ARN 509 Plus Everolimus in Men With Progressive Metastatic Castration-Resistant Prostate Cancer After Treatment With Abiraterone Acetate

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate without neuroendocrine
differentiation or small cell features with progressive metastatic disease based on
any of the following:

- Rise in PSA: minimum of 3 rising levels, with an interval of at least 1 week
between each determination. The last determination must have a value ≥ 2 ng/mL,
obtained within 4 weeks of starting study drug, or

- Measurable disease: new or progressive soft tissue disease on CT or MRI scans, or

- Radionuclide bone scan: at least 2 new bone lesions, as defined by the PCWG2
criteria1

- Castration-resistant prostate cancer: patients must have surgical or ongoing chemical
(androgen deprivation therapy) castration, with baseline testosterone level ≤ 50 ng/dL
determined within 4 weeks of starting study drug.

- Dose-Escalation: Prior treatment with abiraterone acetate. At least 4 weeks must have
elapsed from the last dose of abiraterone acetate.

- Expansion Cohort only (if conducted in the study): Men with mCRPC and disease
progression as defined by PCWG2 within 3 months (primary resistance); or after at
least 6 months of treatment (acquired resistance) of starting treatment with
abiraterone acetate. At least 4 weeks must have elapsed from the last dose of
abiraterone .acetate

- Physiologic doses of corticosteroids are allowed (i.e. no more than 10 mg prednisone
daily).

- Patients currently receiving bone loss prevention treatment (e.g. bisphosphonates,
denosumab, etc.) must be on a stable dose for at least 4 weeks prior to starting study
treatment.

- Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide,
nilutamide) as part of their first-line hormonal therapy must have shown progression
of disease off the anti-androgen prior to enrollment.

- At least 4 weeks must have elapsed from the use of androgen receptor antagonists
(e.g., bicalutamide, flutamide, nilutamide); 5-α reductase inhibitors (e.g.,
dutasteride, finasteride, aminoglutethimide); estrogens; ketoconazole and other
anti-cancer pharmacologic therapy prior to enrollment.

- At least 6 weeks must have elapsed from the use of bicalutamide if used as part of an
initial combined androgen blockage therapy for more than 6 months or if used as second
line hormonal therapy and associated with a PSA response of at least 3 months
duration.

- At least 12 weeks must have elapsed from the use of Strontium-89, Radium-223 or any
investigational or approved immunotherapy (e.g., Provenge) prior to starting study
drug.

- At least 4 weeks must have elapsed from the use of any other investigational agent
prior to starting study drug.

- At least 4 weeks must have elapsed from major surgery prior to starting study drug.

- Patients with treated, non-progressive epidural disease are eligible.

- At least 18 years of age, with a life expectancy of at least 3 months.

- ECOG performance status 0 or 1 (2 is allowed only if due to bone pain).

- Toxicities related to prior therapy must either have returned to ≤ Grade 1, baseline,
or deemed irreversible.

- Physical and laboratory test findings:

- Adequate hepatic function with serum bilirubin ≤ 1.5 times the upper
institutional limits of normal (ULN), ALT and AST ≤ 2.5 x ULN. Patients with a
history of Gilbert's syndrome may be enrolled if the total bilirubin is < 3 mg/dL
with a predominance of indirect bilirubin

- Adequate renal function with serum creatinine ≤ 1.5 x ULN

- Adequate hematologic function with absolute neutrophil counts ≥ 1,500 cells/mm3,
platelets ≥ 100,000 cells/mm3 and hemoglobin value ≥ 9 g/dL (Note: patients whose
anemia has been corrected to a hemoglobin value ≥ 9 g/dL with blood transfusions
are allowed)

- Electrolytes (including potassium, sodium, and serum calcium corrected for
albumin or ionized calcium) must be within normal limits

- Adequate blood clotting time with an INR <2

- Signed and dated informed consent document indicating that the patient (or legally
acceptable representative) has been informed of all pertinent aspects of the trial
prior to enrollment.

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

Exclusion Criteria:

- Prior treatment with apalutamide, or PI3K/mTOR pathway inhibitors.

- History of, or current metastases in the brain, meninges, or untreated spinal cord
compression.

- Patients previously treated with chemotherapy for mCRPC. At least 12 months must have
elapsed from chemotherapy given in the adjuvant or neoadjuvant setting.

- History of any other malignancy within the previous 5 years except for the following:
adequately treated basal cell or squamous cell skin cancer, superficial bladder
cancer, stage I or II cancer currently in complete remission, or any other cancer that
has been in complete remission for at least 5 years.

- History of seizure or condition that may predispose to seizure (e.g., prior stroke
within 1 year of starting study drug, brain arteriovenous malformation)

- Concurrent therapy with medications known to have seizure potential

- Known intolerance or hypersensitivity to Vitamin E, everolimus or to rapamycin
derivatives.

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

- Known human immunodeficiency virus (HIV) infection.

- Patients who have received live attenuated vaccines within 1 week of start of
Everolimus and during the study. Patient should also avoid close contact with others
who have received live attenuated vaccines. Examples of live attenuated vaccines
include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,
varicella and TY21a typhoid vaccines.

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study.

- Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing.

- Male patients whose sexual partner(s) are women of child-bearing potential (WOCBP) who
are not willing to use adequate contraception, during the study and for 8 weeks after
the end of treatment. Highly effective contraception methods include combination of
any two of the following (a+b or a+c or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception or;

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS);

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;

4. Total abstinence or;

5. Male/female sterilization.

- Patients with a known impairment of gastrointestinal (GI) function or GI disease that
may significantly alter the absorption of oral Everolimus.

- Patients with uncontrolled diabetes mellitus as defined by HbA1c >8% 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.

- Patients who have any severe and/or uncontrolled medical conditions such as:

i. unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction ≤6 months prior to start of Everolimus, serious uncontrolled cardiac
arrhythmia, or any other clinically significant cardiac disease ii. Symptomatic
congestive heart failure of New York heart Association Class III or IV iii. active
(acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis,
decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or
positive HbsAg, quantifiable HCV-RNA), iv. known severely impaired lung function
(spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on
room air), v. active, bleeding diathesis;