Biology Reference
In-Depth Information
q3dx15 dosing of either pemetrexed, LY2603618 or
a combination of both agents. In the combination arms,
LY2603618 was dosed 24 hours after pemetexed. Peme-
trexed alone (100 mg/kg) resulted in a T/C of 73%,
while LY2603618 at 45 mg/kg and 90 mg/kg had no
effect and T/C of 82% respectively. In combination
100 mg/kg pemetrexed plus 45 mg/kg LY2603618
reduced tumor growth to 52%, with even greater efficacy
seen in the 100 mg/kg pemetrexed plus 45 mg/kg
LY2603618 group, where there was a T/C of 32%.
Thus, LY2603618 was able to increase the efficacy of
pemetrexed
in vivo
in a dose-dependent manner. Similar
trends were observed in the H441 xenograft model. In
similar fashion to the
in vitro
studies, levels of pChk1
Ser296 were measured in H2122 tumors harvested 2
hours after the last dose of LY2603618 in the combination
groups, and 26 hours post dosing of pemetrexed
(100 mg/kg) or LY2603618 (90 mg/kg) alone following
a q3dx4 dosing schedule. In comparison to vehicle-
treated controls, LY2603618 alone had no effect on
pChk1 levels, while pemetrexed alone increased levels
by 2.8-fold. The combination resulted in a lesser increase
in the measured level of pChk1 to two-fold control
mild (grade 1 or 2), the most frequent being nausea,
vomiting, diarrhea, hypokalemia, fatigue, constipation,
and anemia. PK data showed exposure to LY2603618 to
increase in a dose-dependent manner, although with
a small amount of intracycle accumulation. Predictions
to human from preclinical PD studies suggested that
the maximal PD effect would be reached at a human
exposure of AUC
21,000 ng*hr/ml and/or Cmax
>
2000 ng/ml. Both of these criteria were met at the
105 mg/m
2
dose, and exceeded at the MTD. Of the
patients treated, nine (of 31) had stable disease, and
one patient achieved a confirmed partial response in
pancreatic cancer. Based on these findings, LY2603618
was advanced into a phase II trial to determine safety
and efficacy in combination with pemetrexed in
patients with NSCLC. In addition, the clinical investiga-
tion of the agent was broadened into additional areas,
with the initiation of two phase I/II trials to determine
safety, efficacy and MTD, namely LY2603618 in combi-
nation with gemcitabine versus gemcitabine alone in
patients with pancreatic neoplasms, and most recently
an investigation of the triplet combination of
LY2603618 with pemetrexed and cisplatin versus the
combination of cisplatin and pemetrexed in NSCLC.
<
e
a decrease of about 29% over pemetrexed alone. These
results are consistent with the observations made
in vitro
.
118,119
Emerging data from the early clinical studies with
LY2603618 in combination with pemetrexed have
recently been reported.
120
The trial was an open-label,
multicenter, dose escalation of LY2603618 in combina-
tion with 500 mg/m
2
pemetrexed in patients with solid
tumors. The objective of the trial was to assess the
safety, tolerability, and MTD of LY2603618 in combina-
tion with pemetrexed, as well as to assess PK and anti-
tumor activity. In the first treatment cycle, LY2603618
was given on days 1 and 9, with pemetrexed on day 8
of a 28-day cycle. Subsequent cycles gave pemetrexed
on day 1 and LY2603618 on day 2 of a 21-day cycle.
Patients were assessed every two cycles using RECIST
criteria. In the first cohort of patients treated,
LY2603618 was administered as an infusion over
a 4-and-a-half hour period, but this was reduced to
a one-hour infusion time in subsequent cohorts based
on the PK data from the first cohort. In total, 31 patients
were treated in the study at doses of LY2603618 ranging
from 40 to 195 mg/m
2
. Over the course of the trial, four
patients experienced DLTs
SCH-900776
SCH-900776 (
Figure 10.2
), now under development
by Merck, is the latest Chk inhibitor to enter clinical
trials.
121
The compound is a potent, ATP-competitive
inhibitor, and is the most selective agent for Chk1 (IC
50
3 nM) over Chk2 (IC
50
1.5
m
M) currently under investiga-
tion, although it carries some activity against CDK2 (IC
50
160 nM), which could, depending upon dosing and
scheduling, have the potential to partially mask the
phenotype of Chk1 inhibition by inducing an additional
cell cycle arrest that cannot be bypassed by Chk1 inhibi-
tion. SCH-900776 was identified by employing a high
throughput functional screen of replication checkpoint
override. The screen was developed based on the fact
that exposure to DNA antimetabolites activates Chk1
as part of the replication checkpoint, and data from
RNAi studies that revealed that knockdown of Chk1
results in rapid and irreversible induction of double-
stranded DNA breaks, which can be assayed quantita-
tively by measuring
-H2AX levels. There is no effect
on the replication checkpoint on inhibition of Chk2,
implying a non-redundant role for Chk1 in this setting,
thus tracking these changes were highly discriminatory
and lead to the identification of SCH-900776.
The compound has an EC
50
of 125 nM for
g
-H2AX in
a cell-based assay of replication checkpoint override, and
this was readily apparent in multiple cell lines, and was
observed after even short exposures. The observed
cellular
g
diarrhea (105 mg/m
2
),
reversible infusion-related reaction (150 mg/m
2
)and
two occurrences of pancytopenia (195 mg/m
2
). The
maximum tolerated dose was defined as 150 mg/m
2
.
In total, 11 patients experienced severe adverse events
(SAEs) that were deemed to be treatment-related (diar-
rhea, fever, pancytopenia, infusion-elated reaction,
pneumonia, anemia, fatigue, leucopenia, and neutrope-
nia). Other reported adverse reactions were generally
e
phenotype
resulting
from SCH-900776
