Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer. Phase II Randomized, Multicenter, Open Label Trial
Phase: PHASE2
Conditions: Rectal Cancer
Sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo

 
 
 
 
1.
TITLE  PAGE   
  
 
 
ADAPTATION 
 CLINICAL 
 TRIAL 
 PROTOCOL 
 AND 
 STATISTICAL 
 PLAN 
 FOR  
 
 
 
 
 
 
 
 
CLINICALTRIALS.GOV:  
 
Induction 
 treatment 
 with 
 FOLFOX, 
 with 
 or 
 without 
 Aflibercept, 
 followed 
 by  
 
 
 
 
 
 
 
 
 
 
chemo-radiotherapy  in  locally  advanced  high-risk  rectum  adenocarcinoma.  An  open,  phase  II  
 
 
 
 
 
 
 
 
 
  
randomized  trial  (The  RIA  study)  
 
 
 
This  study  was  conducted  in  compliance  with  Good  Clinical  Practices,  including  the  archiving  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
essential  documents.  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Sponsor:  
 
GEMCAD  (Grupo  Español  Multidisciplinar  en  Cáncer  
 
 
 
 
 
 
Digestivo)  
 
 
 
Business  address:  
 
Secretari  Coloma,  64-68,  esc.B,  entlo.  5ª   
  
08024  Barcelona,  Spain   
  
Phone:  +34  93  434  44  12   
  
Fax:  +34  93  253  11  68  
 
e-mail:  secretaria@gemcad.org  
 
Test  Drug:  
 
mFOLFOX6  with  or  without  aflibercept  
 
Indication  Studied:  
 
High  risk  locally  advanced  rectal  carcinoma  
 
Protocol  Number:  
 
GEMCAD-1402  
 
EUDRACT  Number  
 
2014-002063-14  
 
Study  Phase:  
 
II  
 
Study  Initiation  Date:  
 
FPI:  27-Jan-2015   
  
Coordinating  Investigator:  
 
Carlos  Fernández-Martos,  MD   
  
Fundación  Instituto  valenciano  de  Oncología  (Spain)  
 
Phone:  +34  96  1114000  ext.  4042   
  
Fax:  +34  96  1114341   
  
Clinical  Research  Organization:  
 
 
 
 
 
Protocol  version  and  d ate: 
2.0;  April  9th,  2015  
 
 
 
 
 
PIVOTAL  S.L.   
  
c/  Gobelas  19.  La  Florida,  28023   
  
Madrid,  Spain   
  
Phone:  +34  917081250   
  
Fax:  +34  917081301   
  

 
 
 
 
 
 
SIGNATURES  
 
 
 
Sponsor  
 
 
 
This  clinical  study  protocol  numbered  GEMCAD-1402  entitled  Induction  treatment  with  FOLFOX,  
 
 
 
 
 
 
 
 
 
 
 
with  or  without  Aflibercept,  followed  by  chemoradiotherapy  in  locally  advanced  high-risk  
 
 
 
 
 
 
 
 
 
 
 
rectum  adenocarcinoma.  An  open,  phase  II  randomized  trial  (The  RIA  study)  with  EUDRACT  
 
 
 
 
  
 
 
 
 
 
 
 
No.  2014-002063-14  was  subject  to  critical  review  and  has  been  approved  by  the  Sponsor.  
 
 
 
Approved  by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Version  2.0;  April  9th  2015 
 
 
 
 
 
 
__________________  
 
Signature  
 
 
 
  
 
 
 
___________________________________  
 
Name  and  title  of  Sponsor  signatory  
 
On 
 behalf 
 of 
 GEMCAD 
 (Grupo 
 Español  
 
 
 
 
 
 
Multidisciplinar  en  Cáncer  Digestivo)  
 
 
 
______________________  
 
Date  
 

 
 
 
 
 
 
 
 
 
 
2.
SYNOPSIS  
 
 
 
Title  of  study  
 
 
 
Induction 
 treatment 
 with 
 FOLFOX, 
 with 
 or 
 without 
 Aflibercept, 
 followed 
 by  
 
 
 
 
 
 
 
 
 
 
chemo-radiotherapy  in  locally  advanced  high-risk  rectum  adenocarcinoma.  An  open,  phase  II  
 
 
 
 
 
 
 
 
 
  
randomized  trial  (The  RIA  study:  GEMCAD-1402)  
 
 
 
 
 
INVESTIGATOR(S)  AND  STUDY  CENTRE(S):  
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Centres  
 
Investigators  
 
01-IVO  
 
Dr.  Carlos  Fernández-Martos  
 
 
02-H.  Arnau  de  Vilanova  Lleida  
 
Dra.  Antonieta  Salud  Salvia  
 
 
03-C.  Sanit.  Parc  Tauli  
 
Dr.  Carles  Pericay  Pijaume  
 
04-  H.  del  Mar  
 
Dra.  Clara  Montagut  
 
05-  H.  Clinic  i  Prov  Barcelona  
 
Dr.  Joan  Maurel  Santasusana 
06-  H.  Miguel  Servet  
 
Dr.  Vicente  Alonso  Orduña  
 
08-  H.  de  Navarra  
 
Dra.  Ruth  Vera  García  
 
09-  H.  Gral.  U.  Elche  
 
Dr.  Javier  Gallego  Plazas  
 
10-  H.  La  Paz  
 
Dra.  Núria  Rodríguez  Salas  
 
11-H.  Sta.  Creu  i  Sant  Pau  
 
Dra.  Marta  Martín-Richard  
 
 
12-C.I.O.  Clara  Campal  
 
Dr.  Antonio  Cubillo  
 
 
13-H.  Gral.  Alicante  
 
Dr.  Bertomeu  Massuti  
 
14-H.  de  Granollers  
 
Dr.  Miguel  Nogué  
 
15-H.  Sant  Joan  Despí-Moisés  Broggi Dr.  Ferrán  Losa  
 
16-H.  Vall  d’Hebrón  
 
Dr.  Jaume  Capdevila  
 
17-H.  Prov.  Castellón  
 
Dra.  Isabel  Busquier  Hernández  
 
18-.  Althaia  Manresa  
 
Dra.  Elena  Cillán   
  
20-  H.  GTiP  
 
Dra.  Laura  Layos  Romero  
 
21-H.  Univ.  12  de  Octubre  
 
Dra.  Rocío  García  Carbonero  
 
22-H.  Univ.  Marqués  Valdecilla  
 
Dr.  Carlos  López  López  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Introduction  and  study  rationale  
 
 
 
Introduction  
 
 
 
Different  treatment  strategies  may  be  indicated  for  intermediate-risk  (T1-T2N1,  T3N0)  versus  
 
 
 
 
 
 
 
 
 
 
 
moderately  high  (T1-2N2,  T3N1,  T4N0)  or  high-risk  rectal  cancer  patients  (T3N2,  T4N1-2)  based  on  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
differential  survival  rates  and  rates  of  relapse 1 .  
 
Neoadjuvant  delivery  of  systemic  therapy  for  patients  with  rectal  cancer  ensures  that  all  patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
obtain  optimal  systemic  treatment  which  is  feasible,  safe,  has  improved  toxicity  and  provides  tumor  
 
 
 
 
  
 
 
 
 
 
 
 
 
downstaging  2 .  This  fact  can  be  important  in  the  higher  risk  population  (>35%  systemic  failure  at  5  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
years)  group  of  patients.   
  
Current  guidelines  to  treat  T3-4  and/or  N+  rectal  cancer  continue  to  recommend  preoperative  
 
 
 
 
 
 
 
 
 
 
 
 
 
strategy  of  combined  chemo  (fluoropyrimidine  based)  with  radiation 6,7 .  
 
 
 
Aflibercept  
 
 
 
Aflibercept  is  a  monoclonal  antibody  inhibiting  VEGF  and  placental  growth  factors  (PIGF).  Further  
 
  
 
 
 
 
 
 
 
 
 
 
details  on  preclinical,  clinical  safety  and  preliminary  efficacy  are  provided  in  the  Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
 
Brochure  (IB),  which  contains  comprehensive  information  on  aflibercept 17 .  
 
Aflibercept  in  combination  therapy  improves  survival  in  advanced  colorectal  cancer  when  combined 
 
 
 
 
 
 
 
 
 
 
 
 
with  FOLFIRI  in  the  second  line 18 .  However,  an  understanding  of  responsive  tumor  characteristics  is  
 
 
 
 
 
 
 
 
 
 
 
 
  
lacking,  and  it  is  crucial  to  identify  early  biomarkers  that  accurately  predict  patients  responding  to  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
aflibercept.   
  
Aflibercept  is  a  specific  antagonist  that  binds  and  inactivates  circulating  VEGF  (A  and  B)  and  PIGF.  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Aflibercept  was  designed  to  prevent  the  growth  of  primary  and  metastatic  tumors  by  blocking  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
angiogenesis  and  vascular  permeability.  
 
 
 
Rationale  
 
 
 
With  the  background  described  above  aflibercept  is  a  highly  attractive  drug  to  be  tested  in  locally  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
advanced  rectal  cancer  in  a  high-risk  population  as  part  of  an  induction  therapy  strategy.  
 
Several  authors  have  studied  the  relationship  between  the  administration  of  antiangiogenic  drugs  
 
 
 
 
 
 
 
 
 
 
 
 
and  their  effect  on  microvessel  density  (MVD)  and  interstitial  fluid  pressure  (IFP)  obtained  directly  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from  tumor  biopsies  in  the  appropriate  timing,  as  the  goal  standard  to  analyze.  Some  preclinical  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  data  strongly  affirm  this  effect 22–27 .  
 
The  antiangiogenic  treatment  is  effective  by  reducing  microvessel  density  and  interstitial  fluid  
 
 
 
 
 
 
 
 
 
 
 
 
pressure  in  the  vascular  network  of  the  tumor,  leading  to  a  more  feasible  penetration  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
chemotherapy  into  the  tumoral  microenvironment  and  lessening  the  degree  of  hypoxia  inside  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
tumor.  In  these  conditions,  the  tumor  itself  would  reach  the  better  setting  for  receiving  radiotherapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment,  thus  increasing  its  effect  in  a  synergistic  way 28,29 .  
 
Otherwise,  there  are  also  publications  finding  relations  between  parameters  of  functional  imaging  
 
 
 
 
 
 
 
 
 
 
 
 
and  MVD  and  IFP  in  several  tumors  studied  by  functional  MRI 30–36 .  And  although  substantial  efforts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
are  being  made  to  identify  molecular  biomarkers  in  tissue  and  blood  that  predict  response  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aflibercept,  there  are  no  validated  biomarkers  of  response  to  aflibercept,  so  far.  The  candidate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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biomarkers  include  proteins  related  to  VEGF  and  VEGFR  family  members,  angiogenic  factors,  
 
 
 
 
 
 
 
 
 
 
 
 
cytokines  or  any  other  analyses  with  potential  role  in  angiogenesis  and  inflammation,  as  previously  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
suggested 12,37–43 .  
 
We  proposed  to  conduct  a  phase  II  randomized  trial  comparing  induction  treatment  with  FOLFOX  
 
 
 
  
  
 
 
 
 
 
 
 
with  or  without  aflibercept  in  a  high  risk  population  selected  by  MRI,  prior  to  receiving  standard  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
chemoradiation  (capecitabine  combined  with  50.4  Gy  in  28  days)  and  surgery 31 .  Moreover,  since  no  
 
 
 
 
 
  
 
 
 
 
 
 
 
molecular  biomarkers  of  response  to  aflibercept  have  been  validated  in  tissue/blood,  we  proposed  
 
 
 
 
 
 
 
 
 
 
 
 
 
to  study  an  extensive  panel  of  biomarkers  at  multiple  time  points  during  therapy.  
 
 
 
 
 
Objectives  
 
Primary  objective:  To  evaluate  the  efficacy  of  induction  therapy  with  mFOLFOX6  +/-aflibercept  
 
 
 
 
 
 
 
 
 
 
 
 
followed  by  CT/RT  in  terms  of  pathologic  complete  response  (pCR).  
 
Secondary  objectives:  
 
●
To  evaluate  pathological  parameters  of  efficacy:  R0  resection,  tumor  regression  grade  
 
 
 
 
 
 
 
 
 
 
 
(TRG),  and  positive  or  negative  circumferential  radial  margin  (CRM)  rate.  
 
●
To  evaluate  the  relationship  between  MRI  changes  and  pathological  tumor  response.  i.e.  
 
 
 
 
 
 
 
 
 
 
 
 
mrTRG.  
 
●
To  further  characterize  the  safety  and  tolerability  of  mFOLFOX6  +/-  aflibercept  followed  by  
 
 
 
 
 
 
 
 
 
 
 
 
 
chemoradiation.  
 
●
To  determine  the  rate  of  30-day  surgical  complications.  
 
●
To  evaluate  the  3-year  local  recurrence  and  disease  free  survival  (DFS).  
 
●
To  determine  the  levels  of  tumor  biomarkers  expression  at  baseline  and  correlate  them  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
response  to  treatment  with  mFOLFOX6  +  aflibercept.   
  
 
 
Methodology  and  Study  design  
 
This  was  an  open-label,  randomized,  multicenter,  prospective  phase  II  study  to  evaluate  the  efficacy  
 
 
 
 
 
 
 
  
 
 
 
 
 
of  aflibercept  as  part  of  an  induction  therapy  strategy  for  locally  advanced  rectal  carcinoma  in  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
high-risk  population  (>35%  systemic  failure  at  5  years)  selected  by  MRI.  20  centers  participated  in  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
the  study.  The  study  population  consisted  of  adult  patients  with  locally  advanced  high-risk  rectal  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cancer  (histological  type:  adenocarcinoma  of  the  rectum),  considered  by  the  surgeon  as  feasible  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
perform  a  curative  resection.   
  
Once  it  was  that  the  subjects  fulfilled  the  eligibility  criteria  (MRI-defined  high-risk  RC),  and  had  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
signed  the  informed  consent,  a  central  review  was  requested  to  confirm  clinical  stage,  and  then  the  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
patients  were  randomized  to  receive  treatment.  
 
All  patients  enrolled  in  the  study  had  to  receive  one  cycle  of  study  medication  every  14  days,  for  6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
cycles.  After  last  cycle,  patients  received  standard  chemo-radiotherapy  (CT/RT)  (capecitabine  825  
 
 
 
 
 
 
 
 
 
 
 
mg/m 2  twice  daily  combined  with  a  total  of  50.4  Gy  in  28  days)  followed  by  surgery,  provided  they 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
had  not  progressed  (Figure  1).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Figure  1.  Study  scheme  
 
 
 
 
 
Patients  with  PD  during  the  treatment  phase  were  withdrawn  from  the  study  and  received  their  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  according  to  the  investigator’s  judgement.  
 
If  a  patient  withdrew  consent  and  refused  to  receive  more  treatment,  the  patient  had  to  be  followed  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
up  for  DFS.  If  a  patient  withdrew  consent  and  refused  to  continue  in  the  study,  the  follow-up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluations  had  to  be  discontinued.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Table  1.  STUDY  TIMELINES:  
 
 
 
Randomization  
 
Once  it  was  confirmed  that  the  subjects  fulfilled  the  eligibility  criteria  and  had  signed  the  informed   
consent,  they  were  randomized  2:1  to  receive  treatment  with  or  without  aflibercept  according  to  the   
study  schema  depicted  in   
  
 
 
Figure  2.  Treatment  assignment  schema  
 
 
 
 
 
 
 
                                            Randomize  2:1   
  
 
 
 
 
 
 
 
 
 
 
Random  assignment  of  treatment  was  stratified  by  EMVI+/EMVI-  T3  versus  T4  stage,  and  by  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
site.  
 
Randomization  (2:1)  was  centralized  and  done  by  Pivotal,  the  selected  Contract  Research  
 
 
 
 
 
 
 
 
 
 
 
 
Organization  (CRO).  The  list  of  randomization  codes  was  generated  centrally  by  the  CRO  and  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatments  were  assigned  centrally  according  to  the  list  of  randomization  codes.  The  data  control  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
centre  communicated  to  the  investigator  by  fax  or  email  the  randomization  number  and  treatment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
group  to  which  each  patient  had  been  assigned.   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Study  times  
 
Time  
 
Screening  (MRI  central  review)  
 
4  weeks  
 
Study  therapy  (mFOLFOX  +/-  aflibercept)  
 
12  weeks  
  
CT-RT  
 
5  weeks  
 
Second  MRI  (according  to  investigator´s  judgement)   
  
4  weeks  +/-5  days  after   
CT-RT  
 
Surgery  
 
6  +/-2  weeks  
 
End  of  Treatment  
 
4-6  weeks  
 
Follow-up  
 
Up  to  three  years  
 

 
 
 
 
 
 
Main  inclusion  criteria  
 
●
High-risk  rectal  cancer  defined  by  MRI  as  with  inferior  border  of  the  tumor  distal  to  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
peritoneal  reflection  or  <  12  cm  from  the  anal  margin  and  considered  by  the  surgeon  as  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
feasible  to  perform  a  curative  resection  (including  pelvic  exenteration  as  curative  resection).  
 
Presence  of  at  least  1  of  the  following  on  high  resolution,  thin-slice  MRI  (3mm):  
 
Middle  Third  Tumors  
 
-mrT3  
 
a) Extramural  vascular  invasion  (EMVI)  positive  
 
b) Extramural  extension  >  5  mms  into  perirectal  fat  
 
c)
Mesorectal  fascia  (MRF)  threatened  or  involved *  
 
 
 
-mrT4 ***  
 
 
 
Distal  Third  Tumors  ( <  5  cm  from  anal  verge)  
 
-mrT3  tumor  at  or  below  levators  
 
-T4  as  above  
 
N2 **  
 
 
 
*tumor  or  lymph  node  <  1  mm  from  the  mesorectal  fascia  
 
** >  4  lymph  nodes  in  the  mesorectum  showing  morphological  signs  on  MRI  indicating  
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic  disease.  >  4  nodes,  whether  enlarged  or  not,  with  a  rounded,  homogeneous  
 
 
  
 
 
 
 
 
  
 
 
appearance  was  thus  not  sufficient.  
 
***T4a:  tumor  infiltrates  peritoneal  reflection.  T4b:  tumor  infiltrates  adjacent  organs.  
 
 
 
●
Histologically  confirmed  adenocarcinoma  of  the  rectum.  All  other  histological  types  were  
 
 
 
 
 
 
 
 
 
 
 
excluded.  
 
 
 
 
 
Main  exclusion  criteria  
 
●
Prior  treatment  with  aflibercept  
 
 
 
●
History  or  evidence  upon  physical  examination  of  metastasis  
 
 
 
●
Concomitant  protocol  unplanned  antitumor  therapy  (e.g.  chemotherapy,  molecular  targeted  
 
 
 
 
 
 
 
 
 
therapy,  immunotherapy)  
 
 
 
●
Treatment  with  any  other  investigational  medicinal  product  within  28  days  prior  to  study  entry  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Statistical  considerations  
 
 
 
The  primary  objective  of  this  study  was  to  evaluate  the  efficacy  of  induction  therapy  with  mFolfox6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+/-  aflibercept  followed  by  CT/RT  in  terms  of  pathologic  complete  response  (pCR).  The  primary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
endpoint  was  to  analyze  the  number  of  patients  achieving  pCR  after  induction  therapy  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mFolfox6  +/-  aflibercept  followed  by  CT/RT.  
 
 
 
One  hundred  and  sixty-two  evaluable  patients  had  to  be  recruited:  108  patients  mFolfox6  +  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aflibercept  group  and  54  patients  for  mFolfox6.  Assuming  10%  of  drop-outs  a  total  of  180  patients  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
were  recruited  (120  patients  for  mFolfox6  +  Aflibercept  group  and  60  patients  for  mFolfox6).  
 
 
 
The  assumptions  were:  
 
●
2  treatment  arms  with  unequal  2:1  group  allocation  
 
●
0.20,  two-sided,  type-I  error  
 
●
mFolfox6  efficacy:  15%  pCR  rate  
 
●
Aflibercept  +  mFolfox6  efficacy:  30%  pCR  rate  
 
●
80%  power  to  detect  a  15%  treatment  difference  
 
●
2  interim  analyses:  
 
o
At  33%  of  the  sample  size  for  safety,  futility/efficacy  
 
o
At  66%  of  the  sample  size  for  safety,  futility/efficacy  
 
●
One  final  analysis  
 
●
Stopping  rules:  
 
o
Efficacy:  Lan  de  Mets  Alpha  spending  function  (O’Brien-Fleming)  
 
o
Futility:  Lan  de  Mets  Alpha  spending  function  (O’Brien-Fleming),  non-blinding  
 
 
 
Study  was  a  two-arm  parallel  randomized  clinical  trial  with  allocation  ratio  2:1  (mFolfox6  +  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aflibercept:  mFolfox6).  
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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3.
TABLE  OF  CONTENTS  
 
 
 
1. 
TITLE  PAGE 
1  
 
2. 
SYNOPSIS 
4  
 
3. 
TABLE  OF  CONTENTS 
11  
 
4. 
LIST  OF  TABLES 
13  
 
5. 
LIST  OF  FIGURES 
13  
 
6. 
LIST  OF  ABBREVIATIONS 
14  
 
7. 
ETHICS 
17  
 
7.1 
I NDEPENDENT  E THICS  C OMMITTEE  (IEC)  OR  I NSTITUTIONAL  R EVIEW  B OARD  (IRB) 
17  
 
7.2 
E THICAL  C ONDUCT  OF  THE  S TUDY 
17  
 
7.3 
P ATIENT  I NFORMATION  AND  C ONSENT 
17  
 
8. 
INVESTIGATORS  AND  STUDY  ADMINISTRATIVE  STRUCTURE 
17  
 
9. 
INTRODUCTION 
18  
 
10. 
STUDY  OBJECTIVES 
20  
 
10.1 P RIMARY  OBJECTIVE 
20  
 
10.2 S ECONDARY  OBJECTIVES 
20  
 
11. 
INVESTIGATIONAL  PLAN 
21  
 
11.1 
O VERALL  S TUDY  D ESIGN  AND  P LAN :  D ESCRIPTION 
21  
 
11.2 
D ISCUSSION  OF  S TUDY  D ESIGN ,  I NCLUDING  THE  C HOICE  OF  C ONTROL  G ROUPS 
21  
 
11.3 
S TUDY  P OPULATION 
22  
 
11.3.1 
Inclusion  criteria 
22  
 
11.3.2 
Exclusion  criteria 
23  
 
11.3.3 
Removal  of  Patients  from  Therapy  or  Assessment 
25  
 
11.4 
T REATMENTS 
25  
 
11.4.1 
Treatments  Administered 
26  
 
11.4.2 
Identity  of  Investigational  Product(s) 
27  
 
11.4.3 
Method  of  Assigning  Patients  to  Treatment  Groups 
28  
 
11.4.4 
Selection  of  Doses  in  the  Study 
28  
 
11.4.5 
Prior  and  concomitant  therapy 
29  
 
11.4.6 
Treatment  Compliance 
30  
 
11.5 
E FFICACY  AND  S AFETY  V ARIABLES 
30  
 
11.5.1 
Efficacy  assessment 
30  
 
11.5.2 
Safety  assessment 
31  
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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11.6 
S TATISTICAL  M ETHODS  P LANNED  IN  THE  P ROTOCOL  AND  D ETERMINATION  OF  S AMPLE  S IZE 
31  
 
11.6.1 
Statistical  and  Analytical  Plans 
31  
 
11.6.2 
Determination  of  Sample  Size 
32  
 
12. 
Study  Subjects 
33  
 
12.1 D ISCONTINUATIONS 
34  
 
12.2 M AJOR  PROTOCOL  DEVIATIONS 
36  
 
13. 
EFFICACY  EVALUATION 
37  
 
13.1 D ATA  S ETS  A NALYZED 
37  
 
13.2 D EMOGRAPHIC  AND  O THER  B ASELINE  C HARACTERISTICS 
38  
 
13.3 E FFICACY  R ESULTS  AND  T ABULATIONS 
41  
 
13.3.1 
Analysis  of  Efficacy 
41  
 
14. 
SAFETY  EVALUATION 
48  
 
14.1 A DVERSE  E VENTS 
49  
 
14.1.1 
Brief  Summary  of  Adverse  Events 
50  
 
14.1.2 
Display  of  Adverse  Events 
51  
 
14.2 D EATHS ,  O THER  SAE S ,  AND  O THER  S IGNIFICANT  A DVERSE  E VENTS 
53  
 
14.2.1 
Deaths 
53  
 
15. 
DISCUSSION  AND  OVERALL  CONCLUSIONS 
55  
 
16. 
Reference  LIST 
57  
 
 
 
●
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.
LIST  OF  TABLES  
 
 
 
Table  1.  STUDY  TIMELINES: 
8  
 
Table  2.  Aflibercept  dose  reduction  level 
28  
 
Table  3.  Dose  reductions  for  mFOLFOX6 
29  
 
Table  4.  Patients  that  did  not  complete  the  study  treatment  (Neoadjuvant  CT  or  Neoadjuvant  CT/RT)  and  end  of   
treatment  reasons 
34  
 
Table  5.  Reasons  for  withdrawal  from  the  Study  Treatment 
35  
 
Table  6.  Major  Deviations 
36  
 
Table  7.  Analysis  populations 
37  
 
Table  8.  Demographic  Characteristics  ITT 
38  
 
Table  9.  Demographic  Characteristics  PP 
39  
 
Table  10.  pCR  Response  in  the  ITT  Population 
41  
 
Table  11.  Secondary  Efficacy  Objectives  in  the  ITT  Population 
42  
 
Table  12.  Disease  free  survival  ITT 
43  
 
Table  13.  pCR  Response  in  the  PP  population 
44  
 
Table  14.  Secondary  Efficacy  Objectives  in  the  PP  Population 
45  
 
Table  15.  Disease  free  survival  in  PP  population 
47  
 
Table  16.  Summary  of  TEAEs  during  the  Study  Period 
50  
 
Table  17.  TEAEs  During  the  Study  Period:  Worst  Grade  per  patient  (Most  Frequent  >  5%) 
51  
 
Table  18.  Surgical  procedures,  toxicities  and  grading  of  TME  in  patients  who  underwent  curative  surgery 
52  
 
Table19.Deaths 
53  
 
5.
LIST  OF  FIGURES  
 
 
 
Figure  1.  Study  scheme 
7  
 
Figure  2.  Treatment  assignment  schema 
8  
 
Figure  3.  Disease  free  survival  ITT 
44  
 
Figure  4.  Disease  free  survival  PP 
48  
 
 
 
 
 
 
 
 
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6.
LIST  OF  ABBREVIATIONS  
 
 
 
 
 
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Abbreviation  
 
Definition  
 
AE  
 
Adverse  Event  
 
AEMPS  
 
 
 
 
 
 
 
Agencia  Española  del  Medicamento  y  Productos  
 
 
 
 
 
 
Sanitarios/  Spanish  Agency  of  Medicines  and  Medical  
 
 
 
 
 
 
 
Devices 
 
 
ANC  
 
Absolute  Neutrophil  Count 
APE  
 
Abdomino  perineal  excission  
 
ASCO  
 
American  Association  of  Clinical  Oncology  
 
CKD-EPI  
 
Chronic  Kidney  Disease  Epidemiology  Group  
 
CNS  
 
Central  Nervous  System  
 
CR  
 
Complete  response  
 
CRM  
 
Circumferential  radial  margin  
 
CRO  
 
Contract  Research  Organization  
 
CT  
 
Computerized  Tomography  
 
CT/RT  
 
Chemotherapy/radiotherapy  
 
CTCAE  
 
Common  Terminology  Criteria  for  Adverse  Events  
 
DBP  
 
Diastolic  blood  pressure  
 
DEHP  
 
Dietilhexilftalato  
 
DFS  
 
Disease  free  survival  
 
ECG  
 
Electrocardiogram  
 
ECOG  
 
Eastern  Cooperative  Oncology  Group  performance  
 
 
 
 
 
status  scale  
 
eCRF  
 
Electronic  case  report  form  
 
EGFR  
 
Epidermal  growth  factor  receptor  
 
EMVI  
 
Extramural  vascular  invasion  
 
ESMO  
 
European  Society  for  Medical  Oncology  
 
FMR  
 
Fascia  mesorectal  
 

 
 
 
 
 
 
 
 
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GCP  
 
Good  Clinical  Practise  
 
GGT  
 
Gamma-glutamyl  transpeptidase  
 
Hb  
 
Haemoglobin  
 
IB  
 
Investigator’s  brochure  
 
ICH  
 
International  Conference  on  Harmonisation  
 
IEC  
 
Investigational  Ethics  Committee  
 
IFP  
 
Interstitial  Fluid  Pressure  
 
ITT  
 
Intent-to-treat  population  
 
LAR  
 
Low  Anterior  Resection  
 
LDH  
 
Lactate  Dehydrogenase  
 
MedDRA  
 
Medical  Dictionary  for  Regulatory  Activities  
 
MRI  
 
Magnetic  Resonance  Imaging  
 
MRF  
 
Mesorectal  Fascia  
 
mrTRG  
 
MRI  Tumor  Regresion  Grade  
 
MVD  
 
Microvessel  density  
 
NCI-CTCAE  
 
National 
 Cancer 
 Institute 
 Common 
 Terminology  
 
 
 
 
 
Criteria  for  Adverse  Events  
 
ORR  
 
Objective  response  rate  
 
OS  
 
Overall  Survival  
 
pCR  
 
Pathological  complete  response  
 
PD  
 
Progression  disease  
 
PFS  
 
Progression-free  survival 
PIGF  
 
Placental  growth  factors  
 
PP  
 
Per  Protocol  population  
 
PR  
 
Partial  response  
 
PS  
 
Performance  Status  
 
PVC  
 
Polyvinyl  chloride  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RC  
 
Rectal  carcinoma  
 
RECIST  
 
Response  Evaluation  Criteria  in  Solid  Tumors  
 
RPLS  
 
Reversible  posterior  leuko-encephalopathy  
 
SAE  
 
Serious  Adverse  Event  
 
SBP  
 
Systolic  blood  pressure  
 
SGOT/AST  
 
Aspartate  aminotransferase  
 
SGPT/ALT  
 
Alanine  aminotransferase  
 
SUSAR  
 
Suspected  Unexpected  Serious  Adverse  Reaction  
 
TME  
 
Total  mesorectal  excision  
 
TKI  
 
Tyrosine  kinase  inhibitor  
 
TOTM  
 
Tri  Octyl  Trimellitate  
 
TRG  
 
Tumor  Regression  Grade  
 
ULN  
 
Upper  Limit  of  Normality  
 
VEGF  
 
Vascular  Endothelial  Growth  Factor   
  
VEGFR  
 
Vascular  Endothelial  Growth  Factor  Receptor  
 

 
 
 
 
7.
ETHICS  
 
7.1
Independent  Ethics  Committee  (IEC)  or  Institutional  Review  Board  (IRB)  
 
The  investigator  submitted  to  the  Independent  Ethics  Committee  (IEC)  the  protocol  and  associated  
 
 
 
 
 
 
 
 
 
 
 
 
 
materials  given  to  the  patient  (such  as  patient  information  sheets  or  descriptions  of  the  study  used  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to  obtain  informed  consent,  as  well  as  documentation  relative  to  advertising  or  compensation  given  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to  the  patient).  The  approval  of  the  IEC  had  to  be  obtained  before  initiating  the  study  and  had  to  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
documented  in  a  letter  to  the  investigator  specifying  the  date  on  which  the  Committee  met  and  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
granted  approval.  
 
Any  modification  made  to  the  protocol  after  its  reception  by  the  IEC  had  to  be  also  submitted  as  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
protocol  amendment  to  the  Committee  in  accordance  with  the  procedures  and  local  legislation.  
 
Any  modification  made  to  the  protocol  after  its  reception  by  the  IEC  must  also  be  submitted  as  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
protocol  amendment  to  the  committee  in  accordance  with  the  procedures  and  local  legislation.  
 
7.2
Ethical  Conduct  of  the  Study  
 
This  study  was  conducted  in  accordance  with  the  ethical  principles  pronounced  in  the  Declaration  of  
 
 
 
  
 
 
 
 
 
  
 
 
 
Helsinki  (Amendment  64 th  of  the  World  Medical  Association  General  Assembly,  Fortaleza,  Brazil,  
 
 
 
 
 
 
 
 
 
 
 
 
October  2013).  
 
7.3
Patient  Information  and  Consent  
 
All  subjects  voluntarily  consented  prior  to  enrollment  in  the  study.  Each  subject  enrolled  in  the  study  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
received  a  copy  of  his  or  her  signed  and  dated  informed  consent  and  a  copy  was  kept  on  file  at  the  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
institution.  Significant  new  study  developments  were  made  known  to  the  subjects  and  documented  
 
 
 
 
 
 
 
 
 
 
 
 
 
via  a  revised  informed  consent  document.   
  
 
 
8.
INVESTIGATORS  AND  STUDY  ADMINISTRATIVE  STRUCTURE  
 
COORDINATING  INVESTIGATOR(S): 
Dr.  Carlos  Fernández-Martos/Fundación  Instituto  Valenciano  de  Oncología  (Spain)  
 
 
 
 
 
CONTRACT  RESEARCH  ORGANIZATION(S):  
 
The  following  CRO  was  contracted  to  perform  the  statistical  analysis  and  the  preparation  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Integrated  Clinical  Trial  Report:   
  
PIVOTAL  S.L.,  C/  Gobelas,  19  La  Florida,  28023  Madrid  (Spain)  
 
Telephone:  +34  91  708  12  50.  Fax:  +34  91  708  13  01  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.
INTRODUCTION  
 
Introduction  
 
 
 
Different  treatment  strategies  may  be  indicated  for  intermediate-risk  (T1-T2N1,  T3N0)  versus  
 
 
 
 
 
 
 
 
 
 
 
moderately  high  (T1-2N2,  T3N1,  T4N0)  or  high-risk  rectal  cancer  patients  (T3N2,  T4N1-2)  based  on  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
differential  survival  rates  and  rates  of  relapse 1 .  
 
Neoadjuvant  delivery  of  systemic  therapy  for  patients  with  rectal  cancer  ensures  that  all  patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
obtain  optimal  systemic  treatment  which  is  feasible,  safe,  has  improved  toxicity  and  provides  tumor  
 
 
 
 
  
 
 
 
 
 
 
 
 
downstaging  2 .  This  fact  can  be  important  in  the  higher  risk  population  (>35%  systemic  failure  at  5  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
years)  group  of  patients.  Attempts  to  intensify  or  modulate  radiosensitization  by  adding  additional  
 
 
 
 
 
 
 
 
 
 
 
 
 
cytotoxic  agents  have  not  been  successful 3 .  A  systematic  and  rational  approach  to  the  development  
 
 
 
 
 
  
 
 
 
 
 
 
 
and  testing  of  novel  radiosensitizers  is  needed  with  platform  serving  a  need  to  rapidly  identify  and  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
test  compounds  with  a  moderately  high  bar  of  certainty  prior  to  definitive  randomized  controlled  
 
 
  
 
 
 
 
 
 
 
 
 
 
studies.  On  the  other  hand,  radiotherapy  may  not  be  needed  in  the  lower  risk  population,  because  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  strategy  of  chemotherapy  alone  before  total  mesorectal  excision  has  shown  100%  of  R0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
resection  with  high  rates  of  pathologic  complete  response  (pCR)  (27-15%) 4,5 .  This  strategy  is  
 
 
 
 
 
 
 
 
 
 
 
 
 
currently  being  tested  versus  the  standard  treatment  (chemo-radiotherapy  (CT/RT)  for  stages  II  and  
 
 
 
 
 
 
 
 
 
 
  
 
III)  in  an  intermediate  risk  population,  in  a  phase  III  cooperative  trial  in  the  USA.  This  strategy  has  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
never  been  tested  in  the  higher  population.  
 
Nonetheless,  current  guidelines  to  treat  T3-4  and/or  N+  rectal  cancer  continue  to  recommend  
 
 
 
 
 
 
 
 
 
 
 
 
 
preoperative  strategy  of  combined  chemo  (fluoropyrimidine  based)  with  radiation 6,7 .  
 
 
 
Anti  VEGF  therapy  in  rectal  cancer  
 
 
 
A  supra-additive  effect  of  growth  inhibition  and  cell  death  has  been  identified  between  ionizing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiation  and  either  antibodies  specific  for  vascular  endothelial  growth  factor  (VEGF)  or  tirosin  
 
 
 
 
 
 
 
 
 
 
 
 
 
kinase  inhibitors  (TKIs)  of  the  vascular  endothelial  growth  factor  receptor  (VEGF-R)  8–10 .  Combining  
 
 
 
 
 
 
 
 
 
 
 
 
 
angiogenesis-targeting  agents  with  cytotoxic  chemotherapy  not  only  provides  the  advantage  of  a  
 
 
 
 
 
 
 
 
 
 
  
non-overlapping  toxicity  and  hence  good  tolerance,  but  also  serves  to  enhance  efficacy.  The  
 
 
 
 
 
 
 
 
 
 
 
 
 
mechanism  of  increased  efficacy  with  combination  therapy  has  been  explored.  Experimental  models  
 
 
 
 
 
 
 
 
 
 
 
 
have  demonstrated  that  tumors  have  disorganized  vasculature  and  lymphatics,  leading  to  increased  
 
 
 
 
 
 
 
 
 
 
 
 
interstitial  fluid  pressure  and  poor  delivery  of  cytotoxic  chemotherapy  and  hypoxia,  thereby  providing  
 
 
 
 
 
 
 
 
 
 
 
 
 
resistance  to  chemotherapy  and  radiation 11 .  In  a  phase  I/II  trial  in  locally  advanced  rectal  cancer  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
patients,  Willet  et  al  showed  that  bevacizumab  decreased  tumor  interstitial  fluid  pressure  and  blood  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
flow,  suggesting  normalization  of  the  tumor  vasculature  12 .  
 
More  recently  in  a  phase  II  trial,  bevacizumab  in  combination  with  capecitabine  and  radiotherapy  in  
 
 
  
  
 
 
 
 
 
 
 
  
locally  advanced  rectal  cancer  does  not  seem  to  improve  pCR  when  compared  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
capecitabine-radiation 13 .  However,  one  Spanish  trial 14  showed  impressive  pCR  rates  (36%)  with  a  
 
 
 
 
 
 
 
 
 
 
  
strategy  consisting  in  induction  therapy  with  bevacizumab  combined  with  capecitabine  and  
 
 
 
 
 
 
 
 
 
 
 
oxaliplatin  followed  by  bevacizumab/capecitabine/radiation  and  then  surgery.  Interestingly  enough,  
 
 
 
 
 
 
 
 
 
this  schema  is  the  same  used  in  the  induction  arm  of  the  phase  II  randomized  above 15  that  obtained  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
14%  of  pCR  in  a  very  similar  population  and  with  the  same  strategy  and  schema  except  for  the  use  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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of  bevacizumab  and  no  oxaliplatin  during  radiation  in  the  Nogue  trial 14 .  These  observations  suggest  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a  positive  effect  of  the  anti-VEGF  therapy  when  used  as  part  of  an  induction  therapy  before  CT/RT.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unfortunately,  in  the  Nogue  trial 14  a  high  rate  of  postsurgical  complications  were  observed  that  led  to  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
24%  of  reoperations.  This  fact  can  be  linked  to  the  use  of  anti-VEGF  therapy  during  the  radiation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
period  as  an  unusual  high  rate  of  major  postsurgical  complications  was  observed  in  some  trials  with  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
the  bevacizumab,  capecitabine  and  radiation  combination 16 .  
 
 
 
Aflibercept  
 
 
 
Aflibercept  is  a  monoclonal  antibody  inhibiting  VEGF  and  placental  growth  factors  (PIGF).  Further  
 
  
 
 
 
 
 
 
 
 
 
 
details  on  preclinical,  clinical  safety  and  preliminary  efficacy  are  provided  in  the  Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
 
Brochure  (IB),  which  contains  comprehensive  information  on  aflibercept 17 .  
 
Aflibercept  in  combination  therapy  improves  survival  in  advanced  colorectal  cancer  when  combined 
 
 
 
 
 
 
 
 
 
 
 
 
with  FOLFIRI  in  the  second  line 18 .  However,  an  understanding  of  responsive  tumor  characteristics  is  
 
 
 
 
 
 
 
 
 
 
 
 
  
lacking,  and  it  is  crucial  to  identify  early  biomarkers  that  accurately  predict  patients  responding  to  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
aflibercept.   
  
Aflibercept  is  a  specific  antagonist  that  binds  and  inactivates  circulating  VEGF  (A  and  B)  and  PIGF.  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Aflibercept  was  designed  to  prevent  the  growth  of  primary  and  metastatic  tumors  by  blocking  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
angiogenesis  and  vascular  permeability.  
 
 
 
Rationale  
 
 
 
With  the  background  described  above  aflibercept  is  a  highly  attractive  drug  to  be  tested  in  locally  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
advanced  rectal  cancer  in  a  high-risk  population  as  part  of  an  induction  therapy  strategy.  
 
With  antiangiogenic  therapy  if  the  goal  is  to  deprive  the  tumor  of  its  blood  supply,  therapy  must  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
continue  until  the  vasculature  no  longer  functions.  If  the  goal  is  to  improve  vascular  efficiency,  as  is  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
the  case  in  the  neoadjuvant  treatment  of  locally  advanced  rectal  cancer,  treatments  should  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
fine-tuned  accordingly.  The  delicate  balance  between  too  many  and  too  few  endothelial  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
perivascular  cells  warrants  careful  attention  to  the  scheduling  and  dosing  of  combination  therapies.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Thus,  measurements  of  vascular  parameters  is  essential  for  assessing  efficacy  and  understanding  
 
 
 
 
  
 
 
 
 
 
 
the  mechanism  of  action  of  these  agents 19 .  Optimal  scheduling  may  take  advantage  of  a  window  of  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
opportunity  created  by  anti-angiogenic  therapy  wherein  cytotoxic  agents  and  oxygen  will  have  
 
 
 
 
 
 
 
 
 
 
 
 
maximal  access  to  cancer  cells.  
 
As  prolonged  anti-VEGF  treatment  can  destroy  vessels  and  tumors  may  become  resistant  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
anti-angiogenic  drugs,  tumor  vessel  normalization  is  limited  to  a  transient  window  of  time.  Although  
 
 
 
 
  
 
  
 
 
 
 
 
the  effects  of  vascular  normalization  have  been  extensively  characterized  in  preclinical  models, 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  evidence  has  not  been  fully  appreciated  yet. 
Tumors  exhibit  interstitial  hypertension  while  tumoral  vessels  become  leaky  and  increase  
 
 
 
 
 
 
 
 
 
 
 
permeability  and  become  poorly  organized.  This  environment  reduces  blood  supply  to  them,  which  
 
 
 
 
 
 
 
 
 
 
 
 
 
impairs  drug  delivery 20,21 .  
 
Several  authors  have  studied  the  relationship  between  the  administration  of  antiangiogenic  drugs  
 
 
 
 
 
 
 
 
 
 
 
 
and  their  effect  on  microvessel  density  (MVD)  and  interstitial  fluid  pressure  (IFP)  obtained  directly  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from  tumor  biopsies  in  the  appropriate  timing,  as  the  goal  standard  to  analyze.  Some  preclinical  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  data  strongly  affirm  this  effect 22–27 .  
 
 
 
 
 
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The  antiangiogenic  treatment  is  effective  by  reducing  microvessel  density  and  interstitial  fluid  
 
 
 
 
 
 
 
 
 
 
 
 
pressure  in  the  vascular  network  of  the  tumor,  leading  to  a  more  feasible  penetration  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
chemotherapy  into  the  tumoral  microenvironment  and  lessening  the  degree  of  hypoxia  inside  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
tumor.  In  these  conditions,  the  tumor  itself  would  reach  the  better  setting  for  receiving  radiotherapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment,  thus  increasing  its  effect  in  a  synergistic  way 28,29 .  
 
Otherwise,  there  are  also  publications  finding  relations  between  parameters  of  functional  imaging  
 
 
 
 
 
 
 
 
 
 
 
 
and  MVD  and  IFP  in  several  tumors  studied  by  functional  MRI 30–36 .  And  although  substantial  efforts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
are  being  made  to  identify  molecular  biomarkers  in  tissue  and  blood  that  predict  response  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aflibercept,  there  are  no  validated  biomarkers  of  response  to  aflibercept,  so  far.  The  candidate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarkers  include  proteins  related  to  VEGF  and  VEGFR  family  members,  angiogenic  factors,  
 
 
 
 
 
 
 
 
 
 
 
 
cytokines  or  any  other  analyses  with  potential  role  in  angiogenesis  and  inflammation,  as  previously  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
suggested 12,37–43 .  
 
In  addition,  single  nucleotide  polymorphisms  (SNP)  data  from  non-tumor  tissue,  have  been  
 
 
 
 
 
 
 
 
 
 
 
 
suggested  to  correlate  outcome  to  therapy 44–47 .  Moreover,  a  “vascular  normalization  index”  that 
 
 
 
 
 
 
  
 
 
 
 
combines  changes  in  Ktrans,  microvessel  volume  and  circulating  collagen  IV  significantly  correlates  
 
 
 
 
 
 
 
 
 
 
 
 
with  survival  in  patients  with  glioblastoma  treated  with  cediranib,  after  a  single  dose  of  treatment 48 .  
 
Several  issues  remain  unanswered  and  several  hypotheses  could  be  rised.  On  the  first  hand,  an  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
imaging  biomarker  would  exhibit  a  decrease  of  blood  flow  volume  and  vascular  permeability  
 
 
 
 
 
 
 
 
 
 
 
 
 
parameters  (BF,  BV  and  k-trans)  if  MVD  and  IFP  decreases  and  would  correlate  with  good  response  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
after  treatment  with  Aflibercept.  On  the  other  hand,  tissue  and  plasma  molecular  biomarkers  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tumoral  and  blood  samples  would  variate  during  treatment  and  correlate  with  response  to  treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Therefore,  a  “Vascular  Normalization  Index  Biomarker”  would  significantly  correlate  with  response  to  
  
 
 
 
 
 
 
 
 
 
 
aflibercept.  
 
We  proposed  to  conduct  a  phase  II  randomized  trial  comparing  induction  treatment  with  FOLFOX  
 
 
 
  
  
 
 
 
 
 
 
 
with  or  without  aflibercept  in  a  high  risk  population  selected  by  MRI,  prior  to  receiving  standard  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
chemoradiation  (capecitabine  combined  with  50.4  Gy  in  28  days)  and  surgery 31 .  Moreover,  since  no  
 
 
 
 
 
  
 
 
 
 
 
 
 
molecular  biomarkers  of  response  to  aflibercept  have  been  validated  in  tissue/blood,  we  proposed  
 
 
 
 
 
 
 
 
 
 
 
 
 
to  study  an  extensive  panel  of  biomarkers  at  multiple  time  points  during  therapy.  
 
 
 
10.
STUDY  OBJECTIVES  
 
10.1
Primary  objective  
 
The  primary  objective  was  to  evaluate  the  efficacy  of  induction  therapy  with  mFOLFOX6  +/-  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aflibercept  followed  by  CT/RT  in  terms  of  pCR.  
 
10.2
Secondary  objectives  
 
The  secondary  objectives  were:  
 
●
To  evaluate  pathological  parameters  of  efficacy:  R0  resection,  TRG,  and  positive  or  negative  
 
 
 
 
 
 
 
 
 
 
 
 
 
CRM  rate.  
 
●
To  evaluate  the  relationship  between  MRI  changes  with  outcome.  
 
●
To  further  characterize  the  safety  and  tolerability  of  mFOLFOX6  +/-  aflibercept  followed  by  
 
 
 
 
 
 
 
 
 
 
 
 
 
chemoradiation.  
 
●
To  determine  the  rate  of  30-day  surgical  complications.  
 
 
 
 
 
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●
To  evaluate  the  3-year  local  recurrence  and  DFS.  
 
●
To  determine  the  levels  of  tumor  biomarkers  expression  at  baseline  and  correlate  them  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
response  to  treatment  with  mFOLFOX6  +  aflibercept.   
  
 
 
11.
INVESTIGATIONAL  PLAN  
 
11.1
Overall  Study  Design  and  Plan:  Description  
 
This  was  a  randomized,  open  and  multicentric  phase  II  trial  comparing  induction  treatment  with  
 
  
 
 
 
 
  
 
 
 
 
 
FOLFOX  with  or  without  aflibercept  in  a  high  risk  population  selected  by  MRI,  prior  to  receiving  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
standard  chemoradiation  (capecitabine  combined  with  50.4  Gy  in  28  days)  and  surgery.  
 
Once  it  was  confirmed  that  the  subjects  fulfilled  the  eligibility  criteria  (MRI-defined  high  risk  RC),  and  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
had  signed  the  informed  consent,  a  central  review  was  requested  to  confirm  clinical  stage,  and  then  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
they  were  randomized  2:1  to  receive  mFOLFOX6+aflibercept  iv  q  14d  versus  mFOLFOX  iv  q  14d.  
 
Random  assignment  of  treatment  was  stratified  by  EMVI+/EMVI-,  T3  versus  T4  stage,  and  by  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
site.  
 
All  the  patients  enrolled  in  the  study  received  one  cycle  of  study  medication  (mFOLFOX6  with  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
without  aflibercept)  every  14  days  for  6  cycles,  unless  unacceptable  toxicity  or  progression  was  
 
 
 
 
 
  
 
 
 
 
 
 
 
detected.  After  this  treatment,  patients  received  standard  chemo-radiotherapy  (CT/RT)(capecitabine  
 
 
 
 
 
 
 
 
 
825  mg/m 2  twice  daily  combined  with  a  total  dose  of  50.4  Gy  in  28  days)  followed  by  surgery,  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
provided  they  had  not  progressed.  
 
 
 
Patients  with  progression  disease  (PD)  during  the  treatment  phase  were  withdrawn  from  the  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  received  their  treatment  according  to  the  investigator’s  judgment.  
 
If  a  patient  withdrew  consent  and  refused  to  receive  further  treatment,  the  patient  had  to  be  followed  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
up  for  3  years  from  randomization  until  progression,  to  evaluate  disease-free  survival.  
 
If  a  patient  withdrew  consent  and  refused  to  continue  in  the  study,  the  follow-up  evaluations  had  to  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  discontinued.  
 
 
 
CT  and  MRI  were  done  at  baseline.  CTs  were  done  prior  to  surgery  (4weeks  +/-  5  days  after  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
chemo-radiotherapy),  between  1-3  months  after  surgery,  and  later  every  6  months  during  follow-up.  
 
 
 
 
 
 
 
 
  
 
 
 
A  second  MRI  was  done,  based  on  investigator’s  judgement,  after  CT-RT  treatment  (4  weeks  +/-  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after  chemo-radiotherapy).  
 
 
 
 
 
11.2
Discussion  of  Study  Design,  Including  the  Choice  of  Control  Groups  
 
The  primary  objective  of  this  study  was  to  evaluate  the  efficacy  of  induction  therapy  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mFOLFOX6  +/-  aflibercept  followed  by  CT/RT  in  terms  of  pCR.  The  primary  endpoint  was  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
analyze  the  number  of  patients  achieving  pCR  after  induction  therapy  with  mFOLFOX6  +/-  
 
 
 
 
 
 
 
 
 
 
 
 
 
aflibercept  followed  by  CT/RT.  pCR  was  defined  as  the  absence  of  viable  tumor  cells  in  the  primary  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
tumor  and  in  the  lymph  nodes  (ypT0N0).  
 
11.3
Study  Population  
 
The  study  population  consisted  of  adult  patients  ( > 18  and  <75  years  of  age)  with  locally  advanced  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
high-risk  rectal  cancer  (histological  type:  adenocarcinoma  of  the  rectum),  considered  by  the  surgeon  
 
 
 
 
 
 
 
 
 
 
 
 
 
as  feasible  to  perform  a  curative  resection.   
  
 
 
 
 
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One  hundred  and  sixty-two  evaluable  patients  had  to  be  recruited:  108  10%  of  drop-outs  a  total  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
180  patients  were  recruited  (120  patients  for  mFOLFOX6  +  aflibercept  group  and  60  patients  for  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
mFOLFOX6).  
 
 
 
11.3.1
Inclusion  criteria  
 
Only  patients  who  fulfilled  all  the  criteria  listed  below  were  enrolled  in  the  study.  Patients  with:  
 
1.
Signed  and  dated  informed  consent,  and  willing  and  able  to  comply  with  protocol  
 
 
 
 
 
 
 
 
 
 
 
 
 
requirement;  
 
2.
Male  or  female  subjects  with  rectal  cancer  >  18  and  <  75  years  of  age;  
 
3.
High-risk  rectal  cancer  defined  by  MRI  as  that  with  inferior  border  of  the  tumor  distal  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  peritoneal  reflection  or  <  12  cm  from  the  anal  margin  and  considered  by  the  surgeon  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
as  feasible  to  perform  a  curative  resection  (including  pelvic  exenteration  as  curative  
 
 
 
 
 
 
 
 
 
 
 
 
resection)  
 
 
 
 
 
 
 
Presence  of  at  least  1  of  the  following  high-resolution,  thin-slice  MRI  (3mm):  
 
 
 
Middle  Third  Tumors  
 
 
 
-mrT3  
 
Extramural  vascular  invasion  (EMVI)  positive  
 
Extramural  extensión  >  5  mms  into  perirectal  fat  
 
Mesorectal  fascia  (MRF)  threatened  or  involved*  
 
-mrT4***  
 
 
 
Distal  Third  Tumors  ( <  5  cm  from  anal  verge)  
 
 
 
-mrT3  tumor  at  below  levators  
 
-T4  as  above  
 
 
 
N2**  
 
 
 
*tumor  or  lymph  node  <  1mm  from  the  mesorectal  fascia.  
 
** >  4  lymph  nodes  in  the  mesorectum  showing  morphological  signs  on  MRI  indicating  metastatic   
disease.  >  4  nodes,  whether  enlarged  or  not,  with  a  rounded,  homogeneous  appearance  is  thus  not   
sufficient.  
 
***T4a:  tumor  infiltrates  peritoneal  reflection.  T4b:  tumor  infiltrates  adjacent  organs.   
  
4.
Histological  or  cytological  documentation  of  adenocarcinoma  of  the  rectum.  All  other  
 
 
 
 
 
 
 
 
 
 
 
histological  types  were  excluded;  
 
5.
ECOG  Performance  Status  of  <  1;  
 
 
 
 
 
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6.
Hematological  status:  neutrophils  (ANC)  >  1.5  x  10 9 /L;  platelets  >  100  x  10 9 /L;  
 
 
 
 
 
 
 
 
 
 
 
 
 
hemoglobin  >  9  g/dL;  
 
7.
Adequate  renal  function:  serum  creatinine  level  <  1.5  x  ULN;  
 
8.
Adequate  liver  function:  serum  bilirubin  <  1.5  x  ULN,  alkaline  phosphatase  <  5  x  ULN,  
 
 
 
 
  
  
 
 
    
 
AST/ALT  <  3  x  ULN;  
 
9.
Proteinuria  <  2+  (dipstick  urinalysis)  or  <  1  g/hour;  
 
10. Regular  follow-up  feasible;  
 
11. For  female  patients  of  childbearing  potential,  negative  serum  pregnancy  test  within  
 
 
 
 
 
 
 
 
 
 
 
1-week  (7  days)  prior  of  starting  study  treatment;  
 
12. Female  patients  must  commit  to  using  reliable  and  appropriate  methods  of  contraception  
 
 
 
 
 
 
 
 
 
 
 
 
until  at  least  three  months  after  the  end  of  study  treatment  (when  applicable).  Male  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  with  a  partner  of  childbearing  potential  must  agree  to  use  contraception  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
addition  to  having  their  partner  use  another  contraceptive  method  during  the  trial.  
 
11.3.2
Exclusion  criteria  
 
Patients  were  excluded  from  the  study  if  they  present  any  of  the  criteria  listed  below :  
 
1.
Prior  treatment  with  aflibercept;  
 
2.  History  or  evidence  upon  physical  examination  of  metastasis; 
3.  Uncontrolled  hypercalcemia;  
 
4.  Pre-existing  permanent  neuropathy  (NCI  grade  >  2);  
 
5.  Uncontrolled  hypertension  (defined  as  systolic  blood  pressure  >  150  mmHg  and/or  diastolic  
 
 
 
 
 
 
 
  
 
 
 
 
blood  pressure  >  100  mmHg),  or  history  of  hypertensive  crisis,  or  hypertensive  
 
 
 
 
 
 
 
 
 
 
 
 
encephalopathy;   
  
6.  Concomitant  protocol  unplanned  antitumor  therapy  (e.g.  chemotherapy,  molecular  targeted  
 
 
 
 
 
 
 
 
 
 
therapy,  immunotherapy);  
 
7.  Treatment  with  any  other  investigational  medicinal  product  within  28  days  prior  to  study  entry;  
 
8.  Other  concomitant  or  previous  malignancy,  except:  i/  adequately  treated  in-situ  carcinoma  of  
 
 
 
 
 
 
  
 
 
 
 
 
the  uterine  cervix,  ii/  basal  or  squamous  cell  carcinoma  of  the  skin,  iii/  cancer  in  complete  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
remission  for  >  5  years;  
 
9.  Any  other  serious  and  uncontrolled  non-malignant  disease,  major  surgery  or  traumatic  injury  
 
 
 
 
 
 
 
 
 
 
 
 
 
within  the  last  28  days;  
 
10.  Pregnant  or  breastfeeding  women;  
 
11.  Patients  with  known  allergy  to  any  excipient  to  study  drugs;  
 
12.  Previous  history  of  stable  angina,  uncontrolled  arrhythmia,  and  acute  coronary  syndrome  
 
 
 
 
 
 
 
 
 
 
 
 
even  if  controlled  with  medication  or  with  myocardial  infarction  or  cerebrovascular  accident  
  
 
 
 
 
 
 
 
 
 
 
within  the  last  12  months.  
 
13.  Bowel  obstruction:  Patients  with  intestinal  occlusion,  candidates  to  participate  in  the  trial,  
 
 
 
 
 
 
 
 
 
 
 
 
 
may  be  included  in  the  study  after  performing  a  derivative  stoma;  
 
14.  Appearance  of  de  novo  deep  vein  thrombosis  in  the  4  weeks  prior  to  randomization.   
  
 
 
 
 
 
 
 
 
 
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11.3.3
Removal  of  Patients  from  Therapy  or  Assessment  
 
 
 
The  clinical  study   ended  when  all  the  clinical  study  subjects  had  concluded  the  follow-up  period.  
 
In  accordance  with  current  revision  of  the  Declaration  of  Helsinki  (Appendix  V)  and  other  applicable  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
regulations,  any  patient  participating  in  the  study  had  the  right  to  withdraw  from  the  study  at  any  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
time  and  for  any  reason  without  prejudice  to  his  or  her  future  medical  care  by  the  physician  or  at  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
institution.  If  a  subject  (or  a  legally  acceptable  representative)  requested  or  decided  to  withdraw,  all  
   
 
  
 
 
 
 
 
 
 
 
 
efforts  had  to  be  made  by  the  investigator  to  complete  and  report  the  observations  as  thoroughly  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
possible  up  to  the  date  of  withdrawal.  All  information  had  to  be  reported  on  the  applicable  pages  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  electronic  Case  Report  Form  (eCRF).  
 
The  investigator  had  the  right  to  withdraw  patients  from  the  study  if  concomitant  disease  or  AE  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
occurred  that,  in  the  investigator’s  opinion,  required  the  withdrawal  of  the  patient  from  the  study,  if  a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
protocol  violation  occurred,  or  for  other  reasons.  
 
 
 
The  reasons  for  premature  interruption  of  treatment  (early  withdrawal)  were  the  following:  
 
●
Voluntary  discontinuation  by  the  patient:  withdrawal  of  consent  and/or  rejection  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
treatment  and/or  uncooperativeness.  
 
●
Safety  reasons:  toxicity,  AEs,  or  intercurrent  disease  that,  in  opinion  of  the  investigator,  
 
 
 
 
 
 
 
 
 
 
 
 
 
justified  withdrawal  from  oncologic  treatment.  If  the  toxicity  required  postponing  treatment  
 
 
 
 
  
 
 
 
 
 
for  more  than  2  weeks,  the  patient  ended  the  treatment  due  to  toxicity  and  entered  the  study  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
follow-up  period.  If  the  investigator  thought  therapy  had  to  be  continued  in  the  best  interest 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
of  the  patient,  this  had  to  be  discussed  with  the  National  Coordinating.  
 
●
Pregnancy.  
 
●
Death.  
 
●
Disease  progression.  
 
●
Significant  protocol  violation  or  severe  protocol  non-compliance  as  judged  by  the  
 
 
 
 
 
 
 
 
 
 
 
investigator  and/or  the  Sponsor.  
 
●
At  the  discretion  of  the  investigator  or  sponsor.  
 
●
Request  by  regulatory  authorities.  
 
 
 
When  early  withdrawal  occurred,  the  corresponding  section  of  the  eCRF  had  to  be  completed,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
indicating  the  reason  for  withdrawal,  the  last  clinical  and  analytical  data  available,  and  the  new  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment.  
 
The  subjects  enrolled  in  the  study  who  later  withdrew  from  study  participation  were  not  replaced.  
 
All  the  patients  who  terminated/discontinued  the  clinical  study  treatment  had  to  remain  in  follow-up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for  3  years  from  randomization  until  progression,  except  for  patients  who  withdrew  their  informed  
  
 
 
 
 
 
 
 
 
 
 
 
 
consent,  died  or  were  lost  to  follow-up.  
 
11.4
Treatments  
 
Patients  were  randomized  to  receive  treatment  with  mFOLFOX6  with  or  without  aflibercept.  All  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients  enrolled  in  the  study  received  one  cycle  of  study  medication  every  14  days,  for  6  cycles,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
unless  unacceptable  toxicity  or  progression  was  detected.  
 
After  they  had  completed  these  cycles  of  the  study  treatment,  patients  received  standard  
 
 
 
 
 
 
 
 
 
 
 
 
 
chemoradiotherapy  (CT/RT)  followed  by  a  second  MRI  and  surgery,  provided  they  had  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
progressed  (a  CT  was  performed  prior  to  surgery).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.4.1
Treatments  Administered  
 
Induction  therapy  
 
Each  cycle  of  the  study  treatment  consisted  of: 
●
mFOLFOX-6  scheme :  5-Fluoruracil  [5-FU],  oxaliplatin  and  leucoverin  were  administered  
 
 
 
 
 
 
 
 
 
intravenously  once  every  14  days  according  to  mFOLFOX-6  scheme:  
 
 
 
Day  1:  Oxaliplatin  85  mg/m 2  IV  infusion  in  250-500  mL  and  leucovorin  400  mg/m 2  IV  bolus  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  a  46h  infusion  of  5-FU  2400  mg/m 2 . 
 
 
Aflibercept,  was  administered  intravenously  (I.V.)  at  doses  of  4  mg/Kg  on  Day  1  every  14  
 
 
 
 
 
 
 
  
 
 
  
 
 
days.  Aflibercept  was  supplied  to  sites  by  the  study  Sponsor  as  4  ml  vials  at  a  concentration  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
of  25  mg/ml.  
 
 
 
Treatment  continued  until  six  cycles  were  administered  unless  unacceptable  toxicity  or  progression  
 
 
 
 
 
 
 
 
 
 
 
 
occurred.  If  it  was  necessary  to  interrupt  or  reduce  the  study  drug  dosage  due  to  toxicity,  dose  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
adjustements  were  made  according  to  the  specific  types  of  toxicities  observed  and  the  standard  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
care  at  each  site.  
 
 
 
●
Chemo-radiotherapy  (CT/RT)  
 
 
 
Standard  CT/RT  consisted  of  capecitabine  825mg/m 2  twice  a  day  combined  with  a  total  dose  of  
 
 
 
 
 
 
  
 
 
  
 
 
 
50-4  Gy  in  28  days,  as  neoadjuvant  standard  therapy.   
  
 
 
Surgery  
 
Surgery  took  place  6  +/-  2  weeks  after  the  last  CT/RT  induction  therapy  dose.  The  following  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
guidelines  were  followed:  
 
 
 
●
A  complete  exploration  of  the  abdominal  cavity  had  to  be  performed  to  rule  out  distant  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastasis  (M),  whether  liver  or  peritoneal.  In  case  of  doubt,  suspicious  tissue  biopsy  had  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be  performed.  If  the  test  was  positive  for  malignancy,  palliative  surgery  had  to  be  performed  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
and,  preferentially,  the  primary  tumor  had  to  be  resected  if  feasible  (radical  resection).  
 
 
 
 
 
 
 
 
  
 
 
 
Similarly,  tumor  stage  T  and  N  had  to  be  assessed.  
 
●
Since  tumor  was  in  the  middle  or  distal  third  of  the  rectum,  a  total  mesorectal  excision  (TME)  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
had  to  be  performed.  Low  anterior  resection  (LAR)  or  Abdomino  Perineal  Excision  (APE)  
 
 
 
 
 
 
 
 
 
 
 
 
 
were  the  techniques  of  choice.  
 
●
The  preservation  of  the  anal  sphincter  was  in  each  case  at  the  surgeon’s  discretion,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
depending  on  oncological  safety  criteria  and  characteristics  of  each  patient  (tumor  distance  
 
 
 
 
 
 
 
 
 
 
 
 
from  anal  margin,  degree  of  tumor  differentiation,  degree  of  continence,  previous  local  tumor  
 
 
 
 
 
 
 
 
 
 
 
 
 
characteristics  and  the  patient’s  pelvis).  
 
  
  
 
 
The  patients  who  discontinued  treatment  for  any  reason  underwent  safety  observation  that  had  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
end  30  days  after  the  last  administration  of  the  study  treatment.  It  was  the  End-of-treatment/Early  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
withdrawal  visit.  
 
 
 
Patients  had  a  follow-up  evaluation  (follow-up  visits)  every  3  months  +  2  weeks.   
  
 
 
 
 
 
 
 
 
 
 
 
 
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11.4.2
Identity  of  Investigational  Product(s)  
 
Aflibercept  presentation  
 
Aflibercept  was  supplied  to  the  sites  by  Sanofi,  in  4mL  vials  at  a  concentration  of  25mg/mL,  and  was  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
packaged  and  labelled  according  to  the  applicable  local  legislation.  
 
 
 
The  clinical  use  and  administration  of  aflibercept  followed  the  instructions  provided  in  the  latest  IB  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
version.  
 
 
 
Preparation  and  administration  of  aflibercept  
 
Preparation   
  
Multiple  vials  of  aflibercept  concentrate  for  solution  for  infusion  could  be  required  depending  on  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patient’s  weight  and  the  intended  dose.  The  necessary  volume  of  aflibercept  had  to  be  withdrawn  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from  the  vials  and  injected  directly  into  the  infusion  bag.  Aflibercept  concentrate  had  to  be  diluted  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
infusion  with  0.9%  sodium  chloride  solution  or  5%  dextrose  by  a  healthcare  professional.  The  
 
 
 
 
 
 
 
 
 
  
 
 
 
dilution  had  to  be  carried  out  under  aseptic  conditions.  Any  unused  portion  left  in  a  vial  must  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
discarded,  as  the  investigational  drug  does  not  contain  any  preservatives.  
 
 
 
Infusion  conditions  
 
The  infusion  sets  contained  a  0.2  µm  polyethersulfone  inline  filter.  PDVF  or  Nylon  filters  couldn’t  be  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
used.  Infusion  could  be  conducted  by  gravity,  with  an  IV  infusion  pump,  or  with  a  syringe  pump  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
using  administration  sets  made  of  the  above  materials.  The  aflibercept  IV  dose  had  to  be  infused  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
over  1  hour.  The  infusion  couldn’t  exceed  2  hours  at  room  temperature  (approximately  25ºC).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parenteral  investigational  drug  products  had  to  be  inspected  visually  for  particulate  matter  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
discoloration  prior  to  administration.  
 
 
 
Storage  period  of  premix  and  infusion  solution  
 
The  aflibercept  concentrate  for  solution  for  infusion  in  its  original  unopened  container  is  stable  for  36  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
months  under  refrigerated  conditions  (2  to  8ºC).  
 
The  Hospital  Pharmacist  was  responsible  for  the  appropriate  storage  of  the  investigational  
 
 
 
 
 
 
 
 
 
 
 
 
medicinal  product  (IMP)  at  the  study  centre,  and  they  had  immediately  to  inform  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monitor/Sponsor  of  non-respect  of  the  required  storage  conditions.  When  closing  the  investigational  
 
 
 
 
 
 
 
 
 
 
 
 
centre,  all  unused  IMP  containers  had  to  be  destroyed  on  site.  if  an  IMP  batch  is  suspected  to  be  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
defective,  Sanofi  had  immediately  to  inform  the  Sponsor  so  that  the  Hospital  Pharmacist  could  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
immediately  got  the  approppriate  information.  The  Hospital   
  
Pharmacist  had  to  organize  the  destruction  of  the  concerned  batch(es)  and  new  batch(es)  had  to  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sent  to  the  investigational  centre  when  approppriate.  
 
 
 
mFOLFOX-6  
 
mFOLFOX-6  was  dispensed  under  the  responsibility  of  the  Pharmacy  Service  of  each  one  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
participating  sites  according  to  the  local  legislation  for  dispensing  marketed  products  for  hospital  
 
 
 
 
 
 
 
 
 
 
 
 
 
use.  Premedication  was  prescribed  according  to  the  sites  procedures.  
 
 
 
Oxaliplatin  administration  
 
Oxaliplatin  had  to  be  administered  at  the  recommended  dose  in  2-hour  intravenous  infusion.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxaliplatin  infusion  had  to  be  administered  by  peripheral  or  central  venous  infusion  over  2  hours.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Pathways  used  to  administer  the  infusion  had  to  be  washed  with  a  solution  of  5%  dextrose  (D5W)  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
after  finishing  oxaliplatin  infusion  and  before  administering  any  other  drug.  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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5-FU/Leucovorin  administration  
 
5-FU  and  leucovorin  were  administered  according  to  the  mFOLFOX6  schedule.  
 
 
 
11.4.3
Method  of  Assigning  Patients  to  Treatment  Groups  
 
Random  assignment  of  treatment  was  stratified  by  EMVI+/EMVI-,  T3  versus  T4  stage  and  by  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
site.  
 
All  the  patients  enrolled  in  the  study  received  one  cycle  of  study  medication  (mFOLFOX6  with  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
without  aflibercept)  every  14  days  for  6  cycles,  unless  unacceptable  toxicity  or  progression  was  
 
 
 
 
 
  
 
 
 
 
 
 
 
detected.  After  that  treatment,  patients  received  standard  chemo-radiotherapy  (CT/RT)  
 
 
 
 
 
 
 
 
 
(capecitabine  825  mg/m 2  twice  daily  combined  with  a  total  dose  of  50.4  Gy  in  28  days)  followed  by  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
surgery,  provided  they  had  not  progressed.  
 
11.4.4
Selection  of  Doses  in  the  Study  
 
The  clinical  use  and  administration  of  aflibercept  followed  the  instructions  provided  in  the  latest  IB  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
version.  
 
mFOLFOX-6  was  dispensed  under  the  responsibility  of  the  Pharmacy  Service  of  each  one  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
participating  sites  according  to  the  local  legislation  for  dispensing  marketed  products  for  hospital  
 
 
 
 
 
 
 
 
 
 
 
 
 
use.  
 
Toxicity  was  graded  according  to  the  National  Cancer  Institute  Common  Terminology  Criteria  for  AE,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
version  4.0.  
 
Dose  modifications  for  aflibercept  
 
Dose  adjustment  and/or  cycle  delay  were  planned  in  case  of  toxicity.  Dose  adjustments  were  made  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
according  to  the  worst  grade  toxicity.  Patient  received  the  next  cycle  after  recovery  from  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
detected  toxicity.  
 
If  a  patient  experienced  several  toxicities  and  there  were  conflicting  recommendations,  the  
 
 
 
 
 
 
 
 
 
 
 
 
conservative  dose  adjustment  recommended  (dose  reduction  appropriate  to  the  most  severe  
 
 
 
 
 
 
 
 
 
 
 
toxicity)  had  to  be  followed.  Once  a  dose  had  been  decreased,  intra-patient  re-escalation  back  to  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
the  previous  dose  level  was  not  permitted.  
 
In  case  of  toxicity  from  treatment,  administration  had  to  be  delayed  until:  
 
●
neutrophil  count  was  >  1.5  x  10 9 /L  and  platelet  count  was  >  75  x  10 9 /L  
 
●
recovery  to  grade  <  1  for  other  toxicities  (except  alopecia  and  otherwise  specified)  
 
The  maximum  delay  allowed  was  of  2  weeks.  In  case  of  treatment  delay  greater  than  2  weeks,  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
patient  had  to  discontinue  aflibercept,  unless  it  was  discussed  with  the  National  Coordinator  and  a  
 
 
 
 
 
  
 
 
 
 
 
 
  
decision  was  made  to  continue  the  treatment  in  the  best  interest  of  the  patient.  
 
 
 
Dose  reduction  
 
Aflibercept  dose  reduction  is  described  in  Table  2.  Only  one  dose  reduction  was  allowed.  
 
 
 
Table  2.  Aflibercept  dose  reduction  level  
 
 
 
 
 
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Initial 
 dose 
 
 
(mg/kg)  
 
 
 
Dose 
 reduction, 
 
 
level  –  1  
 
(mg/kg)  
 

 
 
 
 
 
 
 
 
 
 
Dose  modifications  and  dose  delay  for  any  component  of  mFOLFOX6 
In  addition  to  optimizing  supportive  care,  oxaliplatin  and  5-FU/LV  dose  adjustments  based  on  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
worst  toxicity  encountered  during  the  previous  cycle,  were  recommended.  These  were  at  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator’s  discretion  considering  the  current  local  prescribing  information  and  the  standard  
 
 
 
 
 
 
 
 
 
 
 
clinical  practice.  
 
Table  3  sets  out  the  recommended  dose  reductions  for  each  component  mFOLFOX-6.  Dose  
 
 
 
 
 
 
 
 
 
 
 
 
 
adjustments  for  each  agent  had  to  be  performed  independently  according  to  the  specific  types  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
toxicities  observed.  Dose  leucovorin  400/m 2  couldn’t  be  reduced  and  had  to  be  given  before  5-FU  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
bolus  administration  and  continuous  infusion  5-FU.  
 
Individuals  who  required  a  dose  reduction  for  grade  2  toxicity  and  the  same  toxicity  didn’t  reappear,  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
could  return  to  the  original  dose  level  for  the  next  cycle,  according  to  the  investigator’s  discretion.  If  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
a  dose  reduction  of  any  agent  beyond  the  level  -3  was  required,  the  agent  had  to  be  discontinued  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  rest  of  the  drugs  could  continue  as  per  the  protocol.  
 
 
 
 
 
 
 
Table  3.  Dose  reductions  for  mFOLFOX6  
 
 
 
 
 
11.4.5
Prior  and  concomitant  therapy  
 
 
 
Permitted  treatments  
 
The  use  of  any  medication  that,  in  the  judgment  of  the  investigator,  was  required  by  the  patients  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
their  correct  clinical  care  was  permitted,  with  the  exception  of  the  medications  listed  in  section  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Prohibited  treatments”,  the  use  of  which  entailed  withdrawal  of  the  patient  from  the  study.  The  data  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
related  to  all  concomitant  medication  used,  as  well  as  the  diagnostic,  therapeutic  and  surgical  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
procedures  performed  during  the  study,  had  to  be  recorded  in  the  eCRF.  All  patients  in  this  study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
were  offered  the  necessary  palliative  and  support  measures  for  the  treatment  of  disease-related  
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms.  
 
 
 
 
 
 
 
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Aflibercept  
 
4  
 
→  
 
2  
 
 
Drug  
 
First  dose  
 
Level  -1  
 
Level  -2  
 
Level  -3  
 
Oxaliplatin  
 
85  mg/m 2  
 
65  mg/m 2  
 
50  mg/m 2  
 
40  mg/m 2  
 
5-FU  bolus  
 
400  mg/m 2  
 
320  mg/m 2  
 
270  mg/m 2  
 
230  mg/m 2  
 
5-FU  continuous   
infusion  
 
2400 mg/m 2  
 
in  46-48  hours  
 
1920  mg/m 2  
 
in  46-48 hours  
 
1600  mg/m 2  
 
in  46-48 hours  
 
1360  mg/m 2  
 
in  46-48 hours  
 
 

 
 
 
 
●
In  the  case  of  nausea,  vomiting  or  diarrhea,  effective  symptomatic  treatment  had  to  be  given.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appropriate  measures  had  to  be  taken  to  rehydrate  patients.  
 
●
Low  dose  corticosteroids  were  allowed  as  an  antiemetic  therapy.  
 
●
Therapy  with  hematologic  growth  factors  was  allowed  at  the  investigator’s  discretion.  
 
 
 
 
 
 
 
 
 
 
 
Transfusion  with  blood  products  was  allowed.  
 
●
Vitamin  /  mineral  supplements  (not  containing  St.  John’s  wort)  were  allowed  at  the  
  
 
 
 
 
 
 
 
 
 
 
 
investigator’s  discretion  and  clinical  judgement,  provided  they  didn’t  interfere  with  the  study  
 
 
 
 
 
 
 
 
 
 
 
 
treatment.  Supplements  were  not  allowed  unless  all  components  are  known  and  recorded.  
 
●
Prophylactic  and  therapeutic  anticoagulant  medication  (i.e.  in  therapeutic  range)  was  
 
 
 
 
 
 
 
 
 
 
allowed  as  well  as  antiplatelet  drugs.  
 
 
 
Prohibited  treatments  
 
 
 
●
The  use  of  other  antitumoral  agents  different  from  the  study  drugs  was  not  permitted,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
whether  or  not  they  were  experimental.  Active  or  passive  immunotherapy  was  not  permitted.  
 
●
Cooling  scalp  systems  to  prevent  alopecia,  or  ice  mouthwashes  to  prevent  stomatitis  were  
 
 
 
 
 
 
 
 
 
 
 
 
 
not  allowed  because  of  the  risk  of  causing  cold-induced-oxaliplatin  dysesthesia.  
 
●
The  use  of  vitamin  B6  (pyridoxine)  for  hand-foot  syndrome  prophylaxis/treatment  was  not  
 
 
 
 
 
 
 
 
 
 
 
 
allowed,  because  of  loss  of  efficacy  when  administered  with  oxaliplatin.  
 
●
Subjects  treated  with  oxaliplatin  had  not  take  cold  drinks  and  ice  on  day  1  of  each  treatment  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
cycle,  since  exposure  to  cold  could  exacerbate  oral  or  pharyngeal  dysestesia.  
 
●
Patients  had  to  be  monitored  carefully  for  side  effects,  covering  all  concomitant  medications  
 
 
 
 
 
 
 
 
 
 
 
 
 
regardless  of  the  route  of  administration  of  the  drug,  especially  those  with  narrow  therapeutic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
indices,  such  as  digoxin,  warfarin  (aldocumar)  and  quinidine.  Blood  levels  had  to  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
monitored  and  appropriate  laboratory  tests  performed  as  clinically  indicated.  
 
  
  
 
 
11.4.6
Treatment  Compliance  
 
The  study  drug  was  administered  by  the  nursing  staff  of  the  oncology-day  care  centre  under  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator’s  supervision. 
Since  the  intravenous  infusions  were  administered  in  a  hospital  or  outpatient  clinic  setting,  
 
 
 
 
 
 
 
 
 
 
 
 
 
compliance  with  treatment  could  be  easily  monitored.  The  date  and  time  of  the  beginning  and  end  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  infusion  and  exact  amount  of  study  medication  (aflibercept,  oxaliplatin,  5FU  and  LV)  
 
 
 
 
 
 
 
 
 
 
 
 
 
administered  in  each  infusion  had  to  be  documented  in  the  patient’s  medical  record  and  eCRF.   
  
If  the  treatment  had  to  be  modified  or  interrupted  during  the  infusion,  the  staff  in  charge  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
procedure  had  to  estimate  the  percentage  of  the  dose  received  by  the  patient  and  document  it  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
eCRF.  All  the  reasons  for  non-compliance  with  study  treatment  had  to  be  recorded.  
 
Insufficient  compliance  with  the  dosing  regimen  for  aflibercept,  oxaliplatin,  5FU  or  LV  was  defined  as  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
missing  more  than  2  consecutive  infusions  for  reasons  other  than  toxicity.   
  
11.5
Efficacy  and  Safety  Variables  
 
11.5.1
Efficacy  assessment  
 
Efficacy  variables:  
 
●
Pathological  Complete  response  (pCR):  pCR  was  defined  as  the  percentage  of  patients  
 
 
 
 
 
 
 
 
 
 
 
 
with  no  tumor  viable  cells  in  the  surgical  sample  after  induction  therapy.  
 
 
 
 
 
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●
Disease  -Free  Survival :  time  from  randomization  to  the  appearance  of  any  signs  or  
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms  of  cancer  relapse.  Patients  who  withdrew  from  the  study  before  reaching  relapse  
 
 
 
 
 
 
 
 
 
 
 
 
 
and  without  completing  the  withdrawal  consent  had  to  be  followed  up  to  determine  their  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
status  whenever  possible.  
 
●
“Vascular  Normalization  Index  Biomarker”:  correlation  between  permeability  parameters  
 
 
 
 
 
 
 
 
(BF,  BV  and  k-trans)  and  MVD  and  IFP  were  assessed,  as  well  as  the  correlation  between  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VEGFR,  ANG/ANG2,  and  IL-2  with  response  to  treatment.  
 
11.5.2
  Safety  assessment  
 
The  safety  profile  was  determined  from  the  AEs  reported  by  the  subjects  during  the  clinical  study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Each  patient  was  monitored  regularly  to  detect  possible  AEs  before  beginning  each  cycle.  The  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
number  and  percentage  of  AEs  observed,  and  their  intensity  were  reported.  The  intensity  of  the  AEs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
was  classified  according  to  the  NCI-CTCAE  v4.0.  
 
 
 
The  period  of  notification  of  AEs  began  when  the  informed  consent  was  signed.  Serious  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
non-serious  AEs  related  to  the  study  treatment  that  appeared  up  to  30  days  after  administration  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  last  dose  had  to  be  recorded.  
 
 
 
Any  AE  or  laboratory  anomaly  that  was  serious  and  occurred  during  the  development  of  the  study,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
independently  of  the  treatment  received  by  the  patient,  had  to  be  reported  immediately  by  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator  (within  24  hours  of  first  aware  of  the  case).  
 
 
 
A  follow-up  had  to  be  made  of  the  AEs,  especially  those  whose  relationship  with  the  medication  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigation  could  not  be  classified  as  “non  related”,  until  the  baseline  situation  had  been  restored  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
or  the  AE  was  stabilized.  If  a  clear  explanation  was  stablished,  it  was  recorded  in  the  eCRF.  
 
11.6
Statistical  Methods  Planned  in  the  Protocol  and  Determination  of  Sample   
Size   
  
11.6.1
Statistical  and  Analytical  Plans  
 
 
 
Study  populations :  
 
The  primary  efficacy  analysis  was  based  on  the  Intent  to  treat  (ITT)  Population,  although  a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
secondary  analysis  was  also  be  performed  based  upon  the  Per  Protocol  (PP)  Population  to  assess  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  sensitivity  of  the  analysis  to  the  choice  of  analysis  population.  All  safety  analyses  were  based  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
upon  the  Safety  Population.   
  
 
 
●
ITT  population:  formed  by  all  randomized  patients  who  received  at  least  one  dose  of  Trial  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug.   
  
●
Per  protocol  population :  the  PP  Population  included  ITT  patients  who  met  both  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
following  criteria:  
 
o
Received  at  least  80%  of  their  intended  Trial  Drug.  
 
o
Did  not  have  any  major  protocol  violations.  
 
The  PP  Population  could  be  used  in  efficacy  analyses  as  a  sensitivity  analysis.  
 
●
Safety  population  (PP) :  all  the  subjects  were  evaluable  for  toxicity  so  long  as  they  had  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
received  at  least  a  first  administration  of  the  study  drugs.  
 
 
 
All  primary  analyses  of  the  safety  data  were  conducted  using  the  safety  population.  
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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The  ITT  Population  was  used  for  all  efficacy  analyses.  The  rate  of  pCR  was  analyzed  as  a  binary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
parameter.  A  z  test  was  used  for  the  differences  between  percentages  (or  Fisher’s  exact  test  if  the  
   
 
 
 
 
 
 
 
 
 
 
 
  
 
assumptions  were  not  met).  A  90%  confidence  interval  of  the  between-group  difference  was  added.  
 
Continuous  demographic  parameters,  such  as  age  at  the  time  of  enrollment,  were  summarized  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  ITT  Population  using  descriptive  statistics  (N,  mean,  median,  SD,  minimum,  and  maximum  
 
 
 
 
 
 
 
 
 
 
 
 
 
value).  
 
Categorical  demographic  parameters,  such  as  gender,  were  summarized  as  a  frequency  and  
 
 
 
 
 
 
 
 
 
 
 
 
proportion  of  the  ITT  Population.  
 
R0  resection,  TRG,  and  CRM  rate  were  analyzed  as  binary  parameters,  like  the  main  endpoint:  A  z  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
test  was  used  for  the  differences  between  percentages  (or  Fisher’s  exact  test  if  the  assumptions  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
were  not  met).  
 
The  Kaplan-Meier  plots  were  presented  for  the  Time-to-Event.  Log-rank  test  was  applied  to  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
groups’  comparison.  Hazard  ratio  through  Cox  model  was  calculated  (if  the  assumptions  were  met).  
 
Quantitative  parameters,  was  analyzed  through  ANCOVA  model,  including  basal  value  as  covariate.  
 
Any  other  continuous  parameters:  ANCOVA  model  on  the  changes  from  baseline  with  treatment,  
 
 
 
 
 
 
 
 
 
 
 
 
 
baseline  value  and  any  stratification  factors  as  fixed  effects.  A  95%  confidence  interval  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
between-group  difference  was  added.  
 
 
 
11.6.2
Determination  of  Sample  Size  
 
Assuming  10%  of  drop-outs  a  total  of  180  patients  were  recruited  (120  patients  for  mFolfox6  +   
Aflibercept  group  and  60  for  mFolfox6).  
 
 
 
Assumptions:  
 
 
 
●
2  treatment  arms  with  unequal  2:1  group  allocation  
 
●
0.20,  two-sided,  type-I  error  
 
●
mFolfox6  efficacy:  15%  pCR  rate  
 
●
Aflibercept  +  mFolfox6  efficacy:  30%  pCR  rate  
 
●
80%  power  to  detect  a  15%  treatment  difference  
 
●
2  interim  analyses:  
 
o
At  33%  of  the  sample  size  for  safety,  futility/efficacy  
 
o
At  66%  of  the  sample  size  for  safety,  futility/efficacy  
 
●
One  final  analysis  
 
●
Stopping  rules:  
 
o
Efficacy:  Lan  de  Mets  Alpha  spending  function  (O’Brien-Fleming)  
 
o
Futility:  Lan  de  Mets  Alpha  spending  function  (O’Brien-Fleming),  non-blinding  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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12.
S TUDY  S UBJECTS  
 
  
   
 
 
Table  3.  Distribution  of  patients  by  sites  
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Centres  
 
Investigators  
 
Patients  enrolled  
 
01-IVO  
 
Dr.  Carlos  Fernández-Martos  
 
 
 
 
02-H.  Arnau  de  Vilanova  Lleida  
 Dra.  Antonieta  Salud  Salvia  
 
 
 
 
03-C.  Sanit.  Parc  Tauli  
 
Dr.  Carles  Pericay  Pijaume  
 
 
 
04-  H.  del  Mar  
 
Dra.  Clara  Montagut  
 
 
 
05-  H.  Clinic  i  Prov  Barcelona  
 
Dr.  Joan  Maurel  Santasusana 
 
 
06-  H.  Miguel  Servet  
 
Dr.  Vicente  Alonso  Orduña  
 
 
 
08-  H.  de  Navarra  
 
Dra.  Ruth  Vera  García  
 
 
 
09-  H.  Gral.  U.  Elche  
 
Dr.  Javier  Gallego  Plazas  
 
 
 
10-  H.  La  Paz  
 
Dra.  Núria  Rodríguez  Salas  
 
 
 
11-H.  Sta.  Creu  i  Sant  Pau  
 
Dra.  Marta  Martín-Richard  
 
 
 
 
12-C.I.O.  Clara  Campal  
 
Dr.  Antonio  Cubillo  
 
 
 
 
13-H.  Gral.  Alicante  
 
Dr.  Bertomeu  Massuti  
 
 
 
14-H.  de  Granollers  
 
Dr.  Miguel  Nogué  
 
 
 
15-H.  Sant  Joan  Despí-Moisés 
 
 
 
 
Broggi  
 
Dr.  Ferrán  Losa  
 
 
 
16-H.  Vall  d’Hebrón  
 
Dr.  Jaume  Capdevila  
 
 
 
17-H.  Prov.  Castellón  
 
Dra.  Isabel  Busquier  Hernández 
 
 
18-.  Althaia  Manresa  
 
Dra.  Elena  Cillán   
  
 
 
20-  H.  GTiP  
 
Dra.  Laura  Layos  Romero  
 
 
 
21-H.  Univ.  12  de  Octubre  
 
Dra.  Rocío  García  Carbonero  
 
 
 
22-H.  Univ.  Marqués  Valdecilla  
 
Dr.  Carlos  López  López  
 
 
 

 
 
 
 
12.1
Discontinuations  
 
 
 
Table  4.  Patients  that  did  not  complete  the  study  treatment  (Neoadjuvant  CT  or  Neoadjuvant  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/RT)  and  end  of  treatment  reasons  
 
 
 
 
 
 
 
Table  5.  Reasons  for  withdrawal  from  the  Study  Treatment  
 
 
 
 
 
 
 
12.2
Major  protocol  deviations  
 
 
 
A  description  of  all  major  deviations  is  shown  in  Table  6.   
  
 
 
Table  6.  Major  Deviations  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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End  of  treatment  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
Total  
 
(N=)  
 
Treatment  withdrawal?  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
Reasons  of  withdrawal  
 
 
 
 
 
 
 
 
 
Toxicity,  AE  
 
n  (%)  
 
 
 
 
 
 
 
Withdrawal  of  inform  consent  and/or  rejection  of  the  treatment   
and/or  uncooperativeness  
 
n  (%)  
 
 
 
 
 
 
 
Progression  disease  
 
n  (%)  
 
 
 
 
 
 
 
Death  
 
n  (%)  
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
At  the  discretion  of  the  Investigator  or  Sponsor  
 
n  (%)  
 
 
 
 
 
 
 
Treatment  arm  
 
Patient   
ID  
 
CT  
 
CT/RT SUR  
 
Was  the  patient   
withdrawn  for   
the  study  
 
Withdrawal  causes  
 
Toxicity  description (1)  
 
Progression   
description  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject  code  
 Major  deviation(s)  
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.
EFFICACY  EVALUATION  
 
13.1
Data  Sets  Analyzed  
 
 
 
Table  7.  Analysis  populations  
 
 
 
 
 
ITT  population  (ITT).  It  will  include  all  randomized  patients  who  received  at  least  one  dose  of  Trial  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug.  
 
 
 
ITT  population  with  curative  surgery  will  include  all  ITT  patients  that  received  curative  surgery.  
 
 
 
PP  population  (PP)  will  include  ITT  patients  who  met  both  of  the  following  criteria:  
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Populations  in  the  study  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
Total  
 
(N=)  
 
ITT  population  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
ITT  population  with  curative  surgery  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
PP  population  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
PP  population  with  curative  surgery  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
SAF  population  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 

 
 
 
 
●
Received  at  least  80%  of  their  intended  Trial  Drug  
 
●
Did  not  have  any  major  protocol  violations  
 
 
 
PP  population  with  curative  surgery  will  include  all  PP  patients  that  received   curative  surgery.  
 
 
 
Safety  Population  (SAF):  It  consists  of  all  patients  who  received  at  least  a  first  administration  of  Trial  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
Drug.  
 
 
 
All  primary  analyses  of  the  efficacy  data  will  be  conducted  using  the  ITT  population  and  safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
analyses  will  be  performed  for  the  SAF  population.  The  PP  population  will  be  used  for  efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
analyses  as  a  sensitivity  analysis.  
 
 
 
13.2
Demographic  and  Other  Baseline  Characteristics  
 
 
 
Demographics  by  treatment  arm  in  ITT  population  are  shown  at  the  Table  8 .  
 
 
 
 
 
 
 
Table  8.  Demographic  Characteristics  ITT   
  
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Demographic  Characteristics  ITT  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6 
(N=))  
 
mFOLFOX-6  
 
(N=)  
 
P  Value  Test  
 
Age  (years) 
 
 
 
 
 
 
 
 
 
 
n  
 
 
 
 
 
 
 
 
 
Mean  (SD)  
 
 
 
 
 
 
 
 
 
Median  [Q1,Q3]  
 
 
 
 
 
 
 
 
 
Min,  Max  
 
 
 
 
 
 
 
Sex  
 
 
 
 
 
 
 
 
 
Female  
 
n  (%)  
 
 
 
 
 
 
 
Male  
 
n  (%)  
 
 
 
 
 
 
 
ECOG  performance  status  
 
 
 
 
 
 
 
 
 
0  
 
n  (%)  
 
 
 
 
 
 
 
1  
 
n  (%)  
 
 
 
 
 
 
 
Clinical  T  stage  (middle  and  distal) 
 
 
 
 
 
 
 
 
Missing n  (%)  
 
 
 
 
 
 
 
mrT2  
 
n  (%)  
 
 
 
 
 
 
 
mrT3  
 
n  (%)  
 
 
 
 
 
 
 
mrT3B 
n  (%)  
 
 
 
 
 
 
 
mrT3A 
n  (%)  
 
 
 
 
 
 
 
mrT3C  
 
n  (%)  
 
 
 
 
 
 
 
mrT3D  
 
n  (%)  
 
 
 
 
 
 
 
mrT4  
 
n  (%)  
 
 
 
 
 
 
 
mrT4A 
n  (%)  
 
 
 
 
 
 
 

 
 
 
 
 
 
Demographics  by  treatment  arm  in  PP  population  are  shown  at  the  Table  9.  
 
 
 
Table  9.  Demographic  Characteristics  PP  
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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mrT4B 
n  (%)  
 
 
 
 
 
 
 
Clinical  T  stage  (grouped)  
 
 
 
 
 
 
 
 
 
Missing n  (%)  
 
 
 
 
 
 
 
T2/T3  
 
n  (%)  
 
 
 
 
 
 
 
T4  
 
n  (%)  
 
 
 
 
 
 
 
FMR  
 
 
 
 
 
 
 
 
 
FMR  +  (distance  <=1  mm)  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
EMVI  
 
 
 
 
 
 
 
 
 
EMVI  -  (score  0/1/2)  
 
n  (%)  
 
 
 
 
 
 
 
EMVI  +  (score  3/4)  
 
n  (%)  
 
 
 
 
 
 
 
N2  
 
 
 
 
 
 
 
 
 
N2  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
Location  
 
 
 
 
 
 
 
 
 
Distal  
 
n  (%)  
 
 
 
 
 
 
 
Middle  
 
n  (%)  
 
 
 
 
 
 
 
Missing n  (%)  
 
 
 
 
 
 
 
Histology  
 
 
 
 
 
 
 
 
 
Adenocarcinoma  
 
n  (%)  
 
 
 
 
 
 
 
Demographics  PP  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
P  Value  Test  
 
Age  (years) 
 
 
 
 
 
 
 
 
 
 
n  
 
 
 
 
 
 
 
 
 
Mean  (SD)  
 
 
 
 
 
 
 
 
 
Median  [Q1,Q3]  
 
 
 
 
 
 
 
 
 
Min,  Max  
 
 
 
 
 
 
 
Sex  
 
 
 
 
 
 
 
 
 
Female  
 
n  (%)  
 
 
 
 
 
 
 
Male  
 
n  (%)  
 
 
 
 
 
 
 
ECOG  performance  status  
 
 
 
 
 
 
 
 
 
0  
 
n  (%)  
 
 
 
 
 
 
 
1  
 
n  (%)  
 
 
 
 
 
 
 
Clinical  T  stage  (middle  and  distal)  
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Missing n  (%)  
 
 
 
 
 
 
 
mrT2  
 
n  (%)  
 
 
 
 
 
 
 
mrT3  
 
n  (%)  
 
 
 
 
 
 
 
mrT3B 
n  (%)  
 
 
 
 
 
 
 
mrT3A 
n  (%)  
 
 
 
 
 
 
 
mrT3C  
 
n  (%)  
 
 
 
 
 
 
 
mrT3D  
 
n  (%)  
 
 
 
 
 
 
 
mrT4  
 
n  (%)  
 
 
 
 
 
 
 
mrT4A 
n  (%)  
 
 
 
 
 
 
 
mrT4B 
n  (%)  
 
 
 
 
 
 
 
Clinical  T  stage  (grouped)  
 
 
 
 
 
 
 
 
 
Missing n  (%)  
 
 
 
 
 
 
 
T2/T3  
 
n  (%)  
 
 
 
 
 
 
 
T4  
 
n  (%)  
 
 
 
 
 
 
 
FMR  
 
 
 
 
 
 
 
 
 
FMR  +  (distance  <=1  mm)  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EMVI  
 
 
 
 
 
 
 
 
 
EMVI  -  (score  0/1/2)  
 
n  (%)  
 
 
 
 
 
 
 
EMVI  +  (score  3/4)  
 
n  (%)  
 
 
 
 
 
 
 
N2  
 
 
 
 
 
 
 
 
 
N2  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
Location  
 
 
 
 
 
 
 
 
 
Distal  
 
n  (%)  
 
 
 
 
 
 
 
Middle  
 
n  (%)  
 
 
 
 
 
 
 
Missing n  (%)  
 
 
 
 
 
 
 
Histology  
 
 
 
 
 
 
 
 
 
Adenocarcinoma  
 
n  (%)  
 
 
 
 
 
 
 

 
 
 
 
13.3
Efficacy  Results  and  Tabulations  
 
13.3.1
Analysis  of  Efficacy  
 
 
 
ITT  population  will  be  used  for  the  efficacy  analyses.  
 
 
 
Primary  Efficacy  Analysis  in  the  ITT  Population  
 
 
 
The  primary  objective  of  this  study  is  to  assess  the  efficacy  of  induction  therapy  with  mFOLFOX  +/-  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Aflibercept  followed  by  CT/RT  in  terms  of  pathologic  response  (pCR)  (Yes/No).  pCR  is  defined  as  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
the  absence  of  viable  tumor  cells  in  the  primary  tumor  and  in  the  lymph  nodes  (ypT0N0).  The  values  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
from  ypTNM  stage  are  taken  to  create  pCR  categorical  variable  (Yes/No).  
 
  
  
Table  10.  pCR  Response  in  the  ITT  Population  
 
 
 
 
 
 
 
 
 
Secondary  Efficacy  Objectives  in  the  ITT  Population  
 
 
 
The  secondary  efficacy  objectives  are  the  following:  
 
 
 
●
To  evaluate  pathological  parameters  of  efficacy:  R0  resection.  Endpoint :  To  determine  
 
 
 
 
 
 
 
 
 
 
 
CRM  negative  (negative  vs  positive)  and  R0  resection  rates  (Yes/No)  
 
●
To  evaluate  the  relationship  between  MRI  changes  and  pathological  tumor  response.  i.e  
 
 
 
 
 
 
 
 
 
 
 
 
mrTRG.  Endpoint :  TRG;  residual  tumor  after  preoperative  therapy  was  evaluated  according  
 
 
 
 
 
 
 
 
 
 
 
to  the  5-point  regression  grading  scale  stablished  by  Mandard.  Involvement  of  the  histologic  
 
 
 
 
 
 
 
 
 
 
 
 
 
CRM  was  defined  as  tumor  <  2  mm  from  the  resection  margin.  
 
●
T  Downstaging  (Yes/No):  defined  as  a  lower  pathologic  T  stage  compared  to  pre-treatment  
 
 
 
 
  
 
  
 
 
 
 
mrT  stage.  
 
●
To  evaluate  the  3  years  local  recurrence  and  disease-free  survival.  Endpoint :  To  determine  
 
 
  
 
 
 
 
 
 
 
 
 
the  rate  of  local  recurrence  and  disease-free  survival  (DFS)  at  3-years.  
 
 
 
In  Table  11  are  enclosed  the  results  related  to  the  first  three  first  secondary  efficacy  variables.  
 
 
 
Table  11.  Secondary  Efficacy  Objectives  in  the  ITT  Population  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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pCR  response  (ITT)  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
P  Value  Test  
 
pCR  (Yes/No)  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
Secondary  efficacy  objectives  (ITT)  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6 
(N=)  
 
mFOLFOX-6 
(N=)  
 
P  Value  Test  
 
Resection  type  
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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NA  
 
n  (%)  
 
 
 
 
 
 
 
R0  
 
n  (%)  
 
 
 
 
 
 
 
R1  
 
n  (%)  
 
 
 
 
 
 
 
R2  
 
n  (%)  
 
 
 
 
 
 
 
RX  
 
n  (%)  
 
 
 
 
 
 
 
Circumferential  Resection  Margin  (CRM)  
 
 
 
 
 
 
 
 
 
<=  1  mm  
 
n  (%)  
 
 
 
 
 
 
 
>  1  mm  
 
n  (%)  
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
Tumor  Regression  Grade  (TRG)  
 
 
 
 
 
 
 
 
 
TRG1  
 
n  (%)  
 
 
 
 
 
 
 
TRG2  
 
n  (%)  
 
 
 
 
 
 
 
TRG3  
 
n  (%)  
 
 
 
 
 
 
 
TRG4  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
TRG5  
 
n  (%)  
 
 
 
 
 
 
 
TRG1+TRG2  vs  others?  
 
 
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
Local  invasion  (ypT)  
 
 
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
T0  
 
n  (%)  
 
 
 
 
 
 
 
T1  
 
n  (%)  
 
 
 
 
 
 
 
T2  
 
n  (%)  
 
 
 
 
 
 
 
T3  
 
n  (%)  
 
 
 
 
 
 
 
T4A  
 
n  (%)  
 
 
 
 
 
 
 
T4B  
 
n  (%)  
 
 
 
 
 
 
 
TIS  
 
n  (%)  
 
 
 
 
 
 
 
T-Downstaging  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
T-Downstaging  (details)  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
At  least  one  value  not  recorded  in  CRF  
 
n  (%)  
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
In  Table  12  it  is  shown  the  DFS  of  ITT  population.  
 
 
 
Table  12.  Disease  free  survival  ITT  
 
 
 
Figure  3.  Disease  free  survival  ITT  
 
 
 
 
 
 
 
PP  population  will  be  used  for  the  efficacy  sensitivity  analyses.  
 
 
 
Primary  Efficacy  Analysis  in  the  PP  Population  
 
 
 
 
 
Table  13.  pCR  Response  in  the  PP  population  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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AFLIBERCEPT  +  mFOLFOX-6  
 
mFOLFOX-6  
 
Summary  of  events  
 
 
 
 
 
    No  of  patients  
 
 
 
 
 
    No  of  patients  with  event  
 
 
 
 
 
    No  of  censored  patients  
 
 
 
 
 
Progression  free  survival  ITT  
 
 
 
 
 
    Median  (95%  CI)  
 
 
 
 
 
    25th-75th  percentile  
 
 
 
 
 
Percent  Survival  (%,  95%  CI)  
 
 
 
 
 
    0  Months  
 
 
 
 
 
    12  Months  
 
 
 
 
 
    24  Months  
 
 
 
 
 
    36  Months  
 
 
 
 
 
    48  Months  
 
 
 
 
 
Kaplan_Meier  Model  
 
 
 
 
 
    P-value  (Log-rank)  
 
 
 
 
 
Cox  Model  
 
Hazard  ratio  (95%  CI)  
 
Cox  Model  P-value  
 
    mFOLFOX-6                vs  AFLIBERCEPT  +  mFOLFOX-6  
 
 
 
 
 
pCR  response  (PP)  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
P  Value  Test  
 

 
 
 
 
 
 
 
 
 
 
Secondary  Efficacy  Objectives  in  the  PP  Population  
 
 
 
The  secondary  efficacy  objectives  are  the  following:  
 
 
 
●
To  determine  CRM  negative  (negative  vs  positive)  and  R0  resection  rates  (Yes/No).  
 
●
TRG;  residual  tumor  after  preoperative  therapy  was  evaluated  according  to  the  5-point  
 
 
 
 
 
 
 
 
 
 
 
 
regression  grading  scale  stablished  by  Mandard.  Involvement  of  the  histologic  CRM  was  
 
 
 
 
 
 
 
 
 
 
 
 
defined  as  tumor  <  2  mm  from  the  resection  margin.  
 
●
T  Downstaging  (Yes/No):  defined  as  a  lower  pathologic  T  stage  compared  to  pre-treatment  
 
 
 
 
  
 
  
 
 
 
 
mrTstage.  
 
●
To  determine  the  rate  of  local  recurrence  and  disease-free  survival  (DFS)  at  3-years.  
 
 
 
In  Table  14  we  can  see  the  results  related  to  the  first  three  first  efficacy  variables.  
 
 
 
 
 
Table  14.  Secondary  Efficacy  Objectives  in  the  PP  Population  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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pCR  (Yes/No)  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
Secondary  efficacy  objectives  (PP)  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6 
(N=)  
 
mFOLFOX-6 
(N=)  
 
P  Value  Test  
 
Resection  type  
 
 
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
R0  
 
n  (%)  
 
 
 
 
 
 
 
R1  
 
n  (%)  
 
 
 
 
 
 
 
R2  
 
n  (%)  
 
 
 
 
 
 
 
RX  
 
n  (%)  
 
 
 
 
 
 
 
Circumferential  Resection  Margin  (CRM)  
 
 
 
 
 
 
 
 
 
<=  1  mm  
 
n  (%)  
 
 
 
 
 
 
 
>  1  mm  
 
n  (%)  
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 
Tumor  Regression  Grade  (TRG)  
 
 
 
 
 
 
 
 
 
TRG1  
 
n  (%)  
 
 
 
 
 
 
 
TRG2  
 
n  (%)  
 
 
 
 
 
 
 
TRG3  
 
n  (%)  
 
 
 
 
 
 
 
TRG4  
 
n  (%)  
 
 
 
 
 
 
 
NR  
 
n  (%)  
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
In  Table  15  it  is  shown  the  DFS  of  PP  population.  
 
 
 
Table  15.  Disease  free  survival  in  PP  population  
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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NA  
 
n  (%)  
 
 
 
 
 
 
 
TRG1+TRG2  vs  others? 
 
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
Local  invasion  (ypT)  
 
 
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 
T0  
 
n  (%)  
 
 
 
 
 
 
 
T1  
 
n  (%)  
 
 
 
 
 
 
 
T2  
 
n  (%)  
 
 
 
 
 
 
 
T3  
 
n  (%)  
 
 
 
 
 
 
 
T4A  
 
n  (%)  
 
 
 
 
 
 
 
T4B  
 
n  (%)  
 
 
 
 
 
 
 
TIS  
 
n  (%)  
 
 
 
 
 
 
 
T-Downstaging  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
T-Downstaging  (details)  
 
 
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
At  least  one  value  not  recorded  in  CRF  
 
n  (%)  
 
 
 
 
 
 
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
mFOLFOX-6  
 
Summary  of  events  
 
 
 
 
 
    No  of  patients  
 
 
 
 
 
    No  of  patients  with  event  
 
 
 
 
 
    No  of  censored  patients  
 
 
 
 
 
Progression  free  survival  PP  
 
 
 
 
 
    Median  (95%  CI)  
 
 
 
 
 
    25th-75th  percentile  
 
 
 
 
 
Percent  Survival  (%,  95%  CI)  
 
 
 
 
 
    0  Months  
 
 
 
 
 
    12  Months  
 
 
 
 
 

 
 
 
 
 
 
Figure  4.  Disease  free  survival  PP  
 
 
 
 
 
14.
SAFETY  EVALUATION  
 
 
 
Safety  analyses  will  be  performed  on  the  SAF  population  and  will  be  based  mainly  on  the  frequency  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  severity  of  the  AEs.  
 
 
 
The  safety  and  tolerability  of  the  study  therapy  will  be  assessed  by  means  of  AEs  and  changes  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
laboratory  data  that  will  be  reported  in  the  AEs  page.  
 
 
 
Treatment-Emergent  Adverse  Events  (TEAEs)  are  defined  as  AEs  that  had  occurred  or  worsened  in  
 
 
 
 
 
 
 
 
 
 
 
 
  
severity  and/or  frequency  after  initiation  of  therapy.  Any  event  with  an  onset  on  the  day  of  the  first  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dose  of  Trial  Drug  on  which  the  time  of  onset  will  be  missing  was  assumed  to  be  a  TEAE.  
 
 
 
14.1
Adverse  Events  
 
For  the  statistical  tables,  adverse  events  will  be  coded  according  to  the  Medical  Dictionary  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regulatory  Activities  (MedDRA  20.1)  system.  Their  intensity  will  be  coded  by  (NCI-CTCAE)  v4.0  
 
 
 
 
 
 
 
 
 
 
 
 
 
toxicity  criteria.  
 
 
 
  
  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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    24  Months  
 
 
 
 
 
    36  Months  
 
 
 
 
 
    48  Months  
 
 
 
 
 
Kaplan_Meier  Model  
 
 
 
 
 
    P-value  (Log-rank)  
 
 
 
 
 
Cox  Model  
 
Hazard  ratio  (95%  CI)  
 
Cox  Model  P-value  
 
    mFOLFOX-6                vs  AFLIBERCEPT  +  mFOLFOX-6  
 
 
 
 
 

 
 
 
 
14.1.1
Brief  Summary  of  Adverse  Events  
 
 
 
Table  16.  Summary  of  TEAEs  during  the  Study  Period  
 
 
 
 
 
14.1.2
Display  of  Adverse  Events  
 
Table  17.  TEAEs  During  the  Study  Period:  Worst  Grade  per  patient  (Most  Frequent  >  5%)  
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
Total  
 
(N=)  
 
P-Value  
 
Summary  of  adverse  events   
  
(Study  period)  
 
 
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  adverse  event  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  grade  3/4  adverse   
event  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  adverse  event  that   
led  to  permanently  treatment  discontinuation  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  adverse  event  that   
led  to  death  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  serious  adverse   
event  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  adverse  event  that   
the  investigator  considered  related  with  study   
medication  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  grade  3/4  adverse   
event  that  the  investigator  considered  related   
with  study  medication  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  adverse  event  that   
the  investigator  considered  related  with  study   
medication  and  lead  to  death  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  adverse  event  that   
the  investigator  considered  related  and  led  to   
permanently  treatment  discontinuation  
 
n  (%)  
 
 
 
 
 
 
 
 
 
Patients  with  at  least  one  serious  adverse   
event  
 
n  (%)  
 
 
 
 
 
 
 
 
 
SOC  MedDRA  Term/Preferred   
MeDDRA  Term  
 
Treatment/Grade  
 
Total  (N=)  
 
AFLIBERCEPT  +  mFOLFOX-6  (N=)  
 
mFOLFOX-6  (N=)  
 
1  
 
2  
 
3  
 
4  
 
5 (1)  
 
1  
 
2  
 
3  
 
4  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
N  
 
%  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
Table  18.  Surgical  procedures,  toxicities  and  grading  of  TME  in  patients  who  undergo  
 
 
 
 
 
 
 
 
 
 
 
 
 
curative  surgery  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Surgical  procedures,  toxicities  and  grading  of  TME  in  patients  who  undergo  curative  surgery  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6  
 
(N=)  
 
 
 
n  (%)  
 
n  (%)  
 
Type  of  curative  surgery  
 
 
 
 
 
Low  anterior  resection  
 
 
 
 
 
Abdominoperineal  resection  
 
 
 
 
 
Others 
 
 
 
 
Postoperative  morbidity  
 
 
 
 
 
Overall  registered  AEs  (any  grade)  
 
 
 
 
 
Overall  registered  AEs  Grade  3-4  
 
 
 
 
 
Overall  complications  (any  grade)*  
 
 
 
 
 
Anastomotic  fistula  
 
 
 
 
 
Wound  infection  (abdominal  or  perineal)  
 
 
 
 
 
Intraabdominal  infection  
 
 
 
 
 
Stoma  complications  
 
 
 
 
 
Reoperation  
 
 
 
 
 
Postoperative  mortality  
 
 
 
 
 
Other  morbidity  
 
 
 
 
 
Grading  of  operative  specimen  
 
 
 
 
 
Mesorectal  plane  (good)  
 
 
 
 
 
Muscularis  propria  plane  (poor)  
 
 
 
 
 
Intramesorectal  plane  (moderate)  
 
 
 
 
 
NR  
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
14.2
Deaths,  Other  SAEs,  and  Other  Significant  Adverse  Events  
 
14.2.1
Deaths  
 
 
 
Table19.  Deaths  
 
 
 
 
 
 
 
Narratives  of    Deaths,  Other  Serious  AEs,  and  Certain  Other  Significant  AEs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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Deaths  
 
 
 
AFLIBERCEPT  +  mFOLFOX-6  
 
(N=)  
 
mFOLFOX-6 
(N=)  
 
Total  
 
(N=)  
 
Number  of  deaths  
 
 
 
 
 
 
 
 
 
No  
 
n  (%)  
 
 
 
 
 
 
 
Yes  
 
n  (%)  
 
 
 
 
 
 
 
Cause  of  death  
 
 
 
 
 
 
 
 
 
Progression  disease  
 
n  (%)  
 
 
 
 
 
 
 
Intercurrent  cause  
 
n  (%)  
 
 
 
 
 
 
 
Other  Causes  
 
n  (%)  
 
 
 
 
 
 
 
NA  
 
n  (%)  
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.
DISCUSSION  AND  OVERALL  CONCLUSIONS  
 
 
 
LIST  MAIN  CONCLUSIONS  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol  number  GEMCAD-1402  
 
 
 
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16.
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