A Phase I, open-label, dose escalation study of oral LGK974 in patients malignancies dependent on Wnt ligands

In vitro and in vivo studies show that LGK974 is a potent, selective inhibitor
of the Wnt pathway by blocking the activity of the protein porcupine. Porcupine
is a ubiquitously expressed protein on the cell membrane. It is involved in
activation of the Wnt pathway, which is required for normal cellular
proliferation and differentiation. Several lines of evidence suggest that Wnt
pathway signaling may be important in breast cancer (lobular and triple
negative), melanoma, pancreatic adenocarcinoma and perhaps other cancers.
Inhibition of the Wnt pathway by blocking the activity of porcupine could
therefore be associated with anti-tumor activity in these patients.
PDR001 is an anti-PD-1 antilichaam which blocks the binding of PD-L1 and PD-L2
to PD-1. PDR001 is cynomolgus cross-reactive and shows functional activity in
vitro and ex vivo. Emerging data demonstrate a correlation between the presence
of PD-L1 surface expression on tumor cells and tumor infiltrating immune cells
and clinical efficacy of checkpoint inhibitors (anti-PD-1/PD-L1 therapies).
Similarly, the presence of pre-existing exhausted tumor infiltrating
lymphocytes (TIL) is associated with response to anti PD-L1/PD-1 treatment
whilst immunological ignorance is associated with absence of clinical response.

Primair:
Determine the MTD and/or recommended dose for expansion (RDE) of LGK974 as a
single agent and
in combination with PDR001 when administered to adult patients with
malignancies dependent on Wnt
ligands as specified in the inclusion criteria

Secundair:
Characterize the safety and tolerability of LGK974 single agent and in
combination with PDR001
Evaluate the single dose and multiple dose PK of LGK974 and its
pharmacologically active metabolite,
LHA333 in single agent dosing, and PK of LGK974 in combination with PDR001
Assess the PD response to LGK974 in tumor tissue and/or skin
Establish the PK/PD relationship of LGK974
Assess the anti-tumor activity of LGK974 as a single agent and in combination
with PDR001

This open-label, multicenter, phase 1 study will be the first to administer
LGK974 single and in combination with PDR001 in humans.

LGK974 single:
The study starts with a dose escalation part, in which patients will daily take
one or more capsules of LGK974. The treatment consists of cylces of 28 days.
Groups of patients will receive a dose, which will be step-wise increased for
each group, to determine the MTD (maximum tolerated dose). The start dose is 10
mg per day. A two-parameter Bayesian logistic regression model will be used to
determine the MTD. It is anticipated that approximately 80 patients will be
treated in the dose escalation part of the study. When the MTD is established,
the patient group will be expanded (dose expansion phase of the study) with at
approximately 30 patients, for further evaluation of the safety and
tolerability, and to make a preliminary assessment of the efficacy of this dose
of LGK974.
Of these 30 patients in the expansion phase approximately 10 patients in each
of the following 3 specific populations:
* - documented B-RAF mutant colorectal cancer with RNF43 mutation and/or RSPO
fusion
* - pancreatic adenocarcinoma with RNF43 mutation.
- tumors of any histological origin with documented genetic alterations
upstream in the Wnt
signaling pathway, such as gene fusions in RSPO and mutations in RNF43 (with
prior
agreement with Novartis).

Combination of LGK974 and PDR001:
same as single. Additionally PDR001 will be given ones in the 28 days by
infuse.
35 patients will be enrolled for the escalation part (patients with melanoma
that was previously primary refractory to anti-PD-1 therapy) and 40 patients
will be enrolled for the expansion part (pancreatic cancer, triple negative
breast cancer (TNBC), melanoma and head and neck squamous cell cancer).

Patients will be treated until disease progression or unacceptable toxicity
occurs. Patients could discontinue the study by withdrawal of consent or
treatment could be discontinued at the discretion of the investigator when it
is no longer in the best interest of the patient.

Daily intake of one or more capsules of LGK974 (alternative dosing schedules
are possible).
PDR001 will be administered via i.v. infusion over 30 minutes once evey 4
weekson day 1 of east cycle.

LGK974 has not yet been given to humans. Based on the results of animal studies
the most likely and most severe side effects of LGK974 in humans are expected
to be in the intestines and include effects such as diarrhea, abdominal
discomfort, infection, and bleeding. The effects on the bone marrow may cause
reduction in the number of blood cells in the body. This can result in fatigue,
infection and bleeding. The effects on the kidneys and liver might cause these
organs to not function properly. The effects seen in animals on growing teeth
and bones are not expected to be seen in adults, but LGK974 may prevent normal
healing of bone fractures and the possibility of tooth problems cannot be
excluded.

Risks that were seen recently with PDR001 include: diarrhea, fatique, nausea,
pruritus, hypotheyroidism, rash and vomiting. As a PD-1 class of drugs also
could cause immune-related toxicities including skin reactions and pneumonitis.
The most common risks supected of LGK974 include: dysgeusia, decresed appetite,
nausea fatique, diarhea, vomiting, hypercalcemia and hypomagnesemia.


Other risks and inconveniences could occur due to blood sampling and collection
of skin or tumor samples. Patiënts will be exposed to radiation when undergoing
a CT, DEXA scan and X ray. The radiation exposure will not exceed the maximum
ranges that are set within the Netherlands. An allergic reaction to the
contrast used for CT scan could occur.