Biomedical Engineering Reference
In-Depth Information
codynamic endpoints for the combination. Pharmacokinetics was
linear with a mean terminal half-life of 7.4-11.7 hours. The estab-
lished PARP inhibitory dose (PID) was 12 mg/m
2
, which was based
on at least 50% inhibition of peripheral blood lymphocyte PARP
activity determined by a validated quantitative immunoassay 24
h after AG014669 administration. At this dose, there was 74-97%
inhibition of PARP in PBMC and there was no further reduction in
PARP activity in PBLs at 18 mg/m
2
. There was, however, increased
inhibition of PARP at the higher dose in the tumor tissue. The drug
remained in all tumor biopsies at 5 hours after administration, with
mean level of PARP inhibition in the tumor at 5 hours post admin-
istration of 92% (range 46-97%). PARP inhibition was reversible in
the PBMCs and PARP function recovered by at least 50% 72 hours
after dosing. Significant toxicities included fatigue, infection, hypo-
phosphatemia, and myelosuppression, which was the DLT at the
dose of 18 mg/m
2
2
/day both
given for 5 days of a 28-day cycle. There was one CR and one PR in
melanoma patients who had not received prior therapy and a PR in a
patient with desmoid tumor. There were seven patients with stable
disease for at least 6 months, including four patients with melanoma,
one patient with prostate cancer, and one patient with pancreatic
cancer. Four patients were homozygous for CYP2D6 G186A allele,
known as CYP2D6 *4, which was expected to decrease the metabo-
lism of AG 014699. Although the AUC was similar for patients with
the CYP mutation compared with patients with wild type, 3 of the 4
patients appeared to benefit. The two melanoma patients who had
objective responses also carried this mutation. The third patient had
prolonged stable disease. The fourth patient with the mutation died
of complications of his disease after the test dose making him in-
evaluable for this purpose [86].
In a phase II trial, 40 patients with chemotherapy-naïve advanced
melanoma were treated with AG014699 at 12 mg/m
in combination with TMZ 200 mg/m
2
plus TMZ at
2
× 5 days in 28-day cycles. Myelosuppression was greater
than expected, with five cases (12.5%) of grade 4 thrombocytopenia,
six cases (15.0%) of grade 4 neutropenia, and one case (2.5%) of
death from febrile neutropenia at the time of the report. Fatigue and
mild nausea also occurred. Twelve patients required dose reduction
of TMZ to 150 mg, and one patient required a reduction to 100 mg.
200 mg/m
