Phase I/II, multi-center, open label study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of ASP9521 in patients with metastatic castrate-resistant prostate cancer

Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer
mortality in men. Prostate cancer is the most common cancer in men in Europe,
with about 190,000 new cases every year [Parkin et al, 2005; Boyle and Ferlay,
2005]. About 80,000 deaths a year result from this cancer in Europe [Ferlay et
al, 2001]. Localized prostate cancer is the most commonly diagnosed stage. The
choice of treatment (active monitoring, radical prostatectomy, or any type of
radiotherapy) is based on factors such as tumor characteristics and the
patient*s life expectancy. At diagnosis, prostate cancer can also be locally
advanced or metastatic and therefore already spread beyond the prostate bed
and/or to distant sites such as bone.
Prostate-specific antigen (PSA) is a glycoprotein that is expressed by both
normal and neoplastic prostate tissue. PSA is consistently expressed in
prostate cancer. The absolute value of serum PSA is useful for determining the
extent of prostate cancer and assessing the response to prostate cancer
treatment. Newer prognostic markers are also being explored. For example,
preliminary data suggest that, in patients with metastatic prostate cancer, the
number of circulating tumor cells (CTC) correlates with survival [Scher et al,
2009].
Prostate cancer growth is dependent on androgens, and depleting or blocking
androgen action has been a mainstay of treatment for over 6 decades. Hormonal
therapies include gonadotropin-releasing hormone (GnRH) analogues, androgen
receptor antagonists, ketoconazole, and estrogenic compounds. Tumors that
progress despite castrate levels of testosterone in the blood are considered
castration-resistant. In clinical practice, treatment of advanced prostate
cancer is therefore limited by the development of resistance to anti androgen
therapies. Most patients receive two or more hormonal manipulations and are
then offered chemotherapy as they continue to progress (European Association of
Urology [EAU] Guidelines, 2010). Despite the early sensitivity of prostate
cancer to hormonal strategies, castration-resistant progression generally
represents a transition to the lethal variant of the illness, and most patients
ultimately succumb to this disease. Currently, the median survival of
castration-resistant disease is approximately 12 months [Petrylak et al, 2004;
Pienta and Bradley, 2006]. Non-hormonal treatments of castrate-resistant
prostate cancer (CRPC) including the anti-mitotic docetaxel have been shown to
extend median survival in patients with advanced prostate cancer that is no
longer responsive to hormone therapy [Picus and Schultz, 1999]. Furthermore, it
has been shown that the effectiveness of docetaxel in survival and disease
progression can be improved when administered concomitantly with prednisone
[Tannock et al, 2004]. However, current guidelines recommend the use of
docetaxel for limited periods and the treatment can have serious side effects.
Results of clinical investigations and studies on the molecular profiles of
progressing prostate cancer show that the androgen receptor remains functional
and that the tumors should respond to strategies directed at the androgen
receptor signaling axis. The most powerful intracellular intraprostatic
androgen, dihydrotestosterone (DHT), is formed through the standard
steroidogenic pathway in which blood-derived testosterone and several blood
derived adrenal steroids are involved. DHT can also be formed by a pathway that
uses progesterone as the primary substrate (the *backdoor pathway*) [Pienta and
Bradley, 2006]. In the standard steroidogenesis pathway, the testes provide the
major source of androgens, particularly testosterone. However, CRPC can utilize
alternative pathways when testosterone and other androgens are not available
from the circulation. Hence, in addition to GnRH agonists/antagonists,
testosterone synthesis interfering agents, such as 17β-hydroxysteroid
dehydrogenase type 5 (17βHSD5) inhibitors, are expected to reduce testosterone
concentration in prostate cancer tissue and suppress the growth of prostate
cancer cells.

The overall objective of this phase I/II three-part study is to evaluate the
benefit of 12 weeks once daily dosing with ASP9521 in a population of patients
with metastatic castrate resistant prostate cancer (CRPC) who have failed one
or more lines of hormonal treatment/androgen deprivation therapy (stratified as
chemotherapy-naïve or post chemotherapy), after first establishing the safety
and pharmacokinetics (PK) of ASP9521 from assessments of single and short term
(4 weeks) multiple dose escalation, and to determine an optimal dose of ASP9521.

Part I - Dose Escalation
Primary Objective:
• To evaluate the safety and tolerability of ASP9521.
Secondary Objectives:
• To determine the maximum tolerated dose (MTD), if possible.
• To evaluate prostate specific antigen (PSA) decline of >=50% from baseline
after 12 weeks of daily dosing with ASP9521.
• To evaluate the PK of ASP9521 following single and multiple dose
administration.
• To evaluate the pharmacodynamics (PD) of ASP9521.

Part II - Expanded Dose Assessment using Combined Data Parts I+II
Primary Objective:
• To evaluate PSA decline of >=50% from baseline after 12 weeks of daily dosing
with ASP9521.
Secondary Objectives:
• To evaluate the safety and tolerability of ASP9521.
• To evaluate the PK of ASP9521 following multiple dose administration.
• To evaluate the efficacy of ASP9521.
Other Objectives:
• To evaluate the PD effect of ASP9521.
• To evaluate the effect of ASP9521 on pain palliation.
• To evaluate pharmacogenetics.

Part III - Food Effect at Assumed Optimal Dose
Primary Objective:
• To evaluate the PK of single doses of ASP9521 under fed and fasted conditions.
Secondary Objectives:
• To evaluate the PD effect of single doses of ASP9521 under fed and fasted
conditions.
• To evaluate the safety and tolerability of single doses of ASP9521 under fed
and fasted conditions.
• To evaluate the efficacy of ASP9521.

Part I
Part I will be an open label, standard oncology 3+3 design, first in man (FIM),
ascending dose evaluation of ASP9521 after a single dosing period and a 4-week
(28-day) multiple daily dosing period separated by a wash out period.
Dose-limiting toxicity (DLT) will be assessed by the Dose Escalation and
Expansion Committee (DEEC) after the 28-day dosing period, and depending on the
DLT up to 5 cohorts of 3 to 6 patients (i.e., 5 dose levels and therefore 4
dose escalation steps) are planned per patient group of chemotherapy-naïve and
post-chemotherapy patients. If possible the MTD of ASP9521 will be established.
The planned doses are 30, 100, 300, 600 and 1200 mg/day. Escalation to higher
doses will only be done if lower doses are adequately tolerable, as assessed by
the incidence of DLT. Additional doses, intermediate to those stated above, may
be assessed at the discretion of the DEEC. Each dose of ASP9521 will be
administered in the morning. On the days that PK blood and urine samples are
taken, the patient will fast overnight for 10 hours prior to dosing, then for a
further 2 hours after dosing. The length of the fasting period will be adjusted
once the results of the Part III evaluation of food on exposure to ASP9521 are
known. Within a patient there will be no increase or reduction of a dose.
Enrolment in every dose will be staggered; the first patient will be enrolled
separately, followed by the remaining patients in that dose 3 days later. The
length of the wash out period between the single and multiple dosing periods
for the first dose group will be set to 10 days. The length of the wash out
period for the following doses may be reduced depending on the accumulated PK
data from previous cohorts.
During the 28 day dosing period patients will be continually monitored for
safety, blood samples will be collected for PK assessments, and patients will
be monitored for clinical benefit, including measurement of PSA levels. Based
on safety data from the 28-day dosing the DEEC will decide whether to escalate
or reduce the dose for the second cohort of patients, or to enroll a further 3
patients to continue on the current dose level. The same procedures will be
repeated for each subsequent cohort of patients. Patients will not be enrolled
to the next dosing cohort until the safety and tolerability of the previous
cohort has been established. The dose escalation decision tree is shown in
Section V.
Following the 28-day multiple dosing period, patients will continue to receive
ASP9521 for up to 12 weeks. During this period, patients will continue to be
monitored for safety and clinical benefit of the drug. The effect of multiple
dosing on PK will be assessed. Evaluations of disease status will include
abdominopelvic computed tomography (CT)/magnetic resonance imaging (MRI) and
bone scan, as well as measurements of PSA and CTC. Patients who have clinical
benefit at 12 weeks may continue to receive this dose of ASP9521 at the
discretion of the investigator until objective or clinical disease progression,
or occurrence of an unacceptable toxicity. All patients will have a safety
follow up visit 30 days after their last dose of study drug, which is their end
of study visit (ESV).

Part II
Part II will be an open label, 12-week multiple dosing expansion of Part I, in
which patients will be recruited to doses found in Part I to be well tolerated
and demonstrating clinical benefit (at least one third of patients [at the
discretion of the DEEC], with a decline in plasma PSA concentrations >=50% from
baseline at that dose level, and based on the PSA response rate at adjacent
doses).
It is expected that at most, 3 dose levels will be expanded in this way. Up to
24 patients (chemotherapy-naïve and post chemotherapy) may be recruited per
dose level to receive 12 weeks treatment. This will be an expansion of up to 30
patients including those already dosed in Part I.
If possible, one dose level, the assumed optimal dose, will be expanded further
to include up to 84 additional patients. This will be an expansion to 90
patients including those already dosed in Part I. This assumed optimal dose is
likely to be the MTD, but a lower dose could be selected by the DEEC after
review of all available safety and efficacy data. Caution will be taken
expanding lower doses which might be less efficacious. Consideration will be
given to: (a) a dose being the first dose with any PSA signal; (b) the number
of patients within a dose cohort showing a PSA response; (c) PSA responders in
one or both patient populations; and (d) any safety consideration and potential
other considerations.
For each of the doses administered for 12 weeks in Part II, only one dose will
be open for enrollment at one time. Patients will take their dose of ASP9521 in
the morning. On the days that PK blood and urine samples are taken, the patient
will fast overnight for 10 hours prior to dosing, then for a further 2 hours
after dosing. The length of the fasting period will be adjusted once the
results of the Part III evaluation of food on exposure to ASP9521 are known.
Patients will be monitored for safety and clinical benefit of the drug, as well
as evaluations of disease status as done in Part I. The effect of multiple
dosing in PK will be assessed.
As in Part I, patients who have clinical benefit at 12 weeks may continue to
receive ASP9521 at the discretion of the investigator until objective or
clinical disease progression, or occurrence of an unacceptable toxicity. All
patients will have a safety follow up visit 30 days after their last dose of
study drug, which is their ESV.

Part III
Part III will be an open label, single dose, evaluation of the effect of food
compared with fasting on the PK of ASP9521 at the assumed optimal dose
established in Parts I and II. Part III will be conducted as soon as the
assumed optimal dose is confirmed from Parts I and II data. Furthermore, based
on the PK profile (t*) established in Parts I and II, it will be decided
whether to conduct Part III as a crossover or parallel group design. If Part
III is conducted in a crossover design 24 patients (chemotherapy-naïve and post
chemotherapy) will be randomized (1:1) on Day 1 to receive the single dose of
ASP9521 under fasted conditions (Period 1) followed by fed conditions (Period
2), or under fed conditions (Period 1) followed by fasted conditions (Period
2). There will be a wash out period after each single dose of ASP9521. The
length of the wash-out period will depend upon the PK profile (t*) of ASP9521
established in Parts I and II.
If the parallel group design is selected 48 patients will be randomized (1:1)
on Day 1 to receive the single dose of ASP9521 either under fasted conditions
(24 patients) or after a high fat breakfast (24 patients). Dosing will be
followed by a wash out period. The length of the wash out period will depend
upon the PK profile (t*) of ASP9521 established in Parts I and II.
Prior to the dosing on Day 1 all patients will have fasted overnight (only
water allowed). For fasted conditions patients will administer the single dose
of ASP9521 in the morning after the overnight fast and will not be allowed food
until at least 4 hours after dosing. For fed conditions, patients will
administer ASP9521 30 minutes after the start and up to 5 minutes after the
completion of the high fat breakfast. Further meals will not be allowed until
at least 4 hours after dosing.
Patients in Part III may continue to take ASP9521 for up to 12 weeks. During
this period, patients will continue to be monitored for safety and clinical
benefit of the drug, as well as evaluations of disease status as done in Part
I. The effect of multiple dosing in PK will be assessed. As in Parts I and II,
patients who have clinical benefit at 12 weeks may continue to receive ASP9521
at the discretion of the investigator until objective or clinical disease
progression, or occurrence of an unacceptable toxicity. All patients will have
a safety follow up visit 30 days after their last dose of study drug, which is
their ESV.

Part I will be an open label, standard oncology 3+3 design, first in man (FIM),
ascending dose evaluation of ASP9521 after a single dosing period and a 4-week
(28-day) multiple daily dosing period separated by a wash out period.

Part II will be an open label, 12-week multiple dosing expansion of Part I, in
which patients will be recruited to doses found in Part I to be well tolerated
and demonstrating clinical benefit (at least one third of patients [at the
discretion of the DEEC], with a decline in plasma PSA concentrations >=50% from
baseline at that dose level, and based on the PSA response rate at adjacent
doses).

Part III will be an open label, single dose, evaluation of the effect of food
compared with fasting on the PK of ASP9521 at the assumed optimal dose
established in Parts I and II. Part III will be conducted as soon as the
assumed optimal dose is confirmed from Parts I and II data. Furthermore, based
on the PK profile (t*) established in Parts I and II, it will be decided
whether to conduct Part III as a crossover or parallel group design.

This is a new research study and the study drug has not been used in any humans
before.
Previous tests (animal tests) have indicated potential effects of slight
decreases in blood pressure and heart rate. Other findings also showed changes
in lipid levels.

The study is undertaken in patients that pertain to the intended target
population for the drug. There is a chance that the patients experience
personal benefit from taking part in the treatment with ASP9521, and that it
may relieve or improve their illness. The information that is collected will
hopefully improve the treatment of other individuals with prostate cancer.