A Phase 2 Study of LY2606368 in Patients with Extensive Stage Disease Small Cell Lung Cancer

LY2606368 is an adenosine-5'-triphosphate-competitive inhibitor of CHK1.
LY2606368
inhibits the enzymatic activity of CHK1 with a half-maximal inhibitory
concentration (IC50) of
<1 nM and CHK2 with an IC50 of 8 nM in in vitro assays (King et al. 2015). In
nonclinical
studies, LY2606368 induced DNA damage as measured by pH2A.X, a marker of
doublestranded
DNA breaks, and replication catastrophe. LY2606368 inhibited tumor growth in
cancer
xenografts, including SCLC models, as monotherapy and in combination with other
agents (Wu
et al. 2012; McNeely et al. 2014; King et al. 2015; Sen et al. 2015). In vitro
data from cell
viability screens across a large panel of tumor lines representing different
tumor histologies
demonstrated increased sensitivity to growth inhibition by LY2606368 in SCLC
compared to
other lung subtypes as well as generally increased sensitivity in tumor cell
lines that were MYC
amplified (data on file). In a panel of 39 SCLC lines, proteomic analysis
revealed that sensitivity
to LY2606368 was associated with elevated basal expression of total and
phosphor cMYC
(p=0.01) (Sen et al. 2015).
LY2606368 has been evaluated in human clinical trials as a monotherapy for
patients with solid
tumors (Study I4D-MC-JTJA [JTJA], NCT01115790) and in combination with either
chemotherapy or targeted agents (I4D-MC-JTJF, NCT02124148). In these Phase 1
studies,
LY2606368 has shown an acceptable safety/tolerability profile.

Primary:
Cohort 1: To estimate the ORR when a dose of
105 mg/m2 LY2606368 every 14 days is
administered to patients with ED-SCLC that have
platinum-sensitive disease
* Cohort 2: To estimate the ORR when a dose of
105 mg/m2 LY2606368 every 14 days is
administered to in patients with ED-SCLC that have
platinum resistant/refractory disease

Secondary:
To characterize the safety and toxicity profile of
LY2606368
To characterize the PK of LY2606368
To estimate secondary efficacy measures including
DCR, DoR, PFS, and OS
To evaluate the association between best tumor
response and change from baseline in lung cancer
specific-symptoms, symptomatic distress, activity
status, overall quality of life, total LCSS score, and
ASBI for patients who have platinum-sensitive or
platinum resistant/refractory SCLC

Tertiary/Exploratory
To explore biomarkers associated with the efficacy
and safety of LY2606368, the exposure (PK) of
LY2606368, the mechanism of action of CHK1,
DNA damage response pathways or downstream
effects, cell cycle markers, immune function, or
cancer pathobiology
To explore whether ongoing measurement of tumor
shrinkage (such as changes in tumor size) correlate
with efficacy measures

Study I4D-MC-JTJH (JTJH) is a multicenter, nonrandomized, parallel-cohort Phase
2 study of
LY2606368 in patients with ED-SCLC who have either platinum-sensitive or
platinumresistant/
refractory disease.
An open-label, single-arm, nonrandomized study without concurrent controls is
appropriate for
patients with second-line or greater ED-SCLC. There is not currently a uniform
standard of
treatment for patients with resistant/refractory disease, and clinical trials
are recommended (Fruhet al. 2013; Kalemkerian et al. 2013). Historical response
rates are reported to be approximately10%, and so large improvements on these
options can be detected using a single-arm design.Although topotecan is the
standard for patients with platinum-sensitive disease, the responserates
(approximately 20%-25%) are well established from historical controls (von
Pawel et al.1999; Fruh et al. 2013; Kalemkerian et al. 2013).

Patients in both cohorts will receive 105 mg/m2 LY2606368 as an approximately
60 (+10) minute intravenous infusion on Day 1 of a 14-day cycle.
The LY2606368 monotherapy MTD when administered once every 14 days was
determined to
be 105 mg/m2. This dose and schedule was selected as the recommended Phase 2
dose for
monotherapy based on several factors including: the nonclinical LY2606368
monotherapy
pharmacokinetic (PK)/pharmacodynamic model predicted exposure range for maximum
tumor
response coinciding with the observed clinical PK data; human pharmacodynamics
simulations
indicating a pharmacodynamic profile in a predicted efficacious range; and an
acceptable safety profile.

Very common side effects considered related to the use of LY2606368 are listed
below: These occurred in more than 10% of patients (15 patients or more):
* a decrease in the number of white blood cells; this may make infections more
likely to develop and may be serious enough to require hospitalization or
become life-threatening
* a decrease in the number of red blood cells (anemia); this may cause
tiredness and may be serious enough to require a blood transfusion,
hospitalization, or become life-threatening
* a decrease in the number of platelets; this may increase the risk of bruising
or bleeding. If serious bleeding occurs (such as severe nosebleed), a blood
and/or platelet transfusion may be required and in some cases hospitalization
may be necessary.
* feeling tired or a lack of energy
* feeling nauseated or sick to your stomach
* fever occurring when there is a severe decrease in the number of white blood
cells (febrile neutropenia); this often requires hospitalization, may be
associated with serious infection, and could be life-threatening

Given the high unmet need for additional therapies for patients with previously
treated
ED-SCLC, the mechanistic rationale that supports a role for CHK1 inhibition in
improving
outcomes for patients with SCLC, the nonclinical data with LY2606368 as a
monotherapy in
nonclinical models (including SCLC), and the clinical safety profile of
LY2606368, the
risk/benefit assessment supports assessing LY2606368 monotherapy in the
proposed patient
population.