A phase II, open label study to investigate the efficacy and safety of domatinostat in combination with avelumab in patients with advanced unresectable/metastatic Merkel Cell Carcinoma progressing on anti-PD(L)1 antibody therapy - the MERKLIN 2 study

Study Design:

Phase II, multi-centre, single arm, open-labeled with two cohorts according to
previous anti-PD-(L)1 antibody monotherapy:

Cohort 1: progressing on avelumab (anti-PD-L1 antibody).
Cohort 2: progressing on any anti-PD-1 antibody

Objectives:
Primary Objective: to investigate the anti-tumor efficacy of domatinostat in
combination with avelumab in advanced unresectable/metastatic MCC patients
progressing on anti-PD-(L)1 antibody monotherapy.
Secondary Objectives: to investigate safety, tolerability, pharmacokinetics,
avelumab anti-drug antibodies (ADA) and health-related quality of life (HrQoL).
Exploratory Objective: to investigate tumor tissue for molecular
characteristics correlating with clinical parameters/clinical outcome.

STUDY RATIONALE
Unmet Medical Need
Treatment with avelumab or pembrolizumab could achieve response rates of ~33%
in chemotherapy-pretreated and between 40% and 60% in chemotherapy-naïve
advanced MCC patients [Nghiem, 2019; Kaufman, 2016; D*Angelo, 2018; EPAR
Bavencio]. Nonetheless and irrespective of treatment line, a significant number
of patients are either refractory to anti-PD-(L)1 antibody monotherapy or
experience a relapse of the disease after a period of initial response but
still on anti-PD-(L)1 antibody therapy. For these patients no further, approved
treatment options exist; they carry a poor prognosis with a short remaining
life expectancy of a few months. In clinical practice most of these patients
will receive individualized chemotherapy or no further cancer-directed
treatment but best supportive care.
Patients with recurrent MCC, i.e. patients with treatment response and
consecutive anti-PD-(L)1 antibody therapy cessation for more than 3 months will
not be allowed to enter this study due to uncertainties inasmuch those patients
will respond to re-initiation of anti-PD-(L)1 antibody monotherapy again.

Overcoming Tumor Escape Mechanisms

Recent research has shown that the immunological escape of the tumor from the
host*s immune response plays an important role for anti-PD-(L)1-antibody
therapy resistance. Hereby, the following mechanisms should be highlighted in
the context of MCC:

• MHC-I down regulation:

Tumor-associated antigens must be presented in the context of MHC-I molecules
to be recognized immunologically by CD8 T cells. Immunohistochemical
evaluations have shown a markedly down regulated expression of MHC-I in
conjunction with reduced corresponding mRNA content in MCC tumor tissue proving
that endogenous T-cell recognition of MCC tumors antigens is significantly
disrupted, not to say completely impaired [Vandeven, 2016].

• T Cell Response:

A robust intra-tumoral MCC infiltration with CD8 lymphocytes is associated with
a striking 100% survival in a study of N=146 patients [Iyer, 2011].
Furthermore, additional studies have also indicated that MCC tumor infiltrating
lymphocytes, including CD3, CD8 T cells, are associated with improved overall
and disease-specific survival. Importantly, while robust CD8 responses have
been associated with improved outcome in MCC, only 4 to 18% of MCC patients
present with significant CD8+ lymphocytes infiltration suggesting that most MCC
block intra-tumoral CD8 infiltration as a means of evading immune detection
[Andea, 2008; Paulson, 2014].

• CD4 T cell polarization:

In several neuroendocrine cancer types, intra-tumoral infiltration of CD4 T
cells subtype Th1 is strongly associated with good clinical outcomes, due to
induction of IFN-γ secretion which facilitates intra-tumoral priming and
expansion of CD8 T cells. Th1 CD4 cells also serve to recruit pro-inflammatory
NK and type-I macrophages to the tumor site, hereby orchestrating robust
anti-tumor immunity. Several experimental approaches that promote a Th1 CD4
type response have shown first promising results in MCC [Iyer, 2011].
Domatinostat activates the antigen-presenting machinery by increasing MHC I and
MHC II expression on tumor cells and triggers tumor infiltration of cytotoxic
T-cells, mainly Th1 CD4 cells, resulting in an enhanced immunogenicity of the
tumor cells. This primes the tumor and its microenvironment to be more
susceptible to treatment with anti-PD-(L)1 antibodies [Hamm, 2018, Song, 2019].
Combining domatinostat with anti-PD-(L)1 antibodies had better effects on tumor
growth inhibition in pre-clinical models. These synergistic immune modulating
effects of domatinostat plus PD-(L)1 inhibitors favor domatinostat to be a
unique therapeutic partner in malignancies where T-cell infiltration in tumors
plays a main role.
Avelumab Treatment
The data from the JAVELIN Merkel 200 study have defined anti-PD-(L)1 checkpoint
inhibition as the new standard of care for patients with metastatic MCC and
avelumab was the first drug approved in 2017. The second drug now approved for
advanced unresectable/metastatic MCC is pembrolizumab, an anti-PD-1 inhibitor,
cleared by the FDA in January 2019. To take this fact into account, patients
with prior anti-PD-1 antibody treatment will be also allowed to enter this
study. However, once enrolled into the study, all patients will receive
domatinostat in combination with avelumab.
The anti-PD-(L)1 antibody monotherapy must be the last systemic therapy for
MCC. One line of chemotherapy prior to anti-PD-(L)1 antibody monotherapy or
adjuvant anti-PD-(L)1 antibody monotherapy in case of former R0 resection will
be allowed.

Conclusion

In summary, domatinostat is expected to have considerable clinical potential as
an epigenetic modifier synergizing with an anti-PD-(L)1 antibody to achieve an
anti-tumor immune response in patients progressing on anti-PD-(L)1 monotherapy.
This Phase II study is designed to explore efficacy and safety of domatinostat
in combination with avelumab in advanced unresectable/metastatic MCC patients
progressing on anti-PD-(L)1 antibody therapy with avelumab (cohort 1) or any
anti-PD-1 antibody (cohort 2). MCC patients progressing on anti-PD-(L)1
antibody therapy have a poor prognosis and there remains a high unmet medical
need to develop effective new treatment alternatives for these patients.

Phase II, multi-central, single-armed, open label with two cohorts in
accordance with previous anti-PD (L) 1 antibody monotherapy:

All patients receive the study medication, which consists of the following two
components:
• Domatinostat oral intake, 200 mg twice daily (BID)
• Avelumab infusion 800 mg every 2 weeks (Q2W)
All patients receive the study medication in an open-label manner. Temporary
interruption of the study medication (or one of the components) is allowed in
cases of treatment-related toxicities or intolerances.

Domatinostat
The following adverse reactions have been observed in more than 1 patient to
date:
• Effects on blood counts such as:
o Anemia (reduced oxygen-transporting capacity of the blood); this may cause
shortness of breath, tiredness and fatigue
o Reduced number of white blood cells (these are part of the immune system for
the defense against infections, associated with an increased risk of
infections)
o Reduced number of platelets (platelets are involved in the control of
bleeding, e.g. after injuries or surgery)
• Gastrointestinal symptoms such as flatulence, constipation, nausea, vomiting,
diarrhea (which may cause loss of fluid and an imbalance of minerals in the
blood), dry mouth
• General symptoms such as fatigue, fever, chills, insomnia, vertigo,
paresthesia, reduced appetite or inflammation of mucous membranes, cough,
peripheral edema (abnormal accumulation of fluid in certain tissues of the
body; e.g. swelling of the legs)
• Skin reactions such as a rash and dry skin
• Changes in laboratory measurements such as liver function tests
• Hypersensitivity reactions / allergic reactions with symptoms such as rash,
chills, itching, fever, nausea, vomiting and low blood pressure. (In case of
rash due to a suspected hypersensitivity reaction, a skin biopsy may be taken
for clarification of cause).

In patients who were treated with medications from the same drug class as
domatinostat (i.e. histone deacetylase inhibitors) certain changes in the ECG
have been observed (a so-called prolonged QT interval) which, in rare cases,
may lead to severe arrhythmias (irregular heartbeat) up to cardiac arrest. To
date, such significant ECG changes have not been observed under treatment with
domatinostat. Still, for safety reasons, regular ECG recordings are performed
in the course of the study and while on study treatment. You should avoid
co-medications known to have the potential to prolong the QT interval and to
lead to serious cardiac arrhythmias (irregular heartbeat). Your study doctor
will discuss with you the medications you may have to discontinue during the
study treatment.

Avelumab

Three types of risks are associated with avelumab: general signs and symptoms,
reactions that occur during or following the infusion (so called
infusion-related reactions), and immune side effects.
The following general side effects have been observed in >= 10 % of patients
among 1738 patients treated with avelumab according to the results from two
clinical studies in patients with cancer:

Observed in 10% or more of patients
Tiredness
Nausea (feeling sick to the stomach)
Diarrhea (Frequent loose, watery stools)
Constipation (difficulty passing stools)
Decreased appetite
Infusion-related reaction
Weight decreased
Vomiting
Anemia (low number of red blood cells)
Abdominal pain
Cough
Pyrexia (fever)
Dyspnea (shortness of breath)
Pruritus (itching)*
Edema peripheral (buildup of fluid in the body causing swelling)

Musculoskeletal pain (including back pain, neck pain)
Arthralgia (joint pain)
Dizziness*
Headache*
Hypertension (increase in blood pressure)*
Urinary tract infection*

* side effects included in the table even though occurring in less than 10%,
because they are part of the product information

Although avelumab is a fully human protein, the risk cannot be completely
excluded that allergic reactions or reactions in the context with the infusions
might occur during or after the infusion. Symptoms may include chills or
shaking, fever, flushing, back pain, belly pain, shortness of breath or
wheezing, decrease in blood pressure, and hives. Infusion-related reactions
have already been observed under treatment with avelumab. In general, these
reactions are mild to moderate and generally resolve with a slowdown or
discontinuation of the infusion and with appropriate drugs, but in less than 1
% of patients severe to life-threatening reactions might occur, which require
advanced cardiac life support and could potentially be fatal.
For the prevention of infusion-related adverse effects and possible allergic
reactions you will receive a premedication of an antihistamine drug (so-called
H1 blocker) and an anti-inflammatory drug (e.g. paracetamol) 30 to 60 minutes
before the first infusions of avelumab.
In addition, side effects resulting from an increased activity of the immune
system have also been observed. The side effects listed below may be temporary,
long term, permanent or result in death. However, most of these side effects
are reversible. That means they will stop once the drug is discontinued. The
reactions that are more severe require treatment with drugs that decrease the
immune system function, also called immunosuppressant drugs (like
corticosteroids or more potent drugs).
The following immune-mediated side effects have been observed in patients
receiving the study drug and might occur, such as:
Immune side effects observed in 5% to less than 10% of patients
• Abnormal function of the thyroid gland (could include low or high function or
inflammation of the thyroid gland): may include rapid heartbeat; increased
sweating; extreme tiredness; weight gain or weight loss; hair loss; changes in
mood or behavior such as irritability or forgetfulness; feeling cold;
constipation; voice gets deeper.
• Inflammation of the skin (rash): may include skin rash, itchy skin, skin
redness, skin blisters, or peeling.

Immune side effects observed in 1% to less than 5% of patients
• Inflammation of the large intestine (colitis): may include diarrhea (loose
stools) or more frequent bowel movements than usual; blood in stools or dark,
tarry, sticky stools; severe stomach area (abdomen) pain or tenderness.
• Inflammation of the lungs (pneumonitis): may include new or worsening cough,
shortness of breath, chest pain.
Immune side observed in less than 1% of patients
• Inflammation of the liver (hepatitis): may include yellowing of skin or of
the whites of eyes; severe nausea or vomiting; pain on the right side of
stomach area (abdomen); drowsiness; dark urine (tea colored); bleeding or
bruising more easily than normal; feeling less hungry than usual.
• Inflammation of the kidneys (nephritis): may include urinating less than
usual; blood in urine; swelling in ankles; loss of appetite.
• Low function of the adrenal glands (glands on top of the kidneys), which may
be due to the reduced function of the pituitary gland (a gland in the head):
may include very low blood pressure; extreme tiredness.
• Increase in blood sugar (diabetes): may include urinating more often than
usual; feeling more hungry or thirsty than usual, nausea or vomiting, stomach
area (abdomen) pain.
• Inflammation of the eyes (uveitis): may include changes in eyesight.
• Inflammation of the muscles (myositis): may include severe or persistent
muscle or joint pain; severe muscle weakness.
• Inflammation of the heart (myocarditis): may include chest pain or tightness;
tiredness; changes in heartbeat, such as beating fast, or seeming to skip a
beat, or pounding sensation; swelling of feet and legs; trouble breathing.
• Inflammation of the nerves (Guillain-Barre syndrome): may include "pins and
needles" sensations in arms and legs; weakness in legs that spreads to the
upper body and may lead to temporary paralysis.
• Inflammation of the pancreas (pancreatitis): may include pain in upper
abdomen, nausea, vomiting, constipation, weight loss, indigestion.
Single cases of immune-mediated pneumonitis, immune mediated hepatitis,
immune-mediated pancreatitis and immune-mediated myocarditis with fatal outcome
have been observed with avelumab.