Biology Reference
In-Depth Information
lines.
111
Other studies have shown that the potentiation
of cisplatin by PARP inhibitors is cell-line dependent.
112
The cell-line dependency of potentiation of cisplatin
cytotoxicity by PARP inhibitors may reflect the molec-
ular pharmacology of the cells. Cells lacking HR func-
tion, e.g., due to BRCA1 or BRCA2 mutation, are
hypersensitive to cisplatin and to PARP inhibitors (see
later) and AZD2281 (olaparib) was synergistically cyto-
toxic with cisplatin in BRCA2-defective cells suggesting
the interaction might be due to HR defects.
113
In addi-
tion AZD2281 increased the survival of mice genetically
engineered to develop BRCA-defective mammary
tumors.
114
In contrast, in cells and xenografts lacking
Rb inhibition of PARP actually protected from cisplatin
cytotoxicity.
115
PARP inhibitors have shown greater
activity with platinum drugs in the
in vivo
setting.
However this may be due to a potential effect of PARP
inhibitors on tumor vasculature promoting drug
delivery (see later). Consistent with this view is the
observation that CEP-6800 caused a 35% enhancement
of cisplatin-induced reduction in the growth of Calu-
6(human NSCLC) xenografts
76
but failed to enhance
cisplatin cytotoxicity in Calu-6 cells
in vitro
similarly
BGP-15 did not potentiate cisplatin cytotoxicity
in vitro
but did enhance cisplatin-induced reduction in the
growth of xenograft models.
116
ABT-888 increased the
antitumor activity of cisplatin and carboplatin against
MX-1 mammary xenografts,
80
MX-1 cells lack both
BRCA1 and BRCA2 so synergy could be at the level of
HR or drug delivery.
resulting in durable complete tumor regressions,
79,117
the first clinical trial of a PARP inhibitor for the treatment
of cancer was initiated in 2003. This phase 0/I trial
involved dose escalation of the PARPi in combination
with temozolomide (phase I component) combined
with a pre-dose of the PARPi alone so establish PK and
PD (phase 0 component). PARP inhibition in surrogate
normal tissues (PBMCs) was a primary endpoint of the
study with a
50% inhibition for 24 hours being the
target. This figure was based on preclinial pharmacody-
namic studies conducted in parallel with efficacy
studies demonstrating that the efficacious dose inhibited
PARP activity
>
50% for 24 hr and pilot studies to deter-
mine the day-to-day variation in PARP activity in
healthy volunteers and a study in melanoma patients
treated with temozolomide.
118
As this was a first-in-class
clinical trial safety and toxicity endpoints were also
included and a cautious dose escalation scheme used.
AG014699 was escalated from 1 mg/m
2
to 12 mg/m
2
in
combination with 50% of the recommended maximum
dose of temozolomide (100 mg/m
2
/day for 5 days every
28 days) to establish this PARP inhibitory dose endpoint.
A reduced dose of temozolomide was used due to
concerns that the combination might enhance normal
tissue toxicity of temozolomide, similar to the clinical
experience with other DNA damage repair modulating
agents,
O
6
-benzyl guanine and lomaguatrib.
119
e
123
Prior
to the combination dosing a single agent test dose of
AG014699 was given in cycle one to allow safety,
pharmacokinetic (PK), and pharmacodynamic (PD)
evaluation.
124
This studywas driven by the pharmacody-
namic endpoint, establishing a PARP inhibitory dose of
the novel agent, before attempting to evaluate the
maximum tolerated dose (MTD) of the combination by
escalating the temozolomide to its recommended dose.
Thirty-three patients were enrolled in total and PARP
inhibition in PBMCs was seen at all doses tested. The
PID was defined as 12 mg/m
2
based on 74
CLINICAL DEVELOPMENT OF PARP
INHIBITORS
Based on the preclinial data summarized above the
clinical development of PARP inhibitors has been on
two fronts: in combination with chemotherapy in an
attempt to improve tumor cytotoxicity and thus patient
outcomes, and also as single agents in HR defective
cancers based on the preclinical evidence of hypersensi-
tivity of these tumors. This is a rapidly evolving clinical
field with seven agents currently in the clinic and others
due to enter clinical trials in the near future (
Table 4.1
),
the current status of clinical trials is summarized below.
As yet no phase III registration study has reported posi-
tive data so no agent has moved forwards to licensing,
although this is expected within 2011. The key transla-
tional data which has informed the clinical development
paths and the current trials are summarized below.
97% inhibi-
tion of PBL PARP activity in samples taken 24 hours after
a single dose of AG014699. The dose of temozolomide
was increased to the registered dose in cohorts of three
patients with metastatic melanoma. In this study it
proved possible to give full dose temozolomide with
the PID. However, increasing the PARP inhibitor
dose further by 50% to 18mg/m
2
/day did cause dose
limiting myelosuppression. It was already known that
the dose-toxicity relationship for temozolomide is steep,
200 mg/m
2
/day being well tolerated but 225mg/m
2
/
day causing significant myelosuppression.
125
It
would appear that enhanced temozolomide-induced
myelosuppression was observed in this study when
patients were dosed with temozolomide 200mg/m
2
and AG014699 18 mg/m
2
with one patient developing
pancytopenia and three patients having delayed
recovery of neutropenia
e
First Clinical Trial
On the basis of the preclinical activity of AG014361
and AG-014699 in combination with temozolomide,
e
an unusual toxicity with
