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. 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
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. 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. • 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
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. 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
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. 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. 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. 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. 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. 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. 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. 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. 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. Why
do
randomised
phase
3
trials?
PaFent
selecFon
can
make
a
big
difference
to
outcome
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. 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. 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. Advantages
of
being
on
a
trial
• Access
to
an
potenFal
new
drug
therapy
• Close
monitoring
by
a
trial
research
team
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. 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. 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
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. 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.
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.
40.
41.
42. 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
43. 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
44. consensus
• Needs
further
invesFgaFon
• May
be
a
target
for
drug
or
immunotherapy
45. 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
46. • 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