Biology Reference
In-Depth Information
TABLE 4.1 PARP Inhibitors in Clinical Development
Single agent/
combination
Agent/Company/Date
Route
Disease
Clinical status
AG014699/PF0367338
Pfizer 2003
iv
Solid tumors
Melanoma
Various combinations
Single agent
Phase I/II ongoing
KU59436/AZD2281
Olaparib
AstraZeneca 2005
oral
Various
Single agent
Various combinations
Phase I complete
Several phase II
ABT888
2006
oral
Solid and
lymphoblastoid
Single agent
Various combinations
Ph 0/I complete
Several phase II
BSI-201/ iniparib
BiPar/Sanofi 2006
iv
TNBC
Gem-carbo/TMZ
combinations
Phase II complete
Phase III
INO-1001 Inotek/
Genentek 2003/6
iv
Melanoma, GBM
TMZ combinations
Phase II
MK4827 Merck 2008
oral
Solid BRCA ovarian
Single agent
Phase I
CEP-9722
Cephalon 2009
oral
Solid tumors
TMZ combinations
Phase I
GPI 21016/E7016
MGI Pharma 2010
oral
Solid tumors
TMZ combinations
Phase I
LT763 Biomarin 2011
oral
Solid tumors
Single and
combinations
Phase I
single agent temozolomide
126
as would have been pre-
dicted from preclinical data. There was no correlation
between toxicity and PK parameters, and all patients
dosed with AG014699 18mg/m
2
showed similar PBMC
and tumor PARP inhibition patterns. This increase in
toxicity is presumably due to persistence of unrepaired
DNA strand breaks in bonemarrow stem cells. However,
the relative lack of toxicity observed in this study, and the
ability to deliver an enzyme inhibitory dose of AG014699
in combination with full-dose temozolomide is encour-
aging and in marked contrast to studies with MGMT
inactivators.
120,123,127
As well as establishing the proof of mechanism of
action of AG014699 in surrogate tissues it was possible
in this study also to demonstrate this within the tumor.
Patients with melanoma entered onto the study con-
sented to tumor biopsies under local anesthesia to allow
investigation of drug delivery to the tumor and also
tumor levels of PARP inhibition. Mean tumor PARP
inhibition at 5 hours was 92% (range 46
alone was observed and the agent demonstrated linear
pharmacokinetics with no interaction with temozolo-
mide. The complete absence of any symptomatic or
laboratory toxicities as a result of PARP inhibition on
its own is also encouraging for the future use of PARP
inhibitors in indications when they are given as single
agents so overall this first study significantly informed
the clinical development field for PARP inhibitors.
Further Clinical Studies in Combination
with Chemotherapy
In 2005 on completion of the phase I discussed above
this combination of AG014699 and temozolomide was
taken into a phase II study in metastatic melanoma.
However, this second trial demonstrated enhanced
temozolomide-induced myelosuppression when full
dose temozolomide was combined with a PARP inhibi-
tory dose of AG014699 to a wider range of patients.
Following a 25% dose reduction of the temozolomide
dose the regimen was well tolerated and this small
phase II study reported an increase in the response
rate and median time to progression compared to temo-
zolomide alone.
128
These encouraging data need to be
confirmed in a phase III setting and similar studies
have been performed with the Abbott PARP inhibitor
ABT-888 in a randomized phase II setting and the results
of this are awaited in 2011. Another combination study
of a PARP inhibitor (INO-101, Inotech/Genetech) and
97%) and
AG014699 was detected in tumor samples, proving
that the novel agent was delivered to the tumor and
also inhibited the target enzyme within this. Addition-
ally, alkaline COMET assays were performed on PBMCs
from patients at the PID and demonstrated increases in
DNA SSB in all patients.
As all patients also received a test dose of this first-in-
class compound it was possible to start evaluating single
agent
e
toxicity. No toxicity attributable to AG014699
