A Phase 1 Study to Evaluate the Safety, Tolerability and Efficacy of MK-8353 Combination Therapies in Subjects With Advanced Solid Tumors

Extracellular regulated kinase (ERK)1 and ERK2 are closely related
serine-threonine protein kinases. They are components of the
RAS/mitogen-activated protein kinase (MAPK) pathway, a critical signal
transduction pathway that is activated in response to growth factor
binding and regulates cellular growth, differentiation and survival in a
variety of cell types. ERK lies downstream from the small guanosine
triphosphatase (GTPase) RAS and the protein kinases RAF and MEK in this
pathway. Following its activation by RAS, RAF phosphorylates MEK1 and MEK2,
which in turn phosphorylate ERK. Activated, phosphorylated ERK (pERK)
phosphorylates other substrates that govern the transcriptional output of
cells. Constitutive activation of this pathway is frequently observed in human
cancers and is associated with high rates of cancer cell proliferation.
Commonly, pathway activation occurs as a consequence of gain-of-function
oncogenic mutations in RAS or in one
of the RAF kinase family members, e.g., BRAF. The high frequency of RAS or BRAF
mutations in many cancers makes targeting this pathway an attractive strategy
for cancer therapy. Activating mutations of RAS are reported in ~25% of all
cancers, with some, such as pancreatic and colorectal cancer, harboring KRAS
mutation rates of ~90% and ~50%, respectively. NRAS mutations have been
identified in ~10-25% of melanomas and KRAS mutations have been identified in
~30% of non-small cell lung cancers (NSCLCs).
BRAF somatic missense mutations have been identified in ~50-70% of malignant
melanomas, where all mutations are within the kinase domain and a single
substitution (V600E, previously designated V599E) accounts for ~80% of
mutations. Activating BRAF mutations have also been documented in a variety of
human cancers, including colorectal cancer (CRC; ~10-12%), NSCLC (2-3%), and
thyroid cancer (~50%).
With very few exceptions, BRAF and RAS mutations are mutually exclusive.

MK-8353 is a highly selective, orally available, adenosine triphosphate (ATP)
competitive small molecule inhibitor of ERK. MK-8353 not only inhibits the
kinase activity of ERK, but induces a conformational change in ERK that
prevents its phosphorylation and activation by MEK. This unique property of
MK-8353 enables the phosphorylation status of ERK to serve as one of the target
engagement biomarkers for MK-8353 action. To date, there are no known ERK
inhibitors in clinical development.
MK-8353 potently inhibits both ERK1 and ERK2 in vitro with IC50 values of 23.0
nM and 8.8 nM, respectively. MK-8353 caused a dose-dependent decrease in pERK1,
pERK2, and pRSK (phosphorylated p90 ribosomal S6 kinase) levels with complete
suppression of pERK1
and pERK2 at 30 nM in BRAF mutant A2058 cells. Also, the anti-proliferative
effects of MK-8353 were characterized against a large panel of tumor cells.
MK-8353 potently inhibited the growth of BRAF mutant melanoma cell lines, and
also inhibited growth of BRAF mutant CRC and thyroid cancer cell lines. In
addition, MK-8353 inhibited the growth of KRAS mutant colon, pancreatic, and
NSCLC tumor cell lines and NRAS mutant melanoma cell lines. Inhibition of pERK
by MK-8353 correlated with inhibition of cell proliferation and induction of
apoptosis in vitro. The efficacy of the ERK inhibitor MK-8353 as a single agent
was tested in a panel of BRAF and K/NRAS mutant mouse xenograft models. MK-8353
inhibited tumor growth and induced tumor regression in both BRAF mutant and
K/NRAS mutant mouse xenograft models. These results further confirm the in
vitro studies showing that tumor cells harboring BRAF or K- or NRAS mutations
are sensitive to MK-8353.

To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose
(MTD) of MK-8353 administered orally in combination with other agents to adult
subjects with advanced tumors and to determine the recommended Phase 2 dose
(RPTD) of MK-8353 based on safety, tolerability, and pharmacokinetics.

This is a multicenter, worldwide, open label, non-randomized, Phase I study of
MK-8353 in combination with FOLFIRI administered in subjects with KRAS mutant
colorectal cancer, or in combination with MK-8669 or MK-3475, respectively,
administered in subjects with advanced solid tumors. In addition in MK-8353 +
MK-3475 arm, KRAS mutant NSCLC and NRAS/BRAF mutant melanoma subjects will be
enrolled at the MTD to further evaluate efficacy. The goal of this study is to
evaluate the safety, tolerability and PK parameters of MK-8353 in combination
with three different anti-cancer agents (3 arms of combinations).
The dose escalation and confirmation of the MTD will be done using a design
based on Toxicity Probability Interval (TPI) for each arm of this study.
Cohorts of 3 subjects will initially be enrolled sequentially on rising dose
levels of MK-8353 with a fixed dose levels of FOLFIRI or MK-3475, or with
appropriately adjusted dose levels of MK-8669. Barring dose limiting
toxicities, additional subjects will be enrolled, and dose-finding will proceed
according to an algorithm based on TPI, targeting a 25% dose limiting
toxicities (DLT) rate for MK-8353 in combination with MK-8669 or MK-3475, and a
30% DLT rate for MK-8353 in combination with FOLFIRI, until an MTD of each
combination is determined . Approximately 150 subjects evaluable for safety and
tolerability will be enrolled. The final number will depend on safety data and
observed DLTs.

Study visits, administration of MK-8353, administration of Folfiri, MK-8669 or
MK-3475, completion of a dosingdiary, avoid to consume grapefruit or star fruit
for 2 weeks before the first dose of MK-8353 combinations and for the entire
duration of the study, physical examination, ECG, checking of vital signs,
provide tumor biopsy (optional), bloed draw and collection of urine sample.

Possible side effects of MK-8353, MK-8669 or MK3475.
Risk's of blood draw, ECG, infusion, CT-scans, MRI and biopsy.