Fax:  +34  93  253  11  68   
e-mail:  investigacion@mfar.net   
Suspected  Unexpected  Serious  Adverse  Reactions  (SUSAR)  will  be  reported  by  the  study  Sponsor  to  the   
relevant  Authorities  and  into  the  Eudravigilance  database.  The  Sponsor  will  be  provided  with  a   
simultaneous  copy  of  all  adverse  events  filed  with  the  Authorities.   
  
Serious  adverse  events,  whether  related  or  unrelated  to  investigational  product,  must  be  recorded  on  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE  page  and  reported  expeditiously  to  the  Sponsor  (or  designee)  to  comply  with  regulatory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
requirements.  An  SAE  report  should  be  completed  for  any  event  where  doubt  exists  regarding  its  status  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
seriousness.   
  
All  SAEs  must  be  immediately  reported  by  confirmed  facsimile  transmission  (fax)  and  mailing  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
completed  SAE  page.  In  some  instances  where  a  facsimile  machine  is  not  available,  overnight  express  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
mail  may  be  used.  If  only  limited  information  is  initially  available,  follow-up  reports  are  required.  (Note:  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
Follow-up  SAE  reports  should  include  the  same  investigator  term(s)  initially  reported.)  In  selected  
 
 
 
 
 
 
 
 
 
 
 
 
 
circumstances,  the  protocol  may  specify  conditions  that  require  additional  telephone  reporting.   
  
If  the  investigator  believes  that  an  SAE  is  not  related  to  the  investigational  product,  but  is  potentially  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
related  to  the  conditions  of  the  study  (such  as  withdrawal  of  previous  therapy,  or  a  complication  of  a  study  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
procedure),  the  relationship  should  be  specified  in  the  narrative  section  of  the  SAE  page.   
If  an  ongoing  SAE  changes  in  its  intensity  or  relationship  to  the  investigational  product,  a  follow-up  SAE  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
report  should  be  sent  immediately  to  the  sponsor.  As  follow-up  information  becomes  available  it  should  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
be  sent  immediately  using  the  same  procedure  used  for  transmitting  the  initial  SAE  report.  All  SAEs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should  be  followed  to  resolution  or  stabilization.   
8.3.2. Handling  of  Expedited  Safety  Reports  
 
In  accordance  with  local  regulations,  the  Sponsor  will  notify  investigators  of  all  SAEs  that  are  suspected  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(related  to  the  investigational  product)  and  unexpected  (ie,  not  previously  described  in  theSMPC).  In  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
European  Union  (EU),  an  event  meeting  these  criteria  is  termed  a  Suspected,  Unexpected  Serious  
 
 
 
 
 
 
 
 
 
  
 
 
 
Adverse  Reaction  (SUSAR).  investigator  notification  of  these  events  will  be  in  the  form  of  an  expedited  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
safety  report  (ESR).   
  
  
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Other  important  findings  which  may  be  reported  by  the  sponsor  as  an  ESR  include:  increased  frequency  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of  a  clinically  significant  expected  SAE,  a  SAE  considered  associated  with  study  procedures  that  could  
  
 
 
 
  
 
 
 
 
 
 
 
 
modify  the  conduct  of  the  study,  lack  of  efficacy  that  poses  significant  hazard  to  study  subjects,  clinically  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
significant  safety  finding  from  a  nonclinical  (eg,  animal)  study,  important  safety  recommendations  from  a  
 
 
 
  
 
 
 
 
 
 
 
  
study  data  monitoring  committee,  or  sponsor  decision  to  end  or  temporarily  halt  a  clinical  study  for  safety  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
reasons.   
Upon  receiving  an  ESR  from  the  Sponsor,  the  investigator  must  review  and  retain  the  ESR  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
theSMPC.  Where  required  by  local  regulations  or  when  there  is  a  central  IRB/IEC  for  the  study,  the  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
sponsor  will  submit  the  ESR  to  the  appropriate  IRB/IEC.  The  investigator  and  IRB/IEC  will  determine  if  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
the  informed  consent  requires  revision.  The  investigator  should  also  comply  with  the  IRB/IEC  procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for  reporting  any  other  safety  information.   
  
In  addition,  suspected  serious  adverse  reactions  (whether  expected  or  unexpected)  shall  be  reported  by  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor  to  the  relevant  competent  health  authorities  in  all  concerned  countries  according  to  local  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
regulations  (either  as  expedited  and/or  in  aggregate  reports ).   
8.3.3. Nonserious  Adverse  Events  
 
The  collection  of  nonserious  AE  information  should  begin  at  initiation  of  investigational  product.  In  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
general,  the  collection  period  will  last  for  30  days  after  the  last  treatment  administration.  The  exceptions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
are  the  immune-related  AEs  that  occur  within  90  days  of  discontinuation  of  dosing  of  the  investigational  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
product,  which  should  also  be  collected.   
If  an  ongoing  nonserious  AE  worsens  in  its  intensity,  or  if  its  relationship  to  the  investigational  product  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
changes,  a  new  nonserious  AE  entry  for  the  event  should  be  completed.   
  
Nonserious  AEs  should  be  followed  to  resolution  or  stabilization,  or  reported  as  SAEs  if  they  become  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
serious.  Follow-up  is  also  required  for  nonserious  AEs  that  cause  interruption  or  discontinuation  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigational  product,  or  those  that  are  present  at  the  end  of  study  participation.  Subjects  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
nonserious  AEs  at  study  completion  should  receive  post-treatment  follow-up  as  appropriate.   
All  identified  nonserious  AEs  must  be  recorded  and  described  in  the  medical  record.   
8.3.4. Pregnancy   
Sexually  active  WOCBP  must  use  an  effective  method  of  birth  control  during  the  course  of  the  study,  in  a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
manner  such  that  risk  of  failure  is  minimized.  Before  enrolling  WOCBP  in  this  clinical  study,  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator  must  review  the  guideline  about  study  participation  for  WOCBP  which  can  be  found  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP  Manual  for  Investigators.  The  topics  include  the  following:   
●
General  Information   
●
Informed  Consent  Form   
●
Pregnancy  Prevention  Information  Sheet   
●
Drug  Interactions  with  Hormonal  Contraceptives   
●
Contraceptives  in  Current  Use   
●
Guidelines  for  the  Follow-up  of  a  Reported  Pregnancy.   
Before  study  enrollment,  WOCBP  must  be  advised  of  the  importance  of  avoiding  pregnancy  during  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
participation  and  the  potential  risk  factors  for  an  unintentional  pregnancy.  The  subject  must  sign  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
informed  consent  form  documenting  this  discussion.   
  
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All  WOCBP  MUST  have  a  negative  pregnancy  test  within  72 hours  before  receiving  ipilimumab.  The  
 
 
 
  
 
 
 
 
 
 
 
 
 
minimum  sensitivity  of  the  pregnancy  test  must  be  25  IU/L  or  equivalent  units  of  HCG.  If  the  pregnancy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
test  is  positive,  the  subject  must  not  receive  ipilimumab  and  must  not  be  enrolled  in  the  study.   
In  addition,  all  WOCBP  should  be  instructed  to  contact  the  investigator  immediately  if  they  suspect  they  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
might  be  pregnant  (e.g.,  missed  or  late  menstrual  period)  at  any  time  during  study  participation.   
If,  following  initiation  of  the  investigational  product,  it  is  subsequently  discovered  that  a  study  subject  is  
 
 
 
 
 
 
   
 
 
  
 
  
pregnant  or  may  have  been  pregnant  at  the  time  of  investigational  product  exposure,  including  during  at  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
least  6  half-lives  after  product  administration,  the  investigational  product  will  be  permanently  
 
 
 
 
 
 
 
 
 
 
 
 
discontinued  in  an  appropriate  manner  (eg,  dose  tapering  if  necessary  for  subject  safety).  The  investigator 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
must  immediately  notify  the  Sponsor  of  this  event  and  record  the  pregnancy  on  the  Pregnancy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surveillance  Form  (not  an  SAE  form).  Initial  information  on  a  pregnancy  must  be  reported  immediately  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
to  the  Sponsor,  and  the  outcome  information  provided  once  the  outcome  is  known.  Completed  Pregnancy  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Surveillance  Forms  must  be  forwarded  to  the  Sponsor  according  to  SAE  reporting  procedures.   
Any  pregnancy  that  occurs  in  a  female  partner  of  a  male  study  participant  should  be  reported  to  the  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
sponsor.  Information  on  this  pregnancy  will  be  collected  on  the  Pregnancy  Surveillance  Form.   
Protocol-required  procedures  for  study  discontinuation  and  follow-up  must  be  performed  on  the  subject  
 
 
 
 
 
 
 
 
 
 
 
 
 
unless  contraindicated  by  pregnancy  (e.g.,  x-ray  studies).  Other  appropriate  pregnancy  follow-up  
 
 
 
 
 
 
 
 
 
 
 
procedures  should  be  considered  if  indicated.  In  addition,  the  investigator  must  report  to  the  Sponsor,  and  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
follow-up  on  information  regarding  the  course  of  the  pregnancy,  including  perinatal  and  neonatal  
 
 
 
 
 
 
 
 
 
 
 
 
 
outcome.  Infants  should  be  followed  for  a  minimum  of  8 weeks.   
8.3.5. Other  Safety  Considerations   
Any  significant  worsening  noted  during  interim  or  final  physical  examinations,  electrocardiograms,  
 
 
 
 
 
 
 
 
 
 
 
x-rays,  and  any  other  potential  safety  assessments,  whether  or  not  these  procedures  are  required  by  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
protocol,  should  also  be  recorded  in  the  medical  record.   
  
9. 
S TATISTICAL  M ETHODOLOGY   
9.1. 
Sample  size.  
 
The  primary  endpoint  in  this  study  is  the  1-year  actual  survival  rate.  A  one-stage  Fleming  design  has  been  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
adopted.  Assuming  a  historical  1-year  survival  rate  of  20%  (with  radiation  therapy  +  best  supportive  care)  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
for  the  selected  population,  a  sample  size  of  56  evaluable  patients  would  be  needed  to  show  that  the  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
addition  of  ipilimumab  to  radiotherapy  generates  a  1-year  survival  rate  of  35%,  reaching  80%  power  at  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
the  0.05  significance  level.   
  
A  total  of  56  evaluable  patients  would  need  to  be  included.  In  case  that  at  least  17  out  of  these  56  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluable  patients  would  survive  for  at  least  one  year,  the  conclusion  of  the  trial  would  be  that  the  higher  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
1-year  survival  rate  of  35%  is  more  likely  for  the  combination  than  the  historical  20%  survival  rate.  
  
9.2 
Populations  for  Analyses  
 
●
Enrolled  Subjects:  All  subjects  who  signed  and  informed  consent  form  and  were  registered.   
●
Treated  Subjects  (Safety  Population):  Includes  all  subjects  in  the  study  who  receive  at  least  one  dose  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
of  ipilimumab.  Unless  otherwise  indicated,  analyses  of  drug  exposure  and  safety  will  be  performed  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
on  this  population  as  treated.   
  
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●
Evaluable  Subjects:  Includes  all  subjects  who  received  at  least  1  dose  of  ipilimumab  and  the  full  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
WBRT  therapy.   
●
Biomarker  Subjects:  Includes  all  treated  subjects  with  at  least  baseline  biomarker  studies.   
9.3 
Endpoint  Definitions  
 
9.3.1 
Primary  Endpoint  
 
Actuar  survival  rate  at  1  year  since  the  first  dose.  Overall  survival  status  will  be  ascertained,  at  a  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
minimum,  every  12  weeks  from  first  ipilimumab  dose.   
9.3.1.1 
Overall  Survival  (OS)  
 
OS  is  defined  for  each  subject  as  the  time  between  the  date  of  the  first  dose  of  ipilimumab  and  death.  If  a  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
subject  has  not  died,  the  subject  will  be  censored  at  the  time  of  last  contact  (last  known  alive  date).   
9.3.2 
Secondary  and  Exploratory  Endpoints  
 
The  secondary  endpoints  will  be  based  upon  tumor  assessments  which  are  performed  as  described  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
section  6.2.  until  progression  by  irRC,  intolerable  toxicity,  or  withdrawal  of  consent.  Response  based  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
endpoints  will  be  evaluated  based  on  mWHO  criteria  for  secondary  endpoints  and  irRC  for  exploratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
endpoints  (see  Section  6.2  for  definitions).   
9.3.2.1 
Progression  Free  Survival  (PFS)  
 
PFS  is  defined  for  each  subject  as  the  time  between  the  date  of  the  first  dose  of  ipilimumab  and  the  date  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of  progression  or  death,  whichever  occurs  first.  A  subject  who  dies  without  reported  prior  progression  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will  be  considered  to  have  progressed  on  the  date  of  death.  For  a  subject  who  undergoes  tumor  resection  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
on  study,  PFS  will  be  censored  on  the  date  of  the  last  tumor  assessment  prior  to  resection.  For  those  who  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
remain  alive  and  have  not  progressed,  PFS  will  be  censored  on  the  date  of  last  tumor  assessment.  For  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects  who  have  PD  prior  to  Week  12  and  a  subsequent  assessment  of  SD,  PR  or  CR,  the  date  of  PD  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
following  response  (where  available)  will  be  used  in  the  analysis  of  PFS;  otherwise  these  subjects  will  be  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
censored  on  the  date  of  their  last  tumor  assessment.   
9.3.2.2 
Best  Overall  Response  Rate  (BORR)  
 
BORR  is  defined  by  population  subset  as  the  total  number  of  treated  subjects  in  the  subset  whose  BOR  is  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
CR  or  PR,  divided  by  the  total  number  of  treated  subjects  in  the  subset.   
9.3.2.3 
Disease  Control  Rate  (DCR)  
 
DCR  is  as  the  total  number  of  treated  subjects  in  each  population  subset  with  BOR  of  CR,  PR  or  SD,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
divided  by  the  total  number  of  treated  subjects  in  the  subset.   
9.3.2.4 
Duration  of  Response  
 
A  subject’s  duration  of  response  is  defined  as  the  time  between  the  date  measurement  criteria  are  first  met  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
for  overall  response  of  PR  or  CR  (whichever  status  is  recorded  first,  and  if  subsequently  confirmed)  and  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
the  date  of  disease  progression  or  death,  whichever  occurs  first.  For  subjects  who  undergo  tumor  resection  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
on  study,  duration  of  response  will  be  censored  on  the  date  of  last  tumor  assessment  prior  to  resection.  For  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
those  subjects  who  remain  alive  and  have  not  progressed,  duration  of  response  will  be  censored  on  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
date  of  last  tumor  assessment.   
  
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9.3.2.5 
Duration  of  Stable  Disease  
 
Duration  of  stable  disease  is  defined  for  subjects  whose  BOR  is  SD  as  the  time  between  when  SD  is  first  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
docuemtned  and  the  date  of  PD  or  death  (whichever  occurs  first).  For  a  subject  who  undergoes  tumor  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
resection  following  Week  12  but  prior  to  disease  progression,  duration  of  stable  disease  will  be  censored  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
on  the  date  of  the  last  evaluable  tumor  assessment  prior  to  resection.  For  subjects  who  have  BOR  of  SD  at  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Week  12,  the  date  of  PD  following  thereafter  (where  available)  will  be  used  in  the  analysis  of  duration  of  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
stable  disease.  For  subjects  with  BOR  of  SD  who  have  not  subsequently  progressed  and  who  remain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alive,  duration  of  stable  disease  will  be  censored  on  the  date  of  last  evaluable  tumor  assessment.   
9.4 
Analyses  
 
9.4.1 
Demographics  and  Baseline  Characteristics  
 
Demographic  and  baseline  laboratory  results  will  be  summarized  by  population  subset  using  descriptive  
 
 
 
 
 
 
 
 
 
 
 
 
 
statistics.   
9.4.2 
Efficacy  Analyses  
 
9.4.2.1 
Methods  for  Time  to  Event  Primary  Endpoint  
 
The  yearly  rate  of  survivors  will  be  the  actual  proportion  of  patients  alive  after  1  year  of  the  first  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
administration  of  ipilimumab.   
9.4.2.2 
Methods  for  Time  to  Event  Secondary  Endpoints  
 
The  overall  survival  and  event-free  survival  probabilities  will  be  estimated  and  plotted  using  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier  product-limit  method.   
Additionally,  1  and  2  year  rates  will  be  also  based  upon  Kaplan-Meier  estimates  along  with  their  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
corresponding  log-log  transformed  95%  confidence  intervals.   
The  progression-free  survival  probabilities  will  also  be  estimated  and  plotted  using  the  Kaplan-Meier  
 
 
 
 
 
 
 
 
 
 
 
 
 
product-limit  method.  Duration  of  response,  duration  of  stable  disease,  and  overall  survival  in  subjects  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with  brain  metastasis  will  also  be  described  using  these  same  Kaplan-Meier  methods.   
A  differential  analysis  will  be  done  with  intracranial  and  extracranial  disease.   
 
 
9.4.2.3 
Methods  for  Proportion  Based  Rates  Secondary  Endpoints  
 
For  BORR  and  DCR,  descriptive  summary  statistics  (e.g.,  total  number  of  patients,  number  and  percent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
responders,  95%  confidence  interval)will  be  used..  An  exact  two-sided  95%  CI  for  these  rates  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
computed.  A  differential  analysis  will  be  done  with  intracranial  and  extracranial  disease.   
  
9.4.3 
Safety  Analyses  
 
Descriptive  statistics  of  safety  will  be  presented  for  all  treated  subjects  using  the  National  Cancer  Institute  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(NCI)  Common  Terminology  Criteria  for  Adverse  Events  (CTCAE)  version  4.0.  All  on-study  AEs,  
 
 
 
 
 
 
 
 
 
 
 
 
 
drug-related  AEs,  immune-related  AEs,  SAEs,  and  drug-related  SAEs  will  be  tabulated  using  worst  grade  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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per  NCI  CTCAE  v4.0  criteria  by  system  organ  class  and  by  preferred  term.  The  listings  by  subject  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
produced  for  all  deaths,  all  SAEs,  and  all  AEs  leading  to  discontinuation  of  study  drug.  On-study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
laboratory  parameters,  including  hematology,  serum  chemistry,  liver  function,  and  renal  function  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
summarized  using  worst  grade  per  NCI  CTCAE  v4.0  criteria.  The  reporting  period  for  safety  data  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from  the  first  dose  of  study  medication  to  90  days  (>  5  half  lives)  after  the  last  dose  is  received.   
Immune-related  Adverse  Events  (irAEs)  
 
Immune-related  adverse  events  (irAEs)  are  AEs  of  unknown  etiology,  which  are  consistent  with  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
immune  phenomenon  and  identified  by  the  investigator  as  study  treatment  related.  The  irAEs  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
defined  using  a  predefined  list  of  MedDRA  highlevel  group  terms,  high-level  terms  and  preferred  terms;  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
changes  may  be  made  to  this  list  with  each  new  version  of  MedDRA.  Six  (6)  subcategories  of  irAEs  will  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  reported:  GI,  liver,  skin,  endocrine,  neurological,  and  other.  Immune-related  AE  summaries  will  also  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  produced  on  diarrhea  as  a  separate  grouped  term.  Analysis  of  irAEs  will  be  based  on  all  treated  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
subjects  who  received  at  least  one  dose  of  study  therapy,  and  the  reporting  period  will  be  from  the  first  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dose  of  after  the  last  dose  is  received.   
Immune-mediated  Adverse  Reactions  (imARs)  
 
This  study  will  also  describe  immune-mediated  adverse  reactions  (imARs)  using  the  same  adjudication  
 
 
 
 
 
 
 
 
 
 
 
 
 
algorithm  and  predefined  list  of  AEs  of  special  interest  (enterocolitis,  hepatitis,  dermatitis,  
 
 
 
 
 
 
 
 
 
 
 
 
endocrinopathies,  neuropathies,  and  other)  used  for  the  USPI.  Specifically,  the  determination  of  imAR  
 
 
 
 
 
 
 
 
 
 
 
 
 
will  take  into  account  available  clinical  evidence  through  ruling  out  non-inflammatory  etiologies  such  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
infection  or  tumor  progression,  and  consideration  of  evidence  of  inflammation  such  as  tumor  biopsies  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
responsiveness  to  steroids,  but  not  the  causality  assessment  of  the  investigator.  imARs  are  likely  to  be   
 
 
 
  
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inflammatory  events  associated  with  ipilimumab  treatment.  Documentation  of  surveillance,  intervention  
 
 
 
 
 
 
 
 
 
 
and  outcomes  are  to  be  documented  in  the  CRFs  for  inclusion  of  the  imAR  assessment.  Analysis  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
imARs  will  be  based  on  all  treated  subjects  who  received  at  least  one  dose  of  ipilimumab.  The  reporting  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
period  will  be  from  the  first  dose  of  study  therapy  to  90  days  after  the  last  dose  is  received.   
9.4.5 
Exploratory   Analyses  
 
Two  types  of  ALC  analyses  will  be  done:  pharmacodynamic  and  predictive.  Both  analyses  will  include  all  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treated  subjects  with  known  date  of  first  dose  of  ipilimumab.  Pharmacodynamic  analyses  will  examine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  patterns  of  change  in  ALC  over  time,  and  how  these  patterns  might  differ  between  treatment  arms.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predictive  analyses  will  examine  potential  relationships  between  ALC  and  measures  of  response  such  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
overall  survival.   
  
The  proposed  biomarker  study  includes  analysis  of  tumor  tissue  at  diagnosis  and  serum/peripheral  blood  
 
 
 
 
 
 
 
 
  
 
 
 
 
at  different  phases  within  the  treatment  schedule.  All  analysed  parameters  will  be  correlated  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression-free  survival  (PFS),  overall  survival  and  histopathological  parameters.   
For  the  statistical  analysis,  it  will  be  used  binary  variables,  reflecting  the  positivity  status  of  the  measures  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
(yes  or  no;  presence/absence).  Association  with  histopathological  parambles.  The  significance  level  will  
 
 
 
 
 
 
 
 
 
 
 
 
be  set  at  5%.  To  study  the  impact  of  the  histological,  immunohistochemical  and  molecular  factors  on  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression-free  survival  (PFS)  and  overall  survival  (OS),  the  Kaplan-Meier  proportional  risk  test  (log  
 
 
 
 
 
 
 
 
 
 
 
 
 
rank)  will  be  used.  Evidence  of  the  relative  risk  for  each  patient  will  be  also  provided  by  means  of  a  Cox  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
proportional  hazards  model  using  stepwise  selection  to  identify  the  independent  predictors  of  poor  
 
 
 
 
 
 
 
 
 
 
 
 
 
outcome.   
For  the  kinetic  profile  of  the  serum/blood  biomarkers,  each  variable  will  be  considered  as  continuous.  A  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
correlation  at  different  points  of  the  treatment  schedule  will  be  considered  and  the  slope  value  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
used  in  order  to  distinguish  those  cases  with  no  change,  negative  or  positive  trend.  The  threshold  will  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
calculated  after  considering  the  behavior  of  the  whole  series.   
  
9.5 
Interim  Analyses  
 
There  will  not  be  a  planned  interim  analysis.  The  DSMC  will  have  access  to  periodic  interim  reports  of  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
safety  to  allow  them  to  conduct  a  risk-to-benefit  assessment.   
  
10. 
ADMINISTRATIVE  SECTION   
10.1. Compliance  with  the  Protocol  and  Protocol  Revisions   
The  study  must  be  conducted  as  described  in  the  final  approved  protocol.  Documentation  of  approval  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
signed  by  the  chairperson  or  designee  of  the  EC/HA  must  be  sent  to  the  Sponsor’s  protocol  manager.   
  
All  revisions  (protocol  amendments,  administrative  letters,  and  changes  to  the  informed  consent)  must  be  
 
 
 
 
 
 
 
  
 
 
 
 
 
submitted  to  the  Sponsor’s  protocol  manager.  The  investigator  should  not  implement  any  deviation  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
change  to  the  protocol  without  prior  review  and  documented  approval/favorable  opinion  from  the  EC/HA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of  an  Amendment,  except  where  necessary  to  eliminate  an  immediate  hazard(s)  to  study  patients.   
  
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10.2. Informed  Consent   
Two  different  PIS  and  CF  have  been  developed  for  this  trial.  One  for  clinical  trial,  that  is  mandatory,  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
another  for  the  biomarker  study,  that  is  optional.   
Investigators  must  ensure  that  subjects,  or,  in  those  situations  where  consent  cannot  be  given  by  subjects,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
their  legally  acceptable  representative,  are  clearly  and  fully  informed  about  the  purpose,  potential  risks,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  other  critical  issues  regarding  clinical  studies  in  which  they  volunteer  to  participate.  Freely  given  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
written  informed  consent  must  be  obtained  from  every  subject  or,  in  those  situations  where  consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cannot  be  given  by  subjects,  their  legally  acceptable  representative,  prior  to  clinical  study  participation,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
including  informed  consent  for  any  screening  procedures  conducted  to  establish  subject  eligibility  for  the  
 
 
 
 
 
 
 
  
 
 
 
 
 
study.   
The  rights,  safety,  and  well-being  of  the  study  subjects  are  the  most  important  considerations  and  should  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prevail  over  interests  of  science  and  society.   
10.3.   
Records  and  Reports   
An  investigator  is  required  to  prepare  and  maintain  adequate  and  accurate  case  histories  designed  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
record  all  observations  and  other  data  pertinent  to  the  investigation  (e.g.  medical  record)  on  each  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
individual  treated  with  Ipilimumab  or  entered  as  a  control  in  the  investigation.  The  investigator  is  required  
 
 
 
 
 
 
  
  
 
 
 
  
 
to  retain,  in  a  confidential  manner,  the  data  pertinent  to  the  study.   
10.4.   
Good  Clinical  Practice   
This  study  will  be  conducted  in  accordance  with  Good  Clinical  Practice  (GCP),  as  defined  by  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
International  Conference  on  Harmonisation  (ICH)  and  in  accordance  with  the  ethical  principles  
 
 
 
 
 
 
 
 
 
 
 
 
underlying  European  Union  Directive  2001/20/EC  and  the  United  States  Code  of  Federal  Regulations,  
 
 
 
 
 
 
 
 
 
 
 
 
 
Title  21,  Part  50  (21CFR50).   
The  study  will  be  conducted  in  compliance  with  the  protocol.  The  protocol  and  any  amendments  and  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subject  informed  consent  will  receive  Institutional  Review  Board/Independent  Ethics  Committee  
 
 
 
 
 
 
 
 
 
 
(IRB/IEC)  approval/favorable  opinion  prior  to  initiation  of  the  study.   
All  potential  serious  breaches  must  be  reported  to  the  Sponsor  immediately.  A  serious  breach  is  a  breach  
 
 
 
 
 
 
 
 
 
 
  
 
   
 
of  the  conditions  and  principles  of  GCP  in  connection  with  the  study  or  the  protocol,  which  is  likely  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
affect,  to  a  significant  degree,  the  safety  or  physical  or  mental  integrity  of  the  subjects  of  the  study  or  the  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
scientific  value  of  the  study.   
Study  personnel  involved  in  conducting  this  study  will  be  qualified  by  education,  training,  and  experience  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
to  perform  their  respective  task(s).  This  study  will  not  use  the  services  of  study  personnel  where  sanctions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
have  been  invoked  or  where  there  has  been  scientific  misconduct  or  fraud  (eg,  loss  of  medical  licensure, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
debarment).   
Systems  with  procedures  that  ensure  the  quality  of  every  aspect  of  the  study  will  be  implemented.   
10.5.   
Institutional  Review  Board/Independent  Ethics  Committee  (IRB/IEC)   
Before  study  initiation,  the  investigator  must  have  written  and  dated  approval/favorable  opinion  from  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB/IEC  for  the  protocol,  consent  form,  subject  recruitment  materials/process  (eg,  advertisements),  and  
 
 
 
 
 
 
 
 
 
 
 
 
any  other  written  information  to  be  provided  to  subjects.  The  investigator  should  also  provide  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB/IEC  with  a  copy  of  the  SMPCor  product  labeling,  information  to  be  provided  to  subjects  and  any  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
updates.   
  
  
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The  investigator  should  provide  the  IRB/IEC  with  reports,  updates  and  other  information  (eg,  expedited  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
safety  reports,  amendments,  and  administrative  letters)  according  to  regulatory  requirements  or  institution  
 
 
 
 
 
 
  
 
 
 
 
procedures   
10.6.   
Records  Retention   
The  investigator  must  retain  Ipilimumab  disposition  records,  source  documents,  and  case  histories  
 
 
 
 
 
 
 
 
 
 
 
 
designed  to  record  all  observations  and  other  data  pertinent  to  the  investigation  (e.g.  medical  record)  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  maximum  period  required  by  applicable  regulations  and  guidelines,  or  Institution  procedures.   
If  the  investigator  withdraws  from  the  study  (e.g.,  relocation,  retirement),  the  records  shall  be  transferred  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to  a  mutually  agreed  upon  designee  (e.g.,  another  investigator,  IRB).  Documentation  of  such  transfer  must  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
be  provided  to  the  Sponsor.   
 
  
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11.  RE FERENCE S   
  
APPENDIX 1
KARNOFSKY  PERFORMANCE  STATUS  SCALE   
  
      
  
The  Karnofsky  score  runs  from  100  to  0,  where  100  is  "perfect"  health  and  0  is  death.   
  
       
  
  
References:   
1.
Yates  JW,  Chalmer  B,  McKegney  FP.  Evaluation  of  patients  with  advanced  cancer  using  the  Karnofsky   
performance  status.  Cancer.  1980  Apr  15;45(8):2220-4.  [Medline]   
  
2.
Schag  CC,  Heinrich  RL,  Ganz  PA.  Karnofsky  performance  status  revisited:  reliability,  validity,  and   
guidelines.  J  Clin  Oncol.  1984  Mar;2(3):187-93.  [Medline]   
  
    
 
 
 
  
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Value Level  of  functional  capacity   
Definition   
100   
Normal,  no  complaints,  no  evidence  of  disease 
Able  to  carry  on  normal  activity  and  to  work;  no  special  care   
needed   
90   
  
Able  to  carry  on  normal  activity,  minor  signs   
or  symptoms  of  disease   
80   
Normal  activity  with  effort,  some  signs  or   
symptoms  of  disease   
70   
Cares  for  self,  unable  to  carry  on  normal   
activity  or  to  do  active  work   
  
Unable  to  work;  able  to  live  at  home  and  care  for  most   
personal  needs;  various  degrees  of  assistance  needed   
60   
Requires  occasional  assistance,  but  is  able  to   
care  for  most  needs   
50   
  
Requires  considerable  assistance  and  frequent   
medical  care   
40   
Disabled,  requires  special  care  and  assistance   
Unable  to  care  for  self;  requires  equivalent  of  institutional  or   
hospital  care;  disease  may  be  progressing  rapidly   
30   
Severely  disabled,  hospitalization  is  indicated   
although  death  is  not  imminent   
20   
Hospitalization  is  necessary,  very  sick,  active   
supportive  treatment  necessary   
10   
Moribund,  fatal  processes  progressing  rapidly 
0   
Dead   

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APPENDIX 2
B ARTHEL  I NDEX  OF  A CTIVITIES  OF  D AILY  L IVING   
Instructions:  Choose  the  scoring  point  for  the  statement  that  most  closely  corresponds  to  the  patient's  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
current  level  of  ability  for  each  of  the  following  10  items.  Record  actual,  not  potential,  functioning.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information  can  be  obtained  from  the  patient's  self-report,  from  a  separate  party  who  is  familiar  with  the  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
patient's  abilities  (such  as  a  relative),  or  from  observation.  Refer  to  the  Guidelines  section  on  the  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
following  page  for  detailed  information  on  scoring  and  interpretation.   
  
Bowels   
  
0  =  incontinent  (or  needs  to  be  given  enemata)   
1  =  occasional  accident  (once/week)   
2  =  continent   
Patient's  Score: 
  
  
  
Bladder   
0  =  incontinent,  or  catheterized  and  unable  to  manage   
1  =  occasional  accident  (max.  once  per  24  hours)   
2  =  continent  (for  over  7  days)   
Patient's  Score: 
  
  
  
Grooming   
  
0  =  needs  help  with  personal  care   
1  =  independent  face/hair/teeth/shaving  (implements  provided)   
Patient's  Score: 
  
  
  
Toilet  use   
  
0  =  dependent   
1  =  needs  some  help,  but  can  do  something  alone   
2  =  independent  (on  and  off,  dressing,  wiping)   
Patient's  Score: 
  
  
  
Feeding   
  
0  =  unable   
1  =  needs  help  cutting,  spreading  butter,  etc.   
2  =  independent  (food  provided  within  reach)   
Patient's  Score: 
  
  
  
  
  
  
  
  
  
  
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Transfer   
  
0  =  unable  –  no  sitting  balance   
1  =  major  help  (one  or  two  people,  physical),  can  sit   
2  =  minor  help  (verbal  or  physical)   
3  =  independent   
Patient's  Score: 
  
  
  
Mobility   
  
0  =  immobile   
1  =  wheelchair  independent,  including  corners,  etc.   
2  =  walks  with  help  of  one  person  (verbal  or  physical)   
3  =  independent  (but  may  use  any  aid,  e.g.,  stick)   
Patient's  Score: 
  
  
  
Dressing   
  
0  =  dependent   
1  =  needs  help,  but  can  do  about  half  unaided 
2  =  independent  (including  buttons,  zips,  laces,  etc.)   
Patient's  Score: 
  
  
  
Stairs   
  
0  =  unable   
1  =  needs  help  (verbal,  physical,  carrying  aid)   
2  =  independent  up  and  down   
Patient's  Score: 
  
  
  
Bathing   
  
0  =  dependent   
1  =  independent  (or  in  shower)   
Patient's  Score: 
  
  
  
Total  Score:   
 
 
 
  
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Scoring:   
  
Sum  the  patient's  scores  for  each  item.  Total  possible  scores  range  from  0  –  20,  with  lower  scores  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
indicating  increased  disability.  If  used  to  measure  improvement  after  rehabilitation,  changes  of  more  
 
 
 
 
 
 
 
 
 
 
 
 
 
than  two  points  in  the  total  score  reflect  a  probable  genuine  change,  and  change  on  one  item  from  fully  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
dependent  to  independent  is  also  likely  to  be  reliable.   
  
Guidelines  for  the  Barthel  Index  of  Activities  of  Daily  Living   
  
General   
●The  Index  should  be  used  as  a  record  of  what  a  patient  does ,  NOT  as  a  record  of  what  a  patient  could  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
do .   
●The  main  aim  is  to  establish  degree  of  independence  from  any  help,  physical  or  verbal,  however  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
minor  and  for  whatever  reason.   
●The  need  for  supervision  renders  the  patient  not  independent.   
●A  patient's  performance  should  be  established  using  the  best  available  evidence.  Asking  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
patient,  friends/relatives,  and  nurses  will  be  the  usual  source,  but  direct  observation  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
common  sense  are  also  important.  However,  direct  testing  is  not  needed.   
●Usually  the  performance  over  the  preceding  24  –  48  hours  is  important,  but  occasionally  longer  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
periods  will  be  relevant.   
●Unconscious  patients  should  score  '0'  throughout,  even  if  not  yet  incontinent.   
●Middle  categories  imply  that  the  patient  supplies  over  50%  of  the  effort.   
●Use  of  aids  to  be  independent  is  allowed.   
  
Bowels  (preceding  week)   
●If  needs  enema  from  nurse,  then  'incontinent.'   
●'Occasional'  =  once  a  week.   
  
Bladder  (preceding  week)   
●'Occasional'  =  less  than  once  a  day.   
●A  catheterized  patient  who  can  completely  manage  the  catheter  alone  is  registered  as  'continent.'   
  
Grooming  (preceding  24  –  48  hours)   
●Refers  to  personal  hygiene:  doing  teeth,  fitting  false  teeth,  doing  hair,  shaving,  washing  face.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Implements  can  be  provided  by  helper.   
  
Toilet  use   
●Should  be  able  to  reach  toilet/commode,  undress  sufficiently,  clean  self,  dress,  and  leave.   
●'With  help'  =  can  wipe  self  and  do  some  other  of  above.   
  
Feeding   
●Able  to  eat  any  normal  food  (not  only  soft  food).  Food  cooked  and  served  by  others,  but  not  cut  up.   
  
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●'Help'  =  food  cut  up,  patient  feeds  self.   
  
Transfer   
●From  bed  to  chair  and  back.   
●'Dependent'  =  NO  sitting  balance  (unable  to  sit);  two  people  to  lift. 
●'Major  help'  =  one  strong/skilled,  or  two  normal  people.  Can  sit  up.   
●'Minor  help'  =  one  person  easily,  OR  needs  any  supervision  for  safety.   
  
Mobility   
●Refers  to  mobility  about  house  or  ward,  indoors.  May  use  aid.  If  in  wheelchair,  must  negotiate  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
corners/doors  unaided.   
●'Help'  =  by  one  untrained  person,  including  supervision/moral  support.   
  
Dressing   
●Should  be  able  to  select  and  put  on  all  clothes,  which  may  be  adapted.   
●'Half'  =  help  with  buttons,  zips,  etc.  ( check! ),  but  can  put  on  some  garments  alone.   
  
Stairs   
●Must  carry  any  walking  aid  used  to  be  independent.   
  
Bathing   
●Usually  the  most  difficult  activity.   
●Must  get  in  and  out  unsupervised,  and  wash  self.   
●Independent  in  shower  =  'independent'  if  unsupervised/unaided.   
  
References:   
  
●
Collin  C,  Wade  DT,  Davies  S,  Horne  V.  The  Barthel  ADL  Index:  a  reliability  study.  Int  Disabil  Stud .  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
1988;10(2):61-63.   
●
Mahoney  FI,  Barthel  DW.  Functional  evaluation:  the  Barthel  Index.  Md  State  Med  J .  1965;14:61-65.   
●
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