Biomedical Engineering Reference
In-Depth Information
There were four partial responses and four prolonged stable diseases
[87].
There is a phase I trial testing rucaparib (AG-014699) in
combination with carboplatin in solid tumors [88], as well as a phase
II trial of this agent in combination with cisplatin in patients with
TNBC or
mutation associated breast cancer (HER 2 negative,
hormone receptors positive) that will begin accrual soon. The study
will have a safety run-in testing rucaparib at 16 and 24 mg. The study
will randomize between single agent cisplatin and the combination
of cisplatin with rucaparib with the objective of evaluating the 2-year
disease-free survival [89]. An oral formulation of rucaparib is under
evaluation in
BRCA
BRCA
patients.
15.7.4
Iniparib (BSI 201, NSC-746045; IND-71677)
Iniparib, BSI 201, initially thought to be a PARP inhibitor, has recently
been reported not to inhibit PARP 1
. This agent ignited
significant interest in PARP inhibitors in 2009 when it was reported
to improve PFS and OS in TNBC when given with gemcitabine and
carboplatin in a phase II randomized trial; however, the phase III
trial did not confirm a statistical advantage to adding iniparib to the
cytotoxic combination [90,91].
At AACR 2011, data were presented on veliparib, iniparib,
olaparib and MK 4827 demonstrating that iniparib is not a PARP
inhibitor. Unlike the other three agents, iniparib did not inhibit
PARP 1 as measured by a decrease in PAR levels post treatment. In
cell lines with
, in vitro
mutations, iniparib and veliparib both caused
an increase in γ2HAX, signifying double strand breaks, at different
sites of the DNA. Iniparib formed γ2HAX primarily at the telomeres,
though to a lesser degree at non-telomere sites compared with the
telomeric affect and compared with veliparib, whereas veliparib
caused γ2HAX foci at non-telomere sites only. This effect at different
sites of the DNA would suggest that the agents recognize different
sequences of DNA [92] Clinically, iniparib did not significantly
enhance myelosuppression when given with myelosuppressive
chemotherapy, as is seen with olaparib and veliparib [75, 87,
93,94].
BRCA
