Enzalutamide in Combination With PSA-TRICOM in Patients With Non-Metastatic Castration Sensitive Prostate Cancer

Background:

- Androgen deprivation therapy (ADT) and surveillance are standard therapy options for
prostate cancer patients with biochemical progression after localized therapy (or
nonmetastatic castration sensitive prostate cancer; nmCSPC also known as D0 Prostate
Cancer). These patients cannot be cured of prostate cancer and the primary therapeutic
goal is to contain the disease with anti-androgen therapy.

- ADT can be administered intermittently consisting of multiple short courses or
continuously with similar long-term clinical outcomes.

- Previous studies with high dose bicalutamide (androgen receptor antagonist, ARA) have
shown significant biochemical control in nmCSPC.

- Enzalutamide is a modern ARA with greater androgen receptor affinity than bicalutamide
and further impairs downstream effects of androgen receptor activation. This agent is
FDA approved for the treatment of chemotherapy refractory metastatic castration
resistant prostate cancer.

- Given its favorable side effect profile, there is strong interest in using enzalutamide
to treat patients with earlier stages of prostate cancer including nmCSPC.

- PSA-TRICOM (Prostvac ; developed by the National Cancer Institute [NCI] and licensed to
Bavarian Nordic, Mountain View, CA) is a novel candidate prostate cancer immunotherapy
for the treatment of prostate cancer. It is a viral vector based therapeutic cancer
vaccine that is administered via subcutaneous injections. In a randomized controlled
Phase 2 trial, PSA-TRICOM therapy was associated with a prolongation of survival in men
with metastatic castrate-resistant prostate cancer. A phase III trial is currently
enrolling patients in this same population.

- There is also rationale to use therapeutic cancer vaccines such as PSA-TRICOM in earlier
stage prostate cancer patients to maximize the potential therapeutic effect of immune
stimulating therapy.

- An ongoing NCI clinical trial that combined PSA-TRICOM with flutamide (an older FDA
approved ARA) in nonmetastatic castration resistant prostate cancer has demonstrated
safety and suggested the potential to improve time to progression.

- Analysis of previous trials using therapeutic cancer vaccines alone and in combination
suggests that such therapies may alter tumor growth rate. If this hypothesis is correct,
a therapeutic cancer vaccine may alter tumor regrowth rate/recovery after a
cytoreductive therapy such as enzalutamide is discontinued.

- If PSA-TRICOM with enzalutamide can result in a reduced tumor regrowth rate as measured
by PSA after a short course of enzalutamide therapy, it would provide an important proof
of concept and potentially define it more clear role for therapeutic cancer vaccines in
prostate cancer and potentially other cancers.

- To prospectively evaluate this hypothesis, all patients will be treated with
enzalutamidein a manner similar to how short course ADT is used in common clinical
practice. Half the patients will also be given PSA-TRICOM and PSA recovery after
enzalutamide therapy will be compared between patients who received vaccine and those
who did not.

- Preliminary data from the first cohort of randomized patients suggests that enzalutamide
alone can induce an immunologic response. A second cohort of 15 patients will explore a
lower dose of enzalutamide at 80 mg to determine if similar immunologic responses can
also be seen at a lower dose, where toxicity is less likely.

Objectives:

Primary Endpoint:

-Determine if PSA-TRICOM combined with the novel androgen receptor antagonist enzalutamide
will result in a decrease in PSA growth kinestics (tumor re-growth rate) after enzalutamide
discontinuation in patients with non-metastatic, castration sensitive prostate cancer (i.e.
patients with normal testosterone).

Eligibility:

- Patients with nonmetastatic castration sensitive prostate cancer and a PSA over 2.0
ng/ml

- Patients with normal testosterone levels.

- Histologically confirmed adenocarcinoma.

- Patients with a PSA doubling time of 12 months or less.

- ECOG 0-1.

Design:

- Randomized pilot study

- Cohort 1:

- Thirty-four patients to be enrolled and randomized 1:1 to

- Arm A: Enzalutamide for 3 months.

- Arm B: Enzalutamide 3 months + PSA-TRICOM on weeks 1, 3,5,9,13,17 and 21.

Cohort 1:

- Arm A: Enzalutamide (n=17)

- Arm B: Enzalutamide + PSA-TRICOM (n=17)

- Enzalutamide will be given at the standard dose of 160 mg daily for 3 months.
PSATRICOM (Prostvac-V/F) will consist of a single subcutaneous (sc) immunization of
Prostvac-V in Week 1, followed by 6 Prostvac-F immunizations administered in Weeks
3, 5, 9, 13, 17, and 21. Patients will be retreated with a 3-month course of
enzalutamide after PSA has returned to baseline values at study entry or higher.
Patients will have had to be on study for at least 7 months or longer in order to
be retreated with an additional course of enzalutamide therapy. Patients will be
followed for PSA recovery after enzalutamide has been discontinued. Patients who do
not develop a 25% decline in PSA after 3 months will not be evaluated for tumor
re-growth and additional patients will be enrolled to evaluate for that endpoint.
Patients will be stratified based on a doubling time of greater than or less than 6
months.

- INCLUSION CRITERIA:

A. Histopathological documentation of prostate cancer confirmed in the Laboratory of
Pathology at the National Institutes of Health (NIH) Clinical Center, or Walter Reed
National Military Medical Center prior to enrollment. If no pathologic specimen is
available, patients may enroll with a pathologist s report showing a histologic diagnosis
of prostate cancer and a clinical course consistent with the disease.

B. Biochemical progression defined as follows:

- For patients following definitive radiation therapy: a rise in PSA of greater than or
equal to 2 ng/mL above the nadir (per RTOG-ASTRO consensus criteria).

- For patients following radical prostatectomy: rising PSA after surgical procedure.
(Patients must have a PSA greater than or equal to 2ng/ml)

C. ECOG performance status of 0-1 (Karnofsky greater than or equal to 80%).

D. Patients must have a PSA doubling time of 12 months or less. E. Patients must have a
rising PSA as confirmed by 3 values done at least 1 week apart and over no less than 1
month.

F. Recovery from acute toxicity related to prior therapy, including surgery and radiation,
or no toxicity greater than or equal to grade 2.

G. Negative CT scan/MRI and bone scan for metastatic prostate cancer.

H. Hematological eligibility parameters (within 16 days before starting therapy):

Granulocyte count greater than or equal to 1000/mm(3)

Platelet count greater than or equal to 100 000/mm(3)

Hgb greater than or equal to 10 g/dL

I. Biochemical eligibility parameters (within 16 days before starting therapy):

Hepatic function: bilirubin less than or equal to 1.5 mg/dL (OR in patients with Gilbert s
syndrome, a total bilirubin less than or equal to 3.0), AST and ALT less than or equal to
2.5 times upper limit of normal.

J. No other active malignancies within the past 36 months (with the exception of
nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-threatening illnesses

K. Willing to travel to the NIH for follow-up visits.

L. 18 years of age or older.

M. Able to understand and sign informed consent.

N. Baseline testosterone greater than or equal to lower limit of normal.

O. PSA less than or equal to 20 ng/mL.

P. The effects of enzalutamide, PSA-TRICOM or the combination on the developing human fetus
are unknown. For this reason, men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while her
partner is participating in this study, she should inform her treating physician
immediately.

EXCLUSION CRITERIA:

A. Immunocompromised status due to:

- Human immunodeficiency virus (HIV) positivity.

- Active autoimmune diseases such as Addison s disease, Hashimoto s thyroiditis,
systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis,
Goodpasture syndrome or active Grave s disease. Patients with a history of
autoimmunity that has not required systemic immunosuppressive therapy or does not
threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI tract
will be allowed.

- Other immunodeficiency diseases

B. Chronic administration (defined as daily or every other day for continued use greater
than 14 days) of corticosteroids deemed systemic by investigator within 28 days before the
first planned dose of PSA-TRICOM. Use of inhaled steroids, nasal sprays, and topical creams
for small body areas is allowed.

C. Serious intercurrent medical illness that, in the judgment of the investigator, would
interfere with patient s ability to carry out the treatment program.

D. History of seizure, including any febrile seizure, loss of consciousness, or transient
ischemic attack, or any condition that may pre-dispose to seizure (e.g., prior stroke,
brain arteriovenous malformation, head trauma with loss of consciousness requiring
hospitalization).

E. Other medications used for urinary symptoms including 5-alpha reductase inhibitors
(finasteride and dutasteride) and alternative medications known to alter PSA (eg
phytoestrogens and saw palmetto)

F. History of prior chemotherapy

G. History of prior immunotherapy within the last 3 years

H. Major surgery within 4 weeks prior to enrollment (Day 1 visit).

I. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine)

J. Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin
or tobramycin).

K. History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that
disrupts the epidermis

L. Previous serious adverse reactions to smallpox vaccination

M. Unable to avoid close contact or household contact with the following highrisk
individuals for three weeks after the Day 1 vaccination: (a) children 3 years of age, (b)
pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or
other eczemoid skin disorders, or (d) immunocompromised individuals, such as those with
HIV.

N. Receipt of an investigational agent within 30 days (or 60 days for an antibodybased
therapy) before the first planned dose of study drugs.

O. Patients who test positive for HBV or HCV

P. Use of herbal products that may decrease PSA levels (e.g. saw palmetto)

Q. Any gastrointestinal disease that could hinder the absorption of enzalutamide

R. Uncontrolled hypertension (SBP>170/ DBP>105)