Study of Everolimus Added to Combined Hormonal and Radiation Therapy for High Risk Prostate Cancer

Prostate cancer is very prevalent with an estimated > 200,000 new cases and > 25,000 deaths
attributable to prostate cancer in the United States in 2010. Radiation treatment represents
a commonly utilized method to treat prostate cancer with an excellent chance of controlling
disease with biochemical control at 5-years in excess of 75% in men with locally confined
but intermediate to high-risk disease. However, despite impressive biochemical control,
local control remains a problem.

Everolimus is being investigated as an anticancer agent based on its potential to act:

- Directly on the tumor cells by inhibiting tumor cell growth and proliferation

- Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity.

Given the prevalence of PTEN deletion in high-risk prostate cancers as well as the evidence
that tumor hypoxia leads to increased risks of failure after treatment with hormonal therapy
and radiation, we hypothesis that inhibition of mTOR signaling in both tumor and vascular
cells using everolimus concurrent with hormonal and radiation therapy will enhance the
efficacy of radiation therapy without an unacceptable risk of toxicity in men with high-risk
prostate cancer.

Everolimus has not been approved by the FDA for the treatment of prostate cancer by itself
or in combination with radiation and hormonal therapy. It is not known if this combination
is safe and effective in prostate cancer. The FDA has allowed their combined use in this
clinical trial.

Inclusion Criteria:

- Age ≥ 18 years

- Participants must be able to care for themselves

- Adequate function

- Adequate kidney function

- Histologically confirmed diagnosis of adenocarcinoma of the prostate with biopsy
within 90 days of enrollment

- High-risk prostate cancer

- No distant metastases as evaluated by a bone scan and CT of the pelvis (within 90
days of enrollment)

- Participants must have at least 4 biopsy cores containing prostate cancer with tissue
available for histologic analysis

- Signed informed consent

Exclusion Criteria:

- Participants currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy,
radiation therapy, antibody based therapy, targeted therapy, etc.)

- Prior pharmacologic androgen ablation for prostate cancer is not allowed including
LHRH agonist therapy or oral anti-androgen therapy.

o Previous use of either finasteride or dutasteride is allowed

- Participants, who have had a major surgery or significant traumatic injury within 4
weeks of start of study drug, participants who have not recovered from the side
effects of any major surgery (defined as requiring general anesthesia) or
participants that may require major surgery during the course of the study

- Any previous therapeutic radiation therapy to the pelvis.

- Known gastrointestinal dysfunction or an inability to take oral medications that
would preclude taking an oral medication.

- Prior treatment with any investigational drug within the preceding 4 weeks of
registration

- Participants receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent.

o Topical or inhaled corticosteroids are allowed.

- Participants should not receive immunization with attenuated live vaccines within one
week of registration or during study period. Close contact with those who have
received attenuated live vaccines should be avoided during treatment with everolimus.
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.

- Other malignancies within the past 3 years except for adequately treated basal or
squamous cell carcinomas of the skin.

- Participants who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or
IV

- Uncontrolled cardiac arrhythmia

- The use of anti-arrhythmic medications or implanted pacemakers or defibrillators
is allowed and would not exclude a patient from enrollment.

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Severely impaired lung function

- Uncontrolled diabetes

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis or severe hepatic impairment

- Uncontrolled diabetes mellitus despite adequate therapy. Patients with a known
history of impaired fasting glucose or diabetes mellitus (DM) may be included,
however blood glucose and antidiabetic treatment must be monitored closely throughout
the trial and adjusted as necessary;

- A detailed assessment of Hepatitis B/C medical history and risk factors must be done
at screening for all participants.

- Participants with previous documented history of Hepatitis B/C infection are
excluded from enrollment.

- Participants with high risk for hepatitis based upon medical history and risk
factors must be screened for Hepatitis B and C, and if positive are excluded
from enrollment.

- A known history of HIV seropositivity

- Participants with an active, bleeding diathesis

- Male patient whose sexual partner(s) are women of child bearing potential who are not
willing to use adequate contraception, during the study and for 8 weeks after the end
of treatment

- Participants who have received prior treatment with an mTOR inhibitor (e.g.,
sirolimus, temsirolimus, everolimus).

o Sirolimus eluting coronary artery stents are allowed

- Participants with a known hypersensitivity to everolimus or other rapamycins (e.g.,
sirolimus, temsirolimus) or to its excipients

- Participants unwilling to or unable to comply with the protocol