Brain cancer clinical trials in Australia Dr Helen Wheeler

Hosted by Cure Brain Cancer Foundation

Clinical  Trials    

Dr  Helen  Wheeler  1.5.2014  NSCC    

St  Leonards  

How  are  new  treatments  developed?  

•  Rapid  advances  in  molecular  biology  have  allowed  scienFsts  to  compare  the  differences  between  normal  cells  and  malignant  cells—which  control    – Growth  – Division  – Movement  – How  they  interact  with  their  environment  – How  they  interact  with  the  immune  system  

   

1st  human  genome  project  cost  $3.8  billion  and  involved  the  best  labs  from  all  over  the  world  

•  What  iniFally  took  13  years  can  now  take  weeks  to  months  with  new  technology    

•  The  machines  unfortunately  are  expensive  but  cost  is  falling  rapidly  

•  This  new  technology  has  idenFfied  specific  gene  changes  in  individual  tumours  which  can  be  idenFfied  in  days  vs  years,  and  is  helping  to  drive  drug  development,  someFmes  on  a  personalized  level  

Gene  Sequencer  

We  can  then  map  “pathways”  which  are  unique  to  cancer  cells  

Aberrantly activated signalling pathways in malignant glioma

Reardon, D. A. et al. J Clin Oncol; 24:1253-1265 2006

EGFR

IdenFfying  discriminaFng  genes  

KPNA5 Homer1 YKL-40 LGALS1 IGFBP2 IQGAP1 RBP1 COPZ2 SPP1 SERPINA3 ARS

Low Grade Brain Tumours High Grade Brain Tumours

LRRC20 HS75LP C1QL1 CARHSP1 HSxS138 NFYB KIAA0599

Destroying  cancer  cells  

•  Surgery  –  Physically  remove  what  we  can  idenFfy  as  malignant  cells  

•  Radiotherapy-­‐lasers  etc  to  destroy  •  Chemotherapy-­‐poison  the  malignant  cells  •  IdenFfy  a  unique  molecular  pathway  and  use  targeted  drugs  to  block  the  pathway  

•  Make  the  environment  in  which  they  are  living  and  dividing  “hosFle”  

•  AcFvate  the  immune  system  to  aYack  the  malignant  cells  

There  a  number  of  different  kinds  of  clinical  trials    

•  Trials  evaluaFng  new  therapies  •  Epidemiology/genomic  trials  looking  for  associaFons  and  causes  of  Gliomas  

•  Quality  of  life  trials  – What  symptoms  do  paFents  suffer  and  how  might  they  best  be  alleviated  

– What  impact  does  caring  for  someone  with  a  brain  tumour  have  on  carers,  family  and  friends  

•  There  are  a  number  of  different  agents  being  developed  that  allow  the  surgeons  to  idenFfy  malignant  cells  at  the  Fme  of  operaFon  – ALA  – “Tumor  paint”      

•   may  idenFfy  lower  grade  cells  

– Use  of  AceFc  acid  (vinegar)—in  poor  countries  for  detecFng  cervical  cancer      

Fluorescence guided resection will enable interrogation of distinct tumour compartments…..

New  therapy  trials  

Why  do  clinical  trials?  

•  To  test  the  safety  and  efficacy  of  a  new  medicine,  therapy  or  device.    – Whilst  we  can  iniFally  develop  most  things  in  test  tubes  or  animal  models,  its  not  unFl  they  are  introduced  into  human  trials  that  we  can  determine  their  efficacy  and  side  effects  

•  Tumours  only  survive  if  they  have  a  friendly  “host”  to  live  in  (parasites)  

•  Only  1/10,000  promising  bench-­‐side  break-­‐throughs  will  make  it  in  to  clinical  pracFse  

Thalidomide  disaster  

•  All  pre-­‐clinical  tesFng  was  posiFve  and  safe  •  Unfortunately  

– Only  humans-­‐and  “white  New  Zealand  rabbits”  broke  down  thalidomide  into  a  toxin  which  affects  unborn  children  

•  Developed  as  a  sleeping  tablet-­‐very  effecFve  – Not  unFl  they  started  giving  it  to  pregnant  women  for  nausea  that  the  problems  arose    

IniFally  drugs  are  evaluated  in  test  tubes  

They  are  then  evaluated  in  animal  models  

They  eventually  make  their  way  into  clinical  trials  and  potenFally  the  clinic  

•  The  current  cost  from  cell  tesFng  to  clinical  registraFon  is  esFmated  to  be  – $$$$              1.7  billion  dollars            $$$$$  

 

 

How  Trials  are  iniFated    •  Labs  develop  a  new  compound-­‐    

–  Aeer  iniFal  tesFng,  most  smaller  labs  on-­‐sell  their  compound  to  a  big  pharma  for  development,  as  they  simply  cannot  afford  the  costs  of  clinical  trials  

–  Different  trial  units  are  selected  for  early  phase  tesFng  •  Usually  US  or  Europe,  occasionally  Australia  

•  Royal  Melbourne  hospital  performs  a  lot  of  phase  1  tesFng,  but  there  are  other  centres  around  Australia,  usually  focused  at  big  teaching  hospitals  

•  SomeFmes,  local  invesFgators  develop  a  trial  (invesFgator  iniFated)  

•  So  –  Different  centres  may  have  different  trials  open  at  different  Fmes      

How  to  find  a  clinical  trial  

•  NOT  easy  – Ask  your  doctor  or  care  co-­‐ordinator  

•  Search  web  sites  •  clinicialtrials.gov  •  hYp://www.anzctr.org.au  •  Call  state  cancer  councils  •  Try  and  document  specific  references  

–  Friends  of  friends  –  TV  channel-­‐newspaper  –doctor  hospital  involved  etc  

I  want  to  go  to  America!  

•  Many  drugs  are  1st  tested  in  big  US  hospitals  •  Most  Glioma  trials  are  1st  undertaken  on  paFents  with  relapsed  GBM  –  Unwell-­‐unstable-­‐(not  the  Fme  to  travel)  

•  Financial  cost  of  going  to  the  US  –  Airfares-­‐accommodaFon  – Medical  visa  (>$150,000)  

•  EmoFonal  cost—being  away  from  family  and  friends  •  Promising  early  phase  trials  are  then  usually  “rolled  out”  internaFonally  

Four  different  types  of  clinical  trials  

•  Phase1  – 1st  administraFon  of  a  new  medicine  to  a  human  

– Aeer  extensive  tesFng  in  animals,  a  promising  new  medicaFon,  device  or  treatment  modality    is  finally  introduced  into  human  studies  

   

Phase  1  drug  trials  

•  Usually  •  Cohorts  of  3  paFents  are  selected  •  The  1st  group  is  treated  with  a  certain  dose  of  the  new  drug,  and  studied  over  a  number  of  weeks  

•  If  no  side  effects  have  occurred,  the  next  3  paFents  are  treated  at  a  higher  dose  

•  The  process  conFnues  unFl  the  invesFgators  start  to  see  side  effects,  or  the  level  of  the  drug  needed  to  perform  its  effects  is  reached  

Obviously  

•  PaFents  need  to  be  monitored  very  carefully  •  They  need  numerous  blood  tests,  scans  etc  •  They  must  live  close  enough  to  the  test  centre  to  be  able  to  be  admiYed  etc-­‐if  any  problems  occur  

•  If  they  are  tesFng  a  targeted  therapy,  the  1st  thing  to  be  done  is  to  idenFfy  that  the  tumour  has  the  target  before  proceeding  

Phase  2  clinical  trials  

•  1st  trial  of  a  medicine  in  paFents  suffering  from  a  parFcular  condiFon  (?relapsed  Glioma)  – Does  the  drug  appear  to  work?  –  If  the  drug  safe?  

•  If  the  results  of  the  phase  2  trials  are  promising,  then  the  drug  will  be  taken  into  phase  3  trials  

Phase  3  trials  

•  Results  of  phase  2  trials  are  usually  compared  to  “historical  controls”  

•  Although  a  drug  can  look  extremely  promising  in  phase  2  trials,  there  can  be  a  lot  of  bias  – PaFent  selecFon  (Olympic  rowers  vs  general  populaFon)  

– Historical  controls  don’t  take  into  account  general  improvement  in  surgery,  radiaFon,  supporFve  care  etc  

Why  do  randomised  phase  3  trials?  PaFent  selecFon  can  make  a  big  difference  to  

outcome  

Phase 3 trial end points

•  Does  the  new  therapy  have  a  beYer  outcome  than  standard  treatment?  

•  Are  there  a  lot  more  side  effects  from  the  new  treatment  vs  the  standard  treatment  

•  What  is  the  “COST”  of  the  new  treatment  –  Financial  –  Directly  to  the  paFent  

•  Impact  on  quality  of  life  •  Increased  side  effects  •  Increased  Fme  in  clinic    

Most  new  drug  trials  are  conducted  in  GBM  

•  There  are  “strict”  selecFon  criteria  •  They  may  only  be  selecFng  paFents  whose  tumour  has  a  specific  target  

•  Anyone  on  a  trial  will  need  close  monitoring    

   

Challenges  of  phase  3  tesFng  

•  Cost  •  Large  numbers  of  paFents  •  Long  Fme  lag  from  trial  iniFaFon  to  results  

– Efforts  are  being  made  to  try  and  modify  end  points,  and  reduce  paFent  numbers  

– Then  the  problem  will  be  to  convince  regulators  and  financial  organisaFons  to  accept  such  results  for  drug  registraFon  and  financial  reimbursement  

Advantages  of  being  on  a  trial  

•  Access  to  an  potenFal  new  drug  therapy  •  Close  monitoring  by  a  trial  research  team  

Disadvantages  of  being  on  a  trial  •  Extra  hospital  visits  •  They  may  not  be  accessible  in  your  home  town  •  Extra  tests  

–  Regular  blood  evaluaFon  –  Scans  –  ECGs  etc  

•  In  some  cases  these  trials  are  randomised  and  you  may  be  receiving  the  placebo  arm  

•  These  new  therapies  may  have  extra  side  effects  •  The  end  result  may  show  that  the  new  therapy  does  not  work  

Making  the  tumour  environment  hosFle  

•  AnF-­‐angiogenic  therapy  – Block  the  development  of  a  new  blood  supply  

•  Break  “the  anchor  glue”  that  allows  tumour  cells  to  bind  to  the  supporFng  Fssue  

Harnessing  the  immune  response  •  Breakthroughs  in  prostate  cancer  and  melanoma  have  led  to  the  exploraFon  of  new  immunotherapies  for  Glioma  

•  Studies  have  revealed  however  that  cancer  cells  secrete  factors  that  –  AYract  a  populaFon  of  immune  suppressor  cells  that  actually  PROTECT  them  from  aYack  (MDSC)  

•  Immune  aYack  can  only  happen  if  cancer  cells  have  a  “label”  that  can  be  recognised  by  the  immune  system  as  foreign  

•  Immune  therapies  usually  work  best  if  they  have  very  small  volume  of  disease  to  aYack    

Immune  cells  surrounding  colon  cancer  

Immunotherapies  

•  IdenFfy  a  unique  target  and  develop  a  vaccine  against  it  – EGFv3-­‐-­‐-­‐unique  receptor  on  ¼  GBMs  

•  Act1V  randomised  trial  – Open  in  a  >10  Australian  centres  – Comparing  standard  chemo-­‐radiotherapy  (Stupp)  with  Stupp  plus  EGFv3  vaccine  or  placebo  

DendriFc  cell  therapies  •  Isolate  a  fracFon  of  circulaFng  immune  cells  from  the  paFent  •  Grow  them  in  a  test  tube    •  Expose  them  to  something  you  want  them  to  aYack  

–  Fresh  or  frozen  tumour  cells  (Oslo-­‐DCVax)  –  SyntheFc  proteins  –  Viral  parFcles  

•  Re-­‐inject  these  “primed-­‐mature”  dendriFc  cells  back  into  the  paFent  

•  Hope  they  home  in  to  the  tumour-­‐and  recruit  other  immune  cells  to  aYack  and  destroy  

•  Numerous  trials  are  underway,  and  DCVax  has  a  preliminary  licence  in  Europe  

•  Technology  is  enormously  expensive  and  Fme  consuming  •  ?  Anywhere  is  Australia  this  can  be  done    

   Australian  Genomics  and  Clinical  Outcomes  of  

High  Grade  Glioma:  AGOG        •  What  causes  brain  cancer  

–  Currently  we  have  few  clues  about  what  might  lead  to  the  development  of  Gliomas  

–  Rare  •  AGOG  is  a  trial  being  run  at  a  number  of  centres  around  Australia  

–  QuesFonnaire  –  Blood  sample  –  From  paFent  who  was  diagnosed  aeer  1st  August  2013  and  1st  degree  

relaFve  •  IniFal  results  will  be  analysed  in    Australia  and  the  pooled  with  US  •  Only  large  scale  numbers  will  allow  us  to  idenFfy  any  factors  which  

may  be  associated  with  Gliomas  •  Find  a  cause  or  associaFon  will  lead  to  beYer  intervenFons  and  

possibly  therapies  

CMV  

•  CMV  is  a  common  virus  that  may  cause  few  symptoms  at  the  Fme  of  infecFon,  and  only  becomes  recognised  in  people  whose  immune  systems  fail  

•  Following  infecFon  it  can  persist  in  people  for  a  lifeFme  

•  20%  of  brains  tested  at  post  mortem  have  evidence  of  CMV  DNA  1:20,000  get  Glioma  

   

2002  a  researcher  reported  they  found  some  CMV  parFcles-­‐not  live  virus  in  Gliomas  

•  Ongoing  research  has  come  up  with  conflicFng  results  

•  Some  find  it-­‐others  dont  •  Some  preclinical  studies  suggest  it  may  have  a  role  –others  don’t  

•  Randomised  clinical  trial  in  newly  diagnosed  GBM  with  an  anFviral  drug  was  NEGATIVE  – Subset  analysis  of  the  Olympic  rowers  was  posiFve  

– NO  evidence  it  helps  for  relapsed  disease  

consensus  

•  Needs  further  invesFgaFon  •  May  be  a  target  for  drug  or  immunotherapy  

Valcyte  Plague  

•  In  the  interim  •  Desperate  paFents  have  jumped  to  get  on  to  Valcyte  

•  Not  just  a  simple  anFbioFc  •  MORE  toxic  than  chemotherapy  

– Harms  – Kidneys  – Liver    – Bone  marrow  

•  Valcyte  kills  live  viruses—which  are  NOT  found  in  Glioma  

•  Doesn’t  make  a  lot  of  biological  sense  – Eg  stopping  smoking  aeer  diagnosis  of  lung  cancer-­‐doesn’t  stop  the  cancer  from  growing  

•  Example  where  we  desperately  need  properly  conducted  clinical  trials  to  determine  risks  and  benefits