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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	
...
1st	
  human	
  genome	
  project	
  cost	
  $3.8	
  billion	
  and	
  
involved	
  the	
  best	
  labs	
  from	
  all	
  ...
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 B...
Destroying	
  cancer	
  cells	
  
•  Surgery	
  
–  Physically	
  remove	
  what	
  we	
  can	
  idenFfy	
  as	
  malignan...
There	
  a	
  number	
  of	
  different	
  kinds	
  of	
  clinical	
  
trials	
  	
  
•  Trials	
  evaluaFng	
  new	
  ther...
•  There	
  are	
  a	
  number	
  of	
  different	
  agents	
  being	
  
developed	
  that	
  allow	
  the	
  surgeons	
  t...
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,	
  
th...
Thalidomide	
  disaster	
  
•  All	
  pre-­‐clinical	
  tesFng	
  was	
  posiFve	
  and	
  safe	
  
•  Unfortunately	
  
–...
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...
How	
  Trials	
  are	
  iniFated	
  	
  
•  Labs	
  develop	
  a	
  new	
  compound-­‐	
  	
  
–  Aeer	
  iniFal	
  tesFng...
How	
  to	
  find	
  a	
  clinical	
  trial	
  
•  NOT	
  easy	
  
–  Ask	
  your	
  doctor	
  or	
  care	
  co-­‐ordinator...
I	
  want	
  to	
  go	
  to	
  America!	
  
•  Many	
  drugs	
  are	
  1st	
  tested	
  in	
  big	
  US	
  hospitals	
  
•...
Four	
  different	
  types	
  of	
  clinical	
  trials	
  
•  Phase1	
  
– 1st	
  administraFon	
  of	
  a	
  new	
  medici...
Phase	
  1	
  drug	
  trials	
  
•  Usually	
  
•  Cohorts	
  of	
  3	
  paFents	
  are	
  selected	
  
•  The	
  1st	
  g...
Obviously	
  
•  PaFents	
  need	
  to	
  be	
  monitored	
  very	
  carefully	
  
•  They	
  need	
  numerous	
  blood	
 ...
Phase	
  2	
  clinical	
  trials	
  
•  1st	
  trial	
  of	
  a	
  medicine	
  in	
  paFents	
  suffering	
  
from	
  a	
  ...
Phase	
  3	
  trials	
  
•  Results	
  of	
  phase	
  2	
  trials	
  are	
  usually	
  compared	
  
to	
  “historical	
  c...
Why	
  do	
  randomised	
  phase	
  3	
  trials?	
  
PaFent	
  selecFon	
  can	
  make	
  a	
  big	
  difference	
  to	
  
...
Phase 3 trial end points
•  Does	
  the	
  new	
  therapy	
  have	
  a	
  beYer	
  outcome	
  
than	
  standard	
  treatme...
Most	
  new	
  drug	
  trials	
  are	
  conducted	
  in	
  
GBM	
  
•  There	
  are	
  “strict”	
  selecFon	
  criteria	
 ...
Challenges	
  of	
  phase	
  3	
  tesFng	
  
•  Cost	
  
•  Large	
  numbers	
  of	
  paFents	
  
•  Long	
  Fme	
  lag	
 ...
Advantages	
  of	
  being	
  on	
  a	
  trial	
  
•  Access	
  to	
  an	
  potenFal	
  new	
  drug	
  therapy	
  
•  Close...
Disadvantages	
  of	
  being	
  on	
  a	
  trial	
  
•  Extra	
  hospital	
  visits	
  
•  They	
  may	
  not	
  be	
  acc...
Making	
  the	
  tumour	
  environment	
  
hosFle	
  
•  AnF-­‐angiogenic	
  therapy	
  
– Block	
  the	
  development	
  ...
Harnessing	
  the	
  immune	
  response	
  
•  Breakthroughs	
  in	
  prostate	
  cancer	
  and	
  melanoma	
  have	
  
le...
Immune	
  cells	
  surrounding	
  colon	
  
cancer	
  
Immunotherapies	
  
•  IdenFfy	
  a	
  unique	
  target	
  and	
  develop	
  a	
  vaccine	
  
against	
  it	
  
– EGFv3-­‐...
DendriFc	
  cell	
  therapies	
  
•  Isolate	
  a	
  fracFon	
  of	
  circulaFng	
  immune	
  cells	
  from	
  the	
  paFe...
 
	
  Australian	
  Genomics	
  and	
  Clinical	
  Outcomes	
  of	
  
High	
  Grade	
  Glioma:	
  AGOG	
  	
  	
  
	
  •  ...
CMV	
  
•  CMV	
  is	
  a	
  common	
  virus	
  that	
  may	
  cause	
  few	
  
symptoms	
  at	
  the	
  Fme	
  of	
  infe...
2002	
  a	
  researcher	
  reported	
  they	
  found	
  some	
  
CMV	
  parFcles-­‐not	
  live	
  virus	
  in	
  Gliomas	
...
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	
  
V...
•  Valcyte	
  kills	
  live	
  viruses—which	
  are	
  NOT	
  
found	
  in	
  Glioma	
  
•  Doesn’t	
  make	
  a	
  lot	
 ...
Brain tumour patient forum Helen Wheeler brain cancer clinical trials in australia
Brain tumour patient forum Helen Wheeler brain cancer clinical trials in australia
Brain tumour patient forum Helen Wheeler brain cancer clinical trials in australia
Brain tumour patient forum Helen Wheeler brain cancer clinical trials in australia
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Brain tumour patient forum Helen Wheeler brain cancer clinical trials in australia

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Dr Helen Wheeler, NSCC , St Leonards presents at the Brain Tumour Patient Forum, hosted by the Cure Brain Cancer Foundation.

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Transcript of "Brain tumour patient forum Helen Wheeler brain cancer clinical trials in australia"

  1. 1. Brain cancer clinical trials in Australia Dr Helen Wheeler Hosted by Cure Brain Cancer Foundation
  2. 2. Clinical  Trials     Dr  Helen  Wheeler  1.5.2014   NSCC     St  Leonards  
  3. 3. 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      
  4. 4. 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  
  5. 5. Gene  Sequencer  
  6. 6. We  can  then  map  “pathways”  which   are  unique  to  cancer  cells  
  7. 7. Aberrantly activated signalling pathways in malignant glioma Reardon, D. A. et al. J Clin Oncol; 24:1253-1265 2006 EGFR
  8. 8. IdenFfying  discriminaFng  genes   KPNA5 Homer1 YKL-40 LGALS1 IGFBP2 IQGAP1 RBP1 COPZ2 SPP1 SERPINA3 ARS Low Grade Brain TumoursHigh Grade Brain Tumours LRRC20 HS75LP C1QL1 CARHSP1 HSxS138 NFYB KIAA0599
  9. 9. 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  
  10. 10. 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  
  11. 11. •  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      
  12. 12. Fluorescence guided resection will enable interrogation of distinct tumour compartments…..
  13. 13. New  therapy  trials  
  14. 14. 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  
  15. 15. 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    
  16. 16. IniFally  drugs  are  evaluated  in  test   tubes  
  17. 17. They  are  then  evaluated  in  animal   models  
  18. 18. 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   – $$$$              1.7  billion  dollars            $$$$$      
  19. 19. 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      
  20. 20. 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  
  21. 21. 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  
  22. 22. 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      
  23. 23. 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  
  24. 24. 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  
  25. 25. 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  
  26. 26. 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  
  27. 27. Why  do  randomised  phase  3  trials?   PaFent  selecFon  can  make  a  big  difference  to   outcome  
  28. 28. 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    
  29. 29. 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        
  30. 30. 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  
  31. 31. Advantages  of  being  on  a  trial   •  Access  to  an  potenFal  new  drug  therapy   •  Close  monitoring  by  a  trial  research  team  
  32. 32. 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  
  33. 33. 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  
  34. 34. 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    
  35. 35. Immune  cells  surrounding  colon   cancer  
  36. 36. 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  
  37. 37. 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    
  38. 38.    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  
  39. 39. 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      
  40. 40. 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  
  41. 41. consensus   •  Needs  further  invesFgaFon   •  May  be  a  target  for  drug  or  immunotherapy  
  42. 42. 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  
  43. 43. •  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  
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