Sipuleucel-T With Immediate vs. Delayed Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) Blockade for Prostate Cancer

This is an open-label randomized multicenter Phase 2 clinical trial combining SipT with
ipilimumab in patients with chemotherapy-naïve metastatic castration resistant prostate
cancer (CRPC).

All patients will be treated with standard SipT (Q2wks x 3). Patients will be randomized to
one of two arms:

Arm 1 (Immediate Treatment): Ipilimumab Q3wks x 4 started 1 day following the final dose of
SipT (Day 0).

Arm 2 (Delayed Treatment): Ipilimumab Q3wks x 4 started 3 weeks following the final dose of
SipT (Day 0).

Following this ipilimumab treatment, patients will then be followed monthly for 3 months and
then quarterly until disease progression. The definition of unacceptable toxicity is grade 3
or higher treatment-related toxicities (NCI CTCAE v4) excluding immune-related adverse events
(irAEs). The study will assess for the immunogenicity and clinical activity of sequential
sipuleucel-T treatment followed by ipilimumab. Patients who experience an initial clinical
response to ipilimumab followed by subsequent disease progression will be offered reinduction
treatment with ipilimumab.

Inclusion Criteria:

1. Histologically confirmed, metastatic prostate adenocarcinoma (positive bone scan
and/or measurable disease on CT scan and/or MRI of the abdomen and pelvis).

2. Progressive disease after androgen deprivation, as defined by PSA Working Group 2
and/or RECIST criteria. Patients must have disease progression by one or both of the
following:

- For patients with measurable disease, progression is defined as at least a 20%
increase in the sum of the longest diameter (LD) of target lesions or the
appearance of one or more new lesions, as per RECIST criteria version 1.1.

- For patients with no measurable disease, a positive bone scan and elevated PSA
will be required. PSA evidence for progressive prostate cancer consists of a PSA
level of at least 2 ng/milliliter (mL), which has risen on at least 2 successive
occasions, at least 1 week apart. If the confirmatory PSA value is not greater
than the screening PSA value, then an additional test for rising PSA will be
required to document progression.

- If no prior orchiectomy has been performed, patients must remain on uteinizing
hormone-releasing hormone (LHRH) agonist or antagonist (e.g. degarelix) therapy.
Patients who are receiving an antiandrogen as part of primary androgen ablation
must demonstrate disease progression following discontinuation of the
antiandrogen, defined as two consecutive rising PSA values, obtained at least two
weeks apart, or documented osseous or soft tissue progression. At least one of
the PSA values must be obtained at least four weeks (flutamide) or six weeks
(bicalutamide or nilutamide) after discontinuation.

3. Laboratory requirements:

- Absolute neutrophil count (ANC) ≥ 1500/μL

- Bilirubin < 1.5 x upper limit of normal (ULN)

- Hemoglobin ≥ 8 g/dL

- PSA ≥ 2 ng/mL

- Platelets ≥ 100,000/μL

- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or
equal to 2.5 x ULN

- Creatinine clearance ≥ 60 mL/min by the Cockcroft Gault equation

- Testosterone less than or equal to 50 ng/dL

4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1 and life expectancy
≥ 12 weeks.

5. At least 18 years of age or older.

6. Patients receiving any other hormonal therapy, including any dose of megestrol acetate
(Megace), Proscar (finasteride), any herbal product known to decrease PSA levels (e.g.
Saw Palmetto, PC-SPES), or any systemic corticosteroid, must discontinue the agent for
at least four weeks prior to study treatment. Progressive disease as defined above
must be documented after discontinuation of any hormonal therapy (with the exception
of a LHRH agonist).

7. Prior radiation therapy must be completed ≥ 4 weeks prior to enrollment and the
patient must have recovered from all toxicity. Prior radiopharmaceuticals (strontium,
samarium) must be completed ≥ 8 weeks prior to enrollment.

8. Because of the unknown potential risk to a gamete and/or developing embryo from these
investigational therapies, patients must agree to use adequate contraception (barrier
method for males) for the duration of study participation, and for three months after
discontinuing therapy.

Exclusion Criteria:

1. Prior chemotherapy for prostate cancer, with the exception of neoadjuvant
chemotherapy, because of the potential effect of chemotherapy on the immune system.

2. Prior sipuleucel-T treatment or investigational immunotherapy.

3. Prostate cancer pain requiring regularly scheduled narcotics.

4. Current treatment with systemic steroid therapy (inhaled/topical steroids are
acceptable). Systemic corticosteroids must be discontinued for at least 4 weeks prior
to first treatment.

5. History of autoimmune disease including, but not limited to:

- Systemic lupus erythematosis (SLE), scleroderma, CREST syndrome, rheumatoid
arthritis

- Inflammatory bowel disease, celiac disease, primary biliary cirrhosis, autoimmune
hepatitis

- Dermatomyositis, polymyositis, giant cell arteritis

- Autoimmune hemolytic anemia (AIHA), cryoglobulinemia, antiphospholipid antibody
syndrome (APLS)

- Diabetes mellitus type I, myasthenia gravis, Grave's disease

- Wegener's granulomatosis or other vasculitis

- A history of Hashimoto's thyroiditis, psoriasis, or eczema, any of which has been
inactive for at least one year, or isolated Raynaud's phenomenon is acceptable

6. Known central nervous system or visceral metastases.

7. Medical or psychiatric illness that would, in the opinion of the investigator,
preclude participation in the study or the ability of patients to provide informed
consent for themselves.

8. Cardiovascular disease that meets one of the following: congestive heart failure (New
York Heart Association Class III or IV), active angina pectoris, or recent myocardial
infarction (within the last 6 months).

9. Concurrent or prior malignancy except for the following:

- Adequately treated basal or squamous cell skin cancer

- Adequately treated stage I or II cancer from which the patient is currently in
complete remission

- Any other cancer from which the patient has been disease-free for 5 years

10. Known HIV or other history of immunodeficiency disorder.

11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or medical (e.g. infectious) illness.

12. Any underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of ipilimumab hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent diarrhea.

13. A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4
inhibitor or agonist.