Enzalutamide With or Without Vaccine Therapy for Advanced Prostate Cancer

Background:

- Enzalutamide is a well-tolerated, modern androgen receptor antagonist (ARA) with more
enhanced anti-tumor activity compared to previous ARAs. Phase III trial has demonstrated
a 4.8 month improvement in survival and a 37% risk reduction in death in metastatic
castration resistant prostate cancer (mCRPC) patients who have had previous docetaxel.

- PROSTVAC is a therapeutic cancer vaccine which is designed to induce an anti-tumor
immune response. In a randomized controlled Phase 2 trial, PROSTVAC therapy was
associated with a prolongation of survival by 8.5 months in men with metastatic
castrateresistant prostate cancer. An international Phase 3 trial is on-going.

- Preclinical data has demonstrated that hormonal therapies such as ARAs can enhance the
immune response through multiple mechanisms. Specifically, our group has shown that
enzalutamide can increase thymic production of na(SqrRoot) ve T-cells, which could be
activated by a cancer vaccine. Together, these data provide an important rationale to
combine enzalutamide with PSA-TRICOM in mCRPC.

- Data from the clinical trials with these therapies suggest that they are very well
tolerated and without overlapping toxicity.

Objective:

-Determine if PSA-TRICOM combined with enzalutamide will increase time to progression (as
defined by Prostate Cancer Clinical Trials Working Group 2 criteria, incorporated in section
5.2) in chemotherapy-naive metastatic castration resistant prostate cancer patients compared
to enzalutamide alone.

Design:

- The study will randomize chemotherapy-naive, mCRPC patients to either enzalutamide alone
or enzalutamide with PSA-TRICOM. Enzalutamide will be given at the standard dose of 160
mg daily.

- PSA-TRICOM will be administered identical to the Phase III dosing with vaccine given
week 1 (vaccinia-PSA-TRICOM, 2x10(8) units subcutaneously) and then week 3, 5 and then
monthly fowlpox-vaccine (1x10(9) units subcutaneously).

- After completing 6 months of vaccine, fowlpox-vaccine (1x10(9) units subcutaneously will
be administered every 3 months. Patients will be treated until radiographic progression
on scans using Prostate Cancer Working Group Criteria.

Eligibility:

- mCRPC patients with rising PSA or progressive disease despite castration levels of
testosterone.

- Chemotherapy-na(SqrRoot) ve with minimal or no symptoms related to prostate cancer.

- Patients with history of autoimmune disease, brain/leptomeningeal metastasis, a second
malignancy within 3 years of enrollment, or a severe co-morbid condition will be
excluded.

- Patients who have received abiraterone will be excluded

- Patients will be stratified based on previous immunotherapy used as cancer treatment.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed prostate cancer confirmed
by either the Laboratory of Pathology at the NIH Clinical Center or Walter Reed
National Military Medical Center at Bethesda prior to starting this study. If no
pathologic specimen is available, patients may enroll with a pathologist s report
showing a histological diagnosis of prostate cancer and a clinical course consistent
with the disease.

- Castrate testosterone level (<50ng/dl or 1.7nmol /L)

- Metastatic disease documented by one of the following:

- Metastatic bone disease on an imaging study, or

- Soft tissue disease documented by CT/MRI, or

- Progressive disease at study entry defined as one or more of the following criteria
occurring in the setting of castrate levels of testosterone:

i. Radiographic progression defined as any new or enlarging bone lesions or growing
lymph node disease, consistent with prostate cancer OR

ii. PSA progression defined by sequence of rising values separated by >1 week (2 separate
increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria) If patients had
been on flutamide, PSA progression is documented 4 weeks or more after withdrawal.

The requirement for a 4-6 week withdrawal period following discontinuation of flutamide,
nilutamide or bicalutamide only applies to patients who have been on these drugs for at
least the prior 6 months. For all other patients they must stop bicalutamide, nilutamide or
flutamide the day prior to enrollment.

- Asymptomatic or mildly symptomatic from prostate cancer; no use of regularly scheduled
opiate analgesics for prostate cancer-related pain

- Patients must agree to continue to continuation of androgen deprivation therapy (ADT)
with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy

- Age greater than or equal to 18 years.

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

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits; for patients with Gilbert s
syndrome, total bilirubin less than or equal to 3.0mg/dL

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine within 1.5 X normal institutional limits, OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal by Cockcroft-Gault Equation

- The effects of enzalutamide alone or in combination with PSA-TRICOM 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.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Patients who are immunocompromised as listed as follows:

- Human immunodeficiency virus positivity due to the potential for decreased tolerance
and may be at risk for severe side effects

- Chronic administration (defined as daily or every other day for continued use >14
days) of systemic corticosteroids (including steroid eye drops) or other immune
suppressive drugs, within 28 days before the first planned dose of PSA-TRICOM. Nasal,
or inhaled steroid, and topical steroid creams for small body areas are not excluded.

- Patients who have undergone allogeneic peripheral stem cell transplantation, or solid
organ transplantation requiring immunosuppression

- History of splenectomy

- History of, or active autoimmune disease (such as Autoimmune neutropenia,
thrombocytopenia, or hemolytic anemia, systemic lupus erythematosis, Sjogrens
syndrome, scleroderma, myasthenia gravis, Goodpasture's syndrome, Addisons disease,
Hashimotos thyroiditis, Crohns or Graves disease). Patients with type 1 diabetes
mellitus or vitiligo are not excluded if the condition is well controlled.

- Patients with a history of brain/leptomeningeal metastasis

- Patients who have been treated with abiraterone will be excluded

- Patients with history of seizure as an adult including febrile seizure or any
condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous
malformation, head trauma with loss of consciousness requiring hospitalization). Also,
current or prior treatment with anti-epileptic medications for the treatment of
seizures or history of loss of consciousness. Also transient ischemic attack within 12
months prior to randomization will not be permitted.

- Patients with second malignancy within 3 years of enrollment; Patients curatively
treated non-melanoma skin cancers or carcinoma in situ of the bladder, are not
excluded.

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

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

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

- Previous adverse reactions to smallpox vaccination

- Unable to avoid close contact or household contact with the following high-risk
individuals for three weeks after the Day 1 vaccination: (a) children less than or
equal to 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.

- Any condition which, in the opinion of the investigator, would prevent full
participation in this trial (including the long-term follow-up), or would interfere
with the evaluation of the trial endpoints.

- Patients with prior chemotherapy for nonmetastatic prostate cancer within a year are
excluded.

- Receipt of an investigational agent within 28 days (or 56 days for an antibody-based
therapy) before the first planned dose of study drugs. (Immune checkpoint inhibitors
that are antibody-based will only require 28 days before enrollment)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled hypertension (SBP>170/ DBP>105) or psychiatric illness/social
situations within 12 months that would limit compliance with study requirements.

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

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

- Patients who have had chemotherapy for metastatic castration-resistant prostate
cancer. (Patients who have had docetaxel for metastatic castration sensitive disease
per CHAARTED Data35 may enroll as long as they did not have progressive disease while
on docetaxel and are 6 months removed from treatment, with all treatment related
toxicities resolving to at least grade 1.)

- Patients who have received radiation therapy, radionuclide therapy or undergone
surgery within certain duration (4 weeks) of enrollment