An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820, Administered as a Once Daily and Twice Daily Oral Dose to Determine the Maximum Tolerated Dose in Subjects with Unresectable Solid Tumors

E7820 is an orally administered, antiangiogenic sulfonamide that has
demonstrated antitumor effects in several tumor and metastasis models.
Although the exact molecular mechanism by which E7820 inhibits angiogenesis
remains to be fully elucidated, it is known that E7820 selectively inhibits
endothelial cell growth and tube formation in vitro.
The antitumor effects of E7820 were associated with inhibition of integrin
alpha2 expression in endothelial cells, which is considered to be unique for
agents in its class. A time and dose-dependent decrease in integrin alpha2
expression on platelets was also shown following QD E7820 administration to
subjects.

In a first-in-man, dose escalation study (Study 102), E7820 administration with
food resulted in delayed absorption and increased exposure. In the fed state,
area under the concentration-time curve during a dosing interval (AUC(0-t)) and
maximum concentration (Cmax) were approximately 58% and 43% higher,
respectively, suggesting the presence of food effect. However, these results
were considered inconclusive due to the small number of patients tested and the
parallel study design. The first part of this study will determine the effect
of a high-fat meal on the disposition of E7820 in a cross-over design to
ascertain whether there is a clinically meaningful food effect (at least 30%),
which will determine the timing of E7820 administration in subsequent parts of
this study. As per Food and Drug Administration (FDA) guidance, food effect
assessment will be conducted with 50 mg, the highest dosage strength tablet.
Study 102 evaluated chronic daily doses of E7820 ranging from 10 mg to 200 mg.
A maximum tolerated dose (MTD) of 100 mg QD was established. The next dose in
the escalation (200 mg) was associated with unacceptable toxicity. No
intermediate doses between 100 mg and 200 mg were studied. Part B of this
study will explore E7820 doses above 100 mg but less than 200 mg, targeting to
establish a higher MTD for QD dosing.

A pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation analysis
integrating data from preclinical experiments and Study 102 showed that daily
200 mg dosing would result in a reduction in integrin alpha2 expression
accompanied by 90% tumor stasis in more than 95% of patients, while twice daily
50 mg dosing was shown to result in even greater and more sustained inhibition
that was predicted for 200 mg QD dosing.

Additionally, twice-daily administration may allow for better efficacy and
toxicity than once daily administration. This result is supported by the
pharmacokinetic characteristics of E7820 and clinical studies (Study 102, Study
204). The relatively short elimination half-life suggests that twice-daily,
rather than daily administration, will result in plasma exposure that better
sustains efficacious levels of E7820 over 24 h. Additionally, lower Cmax
levels achieved following twice-daily dosing may ameliorate toxicity that is
associated with higher Cmax levels following daily dosing at the MTD. This
result suggests the possibility of achieving a higher total daily dose and
higher MTD with BID dosing, which may be more biologically active.

Part A Food Effect Study
Primary Objective
• To determine the effect of a high fat meal on oral bioavailability of 50 mg
E7820 in comparison with fasting conditions.
Secondary Objectives
• To determine the safety and tolerability of E7820.
• To determine the pharmacokinetics (PK) of E7820.
Part B: MTD Determination for Daily (QD) Dosing Schedule
Primary Objective
• To determine the maximum tolerated dose (MTD) of E7820 administered orally,
once daily (QD).
Secondary Objectives
• To determine the safety and tolerability of E7820 administered QD.
• To determine the pharmacokinetics of E7820 administered QD.
• To assess evidence of efficacy by RECIST 1.1 (Error! Reference source not
found.).
Part C MTD Determination for Twice Daily (BID) Dosing Schedule
Primary Objective
• To determine the MTD of E7820 administered orally, twice daily (BID).
Secondary Objective
• To determine the safety and tolerability of E7820 administered BID.
• To determine the pharmacokinetics of E7820 administered BID.
• To assess evidence of efficacy by RECIST 1.1.

This study consists of three Parts. Part A (Food Effect Study), Part B
(Determination of MTD for QD Dosing), and Part C (Determination of MTD for BID
Dosing).
Part A will be initiated first. Parts B and C will be initiated in parallel
with one another after the PK results of Part A have been evaluated.
E7820 treatment cycles will be defined as 28 days long.
Part A (Food Effect)
This is an open-label, randomized, single-dose, 2-way cross-over, food-effect
study in subjects with unresectable or refractory solid tumors.
Part A will be conducted in three phases: a Pretreatment Phase, a Treatment
Phase, and an Extension Phase.
Part A Pretreatment Phase
• Will last no longer than 21 days and will include:
o A Screening Period to obtain informed consent and to establish each subject*s
eligibility.
o A Baseline Period to establish each subject*s disease characteristics prior
to treatment.
Part A Treatment Phase
• Each subject (a minimum of 12 subjects) will be assigned according to a
randomization code to receive a single 50 mg dose of E7820 on Day 1, either
after fasting for 10 hours, or immediately after consuming a high fat breakfast
. Following a 7-day washout period, the subjects will cross-over and a second
50 mg dose of E7820 will be administered on Day 8.
• The Treatment Phase ends when a subject completes the last PK assessment. At
this time, this subject will transition into the Extension Phase.
Part A Extension Phase
• Subjects still on treatment will continue to receive E7820 100 mg QD in the
fasted state.
• Study treatment will continue until disease progression, development of
unacceptable toxicity, withdrawal of consent, or discontinuation of E7820
development by the Sponsor.
Part B: Determination of MTD following QD dosing
Part B is a multiple dose study designed to establish the MTD of E7820 given by
QD dosing. It will be conducted in three phases: a Pretreatment Phase, a
Treatment Phase with an Expansion Cohort, and an Extension Phase. The results
from Part A will be evaluated to determine if E7820 will be administered with
or without food in Part B.
Part B Pretreatment Phase
• Will last no longer than 21 days and will include:
o A Screening Period to obtain informed consent and to establish each subject*s
eligibility.
o A Baseline Period to establish each subject*s disease characteristics prior
to treatment.
Part B Treatment Phase
Treatment Cycles for QD MTD Determination
• The initial dose will be 150 mg QD. If. Dose escalation above 170 mg will
be such that the dose remains less than 200 mg, and the dose escalation will be
guided by the level of toxicity observed at the previous dose level.
• If 150 mg QD results in unacceptable toxicities, the dose will be
de-escalated to 120 mg. If the 120 mg dose results in unacceptable toxicities,
no further dose de-escalations will be made.
• The MTD will be determined based on the incidence of DLTs in Cycle 1
Treatment Cycles for Expansion Cohort at the QD MTD
• Once the MTD associated with QD dosing is identified, an Expansion Cohort of
six additional subjects will be enrolled and treated at the MTD. These six
additional subjects will undergo DCE-MRI and DWI-MRI imaging to explore the
antiangiogenic and direct antitumor effects of E7820.
The Treatment Phase for all subjects in Part B ends when the last enrolled
subject completes six cycles of treatment or discontinues early. At this time,
all subjects will transition into the Extension Phase.
Part B Extension Phase
• Subjects will continue to receive the same treatment they received during the
Treatment Phase.
Study treatment will continue until disease progression, development of
unacceptable toxicity, withdrawal of consent, or discontinuation of E7820
development by the Sponsor.

Part C: Determination of MTD following BID dosing

Part C is a multiple dose study designed to establish the MTD of E7820 given by
BID dosing. It will be conducted in three phases: a Pretreatment Phase, a
Treatment Phase with an Expansion Cohort, and an Extension Phase. The results
from Part A will be evaluated to determine if E7820 will be administered with
or without food in Part C.
Part C Pretreatment Phase
• Will last no longer than 21 days and will include:
o A Screening Period to obtain informed consent and establish each subject*s
eligibility.
o A Baseline Period to establish each subject*s disease characteristics prior
to treatment.
Part C Treatment Phase
Treatment Cycles for BID MTD Determination
• The initial dose of E7820 will be 50 mg BID. If allowed by the forgoing
rules for dose escalation (3 + 3 design), the dose escalations will be to 60 mg
BID, 80 mg BID, and 100 mg BID. Further escalation to doses greater than 100
mg BID will be considered if 100 mg BID is not identified as the MTD.
• The MTD will be determined based on the incidence of DLTs in Cycle 1
Treatment Cycles for Expansion Cohort at the QD MTD
• Once the MTD associated with BID dosing is identified, an Expansion Cohort of
six additional subjects will be enrolled and treated at the MTD. These six
additional subjects will undergo DCE-MRI and DWI-MRI imaging to explore the
antiangiogenic effects and direct antitumor effects of E7820.
The Treatment Phase for all subjects in Part C ends when the last subject
completes six cycles of treatment or discontinues early. At this time, all
subjects will transition into the Extension Phase.
Part C Extension Phase
• Subjects will continue to receive the same treatment they received during the
Treatment Phase.
Study treatment will continue until disease progression, development of
unacceptable toxicity, withdrawal of consent, or discontinuation of E7820
development by the Sponsor.

This study consists of three Parts. Part A (Food Effect Study), Part B
(Determination of MTD for QD Dosing), and Part C (Determination of MTD
for BID Dosing).

Part A will be initiated first. Parts B and C will be initiated in parallel with
one another after the PK results of Part A have been evaluated. Parts B and C
will be assigned to separate sites until enrolment in one part is complete, at
which time all sites will continue to enroll in the part of the study that is
still
recruiting.
E7820 treatment cycles will be defined as 28 days long.

Part A (Food Effect)

This is an open-label, randomized, single-dose, 2-way cross-over, food-effect
study in subjects with unresectable or refractory solid tumors.
Part A will be conducted in three phases: a Pretreatment Phase, a Treatment
Phase, and an Extension Phase.
Part A Pretreatment Phase
• Will last no longer than 21 days and will include:
o A Screening Period to obtain informed consent and to establish
each subject*s eligibility.
o A Baseline Period to establish each subject*s disease
characteristics prior to treatment.
Part A Treatment Phase
• Each subject (a minimum of 12 subjects) will be assigned according
to a randomization code to receive a single 50 mg dose of E7820 on
Day 1, either after fasting for 10 hours, or immediately after
consuming a high fat breakfast (Appendix 7). Following a 7-day
washout period, the subjects will cross-over and a second 50 mg
dose of E7820 will be administered on Day 8. Subjects will
consume the high fat breakfast within a 30-minute period prior to
study drug administration and will receive E7820 within 30 minutes
after starting to consume the breakfast. Each treatment will be
administered in the morning with 240 mL of noncarbonated room
temperature water. Subjects will continue fasting (or not eat again)
until the 4-hour study procedures are completed, at which time a
standardized lunch will be served. Water will be permitted
throughout the fasting period except for 1 h before and after study
drug administration.
• The Treatment Phase ends when a subject completes the last PK
assessment. At this time, this subject will transition into the
Extension Phase.
• If a subject does not consume the full breakfast (when appropriate)
and complete all PK assessments, an additional subject will be
randomized to ensure that there are 6 subjects in each group with all
PK assessments.

Part A Extension Phase

• Subjects still on treatment will continue to receive E7820 100 mg
QD in the fasted state.
• Study treatment will continue until disease progression, development
of unacceptable toxicity, withdrawal of consent, or discontinuation
of E7820 development by the Sponsor.

Part B: Determination of MTD following QD dosing

Part B is a multiple dose study designed to establish the MTD of E7820 given
by QD dosing. It will be conducted in three phases: a Pretreatment Phase, a
Treatment Phase with an Expansion Cohort, and an Extension Phase. The
results from Part A will be evaluated to determine if E7820 will be
administered with or without food in Part B.
Subjects will be enrolled into Part B of the study using a conventional
algorithm (3+3 subjects per dose level) to identify the MTD. The dose of
E7820 will be escalated if 0 of 3 or <=1 of 6 subjects experience dose limiting
toxicity (DLT). The dose will be de-escalated if two or more subjects
experience DLT.
Before escalating to a higher dose level, the adverse events of patients in the
current cohort will be discussed by the investigators and the sponsor, and the
next level of dose escalation will be decided by mutual agreement.
The MTD is defined as the highest dose level at which no more than 1 of 6
subjects experiences a DLT, with the next higher dose having at least 2 of 3 or
2 of 6 subjects experiencing DLTs. However, if fewer than six subjects have
been tested at this dose level, additional subjects will be enrolled and tested
to
reach the minimum number of 6 subjects required for MTD to be declared.

Part B Pretreatment Phase

• Will last no longer than 21 days and will include:
o A Screening Period to obtain informed consent and to establish
each subject*s eligibility.
o A Baseline Period to establish each subject*s disease
characteristics prior to treatment.
Part B Treatment Phase
Treatment Cycles for QD MTD Determination
• The initial dose will be 150 mg QD. If allowed by the forgoing rules
for dose escalation (3+3 design), the first escalation will be to
170 mg QD. Further escalation to doses greater than 170 mg QD
will be considered if this dose level is not identified as the MTD.
Dose escalation above 170 mg will be such that the dose remains
less than 200 mg, and the dose escalation will be guided by the level
of toxicity observed at the previous dose level.
• If 150 mg QD results in unacceptable toxicities, the dose will be deescalated
to 120 mg. If the 120 mg dose results in unacceptable
toxicities, no further dose de-escalations will be made. (The Part B
Expansion Phase * described below * would then be initiated at
100 mg QD.
• The MTD will be determined based on the incidence of DLTs in
Cycle 1, although toxicities occurring during subsequent cycles will
also be reviewed. If serious toxicities are observed at this dose level
in later cycles, a reduction of the MTD may be considered.
Treatment Cycles for Expansion Cohort at the QD MTD
• Once the MTD associated with QD dosing is identified, an
Expansion Cohort of six additional subjects will be enrolled and
treated at the MTD. These six additional subjects will undergo
DCE-MRI and DWI-MRI imaging to explore the antiangiogenic and
direct antitumor effects of E7820.
• If a subject does not complete at least one post-baseline
DCE-MRI/DWI-MRI assessment in addition to the baseline
assessment, an additional subject will be added to ensure that there
are 6 subjects with at least 2 timepoint assessments.
The Treatment Phase for all subjects in Part B ends when the last enrolled
subject completes six cycles of treatment or discontinues early. At this time,
all subjects will transition into the Extension Phase.

Part B Extension Phase

• Subjects will continue to receive the same treatment they received
during the Treatment Phase.
Study treatment will continue until disease progression, development of
unacceptable toxicity, withdrawal of consent, or discontinuation of E7820
development by the Sponsor.

Part C: Determination of MTD following BID dosing

Part C is a multiple dose study designed to establish the MTD of E7820 given
by BID dosing. It will be conducted in three phases: a Pretreatment Phase, a
Treatment Phase with an Expansion Cohort, and an Extension Phase. The
results from Part A will be evaluated to determine if E7820 will be
administered with or without food in Part C.
Subjects will be enrolled into Part C using a conventional algorithm (3+3
subjects per dose level) to identify the MTD. The dose of E7820 will be
escalated if 0 of 3 or 1 of 6 subjects experience dose limiting toxicity (DLT).
The dose will be de-escalated if two or more subjects experience dose
limiting toxicities (DLTs).
Before escalating to a higher dose level, the adverse events of patients in the
current cohort will be discussed by the investigators and the sponsor, and the
next level of dose escalation will be decided by mutual agreement.
The MTD is defined as the highest dose level at which no more than 1 of 6
subjects experience a DLT, with the next higher dose having at least 2 of 3 or
2 of 6 subjects experiencing DLTs. However, if fewer than six subjects have
been tested at this dose level, additional subjects will be enrolled and tested
to
reach the minimum of six subjects required for MTD to be declared

Part C Pretreatment Phase

• Will last no longer than 21 days and will include:
o A Screening Period to obtain informed consent and establish
each subject*s eligibility.
o A Baseline Period to establish each subject*s disease
characteristics prior to treatment.

Part C Treatment Phase

Treatment Cycles for BID MTD Determination
• The initial dose of E7820 will be 50 mg BID. If allowed by the
forgoing rules for dose escalation (3 + 3 design), the dose escalations
will be to 60 mg BID, 80 mg BID, and 100 mg BID. Further
escalation to doses greater than 100 mg BID will be considered if
100 mg BID is not identified as the MTD. The extent of additional
dose escalation will be determined according to the level of toxicity
observed at the previous dose level.
• The MTD will be determined based on the incidence of DLTs in
Cycle 1, although toxicities occurring during subsequent cycles will
also be reviewed. If serious toxicities are observed at this dose level
in later cycles, a reduction of the MTD may be considered.
Treatment Cycles for Expansion Cohort at the QD MTD
• Once the MTD associated with BID dosing is identified, an Expansion
Cohort of six additional subjects will be enrolled and treated at the
MTD. These six additional subjects will undergo DCE-MRI and DWIMRI
imaging to explore the antiangiogenic effects and direct antitumor
effects of E7820.
• If a subject does not complete at least one post-baseline DCEMRI/
DWI-MRI assessment in addition to the baseline assessment, an
additional subject will be added to ensure that there are 6 subjects with
at least 2 timepoint assessments.
The Treatment Phase for all subjects in Part C ends when the last subject
completes six cycles of treatment or discontinues early. At this time, all
subjects will transition into the Extension Phase.

Part C Extension Phase

• Subjects will continue to receive the same treatment they received
during the Treatment Phase.
Study treatment will continue until disease progression, development of
unacceptable toxicity, withdrawal of consent, or discontinuation of E7820
development by the Sponsor.

Participation involves risk of harm or discomfort from the study drug or the
procedures and tests that are done during the study:

- side effect from the study drug: adverse effects on the bone marrow which
increases the risk of: decrease in the numbers of white blood cells, decrease
in the number of red blood cells, decrease in the number of platelets;
gastrointestinal problems; headache, fatigue, hair loss, weight loss and loss
of appetite, fever, sleeping difficulties, dermatitis; Increased levels of
liver enzymes (AST and ALT) in the blood*
This is not a complete list of all the side effects that have been observed in
association with this product
- The effects of study drug on the unborn child are currently not known.
However it is likely that E7820, like other anti-cancer medication, would harm
an unborn child; therefore, it is a risk for pregnant women and the study
involves contraceptive requirements

- Risk from study specific procedures:
o MUGA Scans: allergic reactions to radiopharmaceuticals may occur but are
extremely rare and are usually mild.
o CT , MRI scans, DCE-MRI/DWI-MRI and for bone scans, a contrast solution is
injected: there is a possible risk of pain, swelling, a bruise, or (rarely)
infection at the injection site. The CT contrast material may cause skin rash,
flushing, nausea, vomiting, or (rarely) an allergic reaction.
o
o Blood samples: possibility of pain, swelling, bruise, bleeding or infection
at the site where the needle is inserted, or light-headedness or fainting