Sipuleucel-T, CT-011, and Cyclophosphamide for Advanced Prostate Cancer

Background:

- Prostate cancer is the most common cancer and the second leading cause of cancer deaths
among males in most Western countries.

- Sipuleucel-T, a recently FDA approved treatment for prostate cancer, is designed to
induce an immune response targeted against PAP, an antigen expressed in most prostate
cancers. .

- Blockade of PD-1/PD-L1 has been shown to enhance the therapeutic efficacy of peptide
cancer vaccines in pre-clinical animal models. CT-011 is a humanized IgG1 kappa
recombinant monoclonal antibody against PD-1 receptor that blocks the interaction of
PD-L1 with PD-1.

- Preclinical studies demonstrated that CT-011 when administered with low dose
cyclophosphamide led to synergistic antitumor effects when combined with HPV16 E749-57
peptide vaccine.

- Given the role CT-011 plays in down-regulating peripheral tolerance and the synergistic
relationship it has with cyclophosphamide in doing so, in this study we propose to
treat patients with advanced, castrate-resistant disease with CT-011 and low-dose
cyclophosphamide as adjuvants in combination with Provenge(Trademark) activated cell
vaccine.

Objectives:

- To assess the feasibility of administration of Sipuleucel-T (Provenge(Trademark))
autologous active cellular immunotherapy in combination with low dose cyclophosphamide
in men with advanced castrate-resistant (hormone refractory) prostate cancer.

- To determine the immune efficacy of Sipuleucel-T (Provenge(Trademark)) autologous
active cellular immunotherapy alone vs. Sipuleucel-T (Provenge(Trademark)) in
combination with CT- 011 vs. Sipuleucel-T (Provenge(Trademark)) in combination with
low-dose cyclophosphamide and CT-011 on the change in PA2024-specific IFN-? ELISPOT
responses in men with advanced, castrate-resistant prostate cancer.

- Secondary objectives will determine the tolerability and toxicities of the combination
of low-dose cyclophosphamide/CT-011/ Sipuleucel-T (Provenge(Trademark)) and determine
in a preliminary fashion whether this regimen correlates with increased
progression-free survival (PFS) and overall survival (OS) in patients and with growth
rate in an exploratory fashion.

Eligibility:

- Males greater than or equal to 18 years old with chemotherapy na ve metastatic
progressive castrate-resistant prostate cancer defined as progressive disease (two
consecutively rising PSA values at a minimum of 1-week intervals (2.0 ng/mL is the
minimum starting value for PSA), appearance of one or more new lesions on bone scans,
progressive disease by Recist 1.1).

- Must meet minimum organ safety requirements and length of time since prior therapy.

- May not have active infections, autoimmune disease or require immunosuppressive
therapies.

Design:

Part 1: Initially the feasibility generating Sipuleucel-T after administration of low dose
cyclophosphamide , and will be evaluated using a standard 3 + 3 design for doses of
cyclophosphamide 250 mg/m2 or 125 mg/m2. Initially 3 patients will receive cyclophosphamide
on day -1 of the first cycle (one day prior to the first infusion of Sipuleucel-T). All
patients will receive Sipuleucel-T cell infusion on Day 0. The Sipuleucel-T cell infusion
will be repeated every two weeks for a total of three cycles. If Sipuleucel-T active
cellular immunotherapy from an apheresis obtained after infusion of cyclophosphamide, which
meets the FDA approved Certificate of Analysis (COA) release criteria from Dendreon, cannot
be generated, a second apheresis will be performed. Failure of two attempts to generate
Sipuleucel-T product after two aphereses at either the 2nd or 3rd scheduled Sipuleucel-T
infusion will be considered failure of one patient to meet release criteria .

- INCLUSION CRITERIA:

Patients must have histopathological documentation of prostate cancer prior to starting
this study.

Patients must have metastatic progressive castrate-resistant prostate cancer defined as
progressive disease (see below) despite surgical castration or ongoing use of
gonadotropin-releasing hormone agonists with confirmed castrate levels of testosterone.
Criteria of progression for trial eligibility are defined from the Prostate Cancer
Clinical Trials Working Group-253. Clinically progressive prostate cancer must be
evidenced and documented by any of the following parameters:

1. Two consecutively rising PSA values at a minimum of 1-week intervals (2.0 ng/mL is
the minimum starting value for PSA)

2. Appearance of one or more new lesions on bone scans

3. Progressive measurable disease by RECIST 1.1

Patients on flutamide for at least 6 months must have disease progression at least 4
weeks after withdrawal. Patients on bicalutamide or nilutamide for at least 6 months
must have progression at least 6 weeks after withdrawal.2.1.1.4 Performance Status:
ECOG 0-1 or Karnofsky 80-100% (asymptomatic or minimally symptomatic from metastatic
disease).

No previous chemotherapy use.

No therapeutic immunosuppression or immunomodulation altering bone marrow function
within 6 weeks prior to study entry e.g. G-CSF, GM-CSF, EPO, prednisone etc.

Must have adequate:

- Bone marrow function: Absolute neutrophil count (ANC) greater than or equal to
1,500/mcl. Platelets greater than or equal to 100,000/mcl.

- Renal function: Creatinine less than or equal to 1.5 times institutional upper
limit normal (ULN)

- Hepatic function: Bilirubin less than or equal to 1.5 x ULN (CTCAE v4.0 grade 1)
except patients with Gilbert's disease (up to 5.0 mg/dL). SGOT and alkaline
phosphatase less than or equal to 2.5 x ULN.

- Normal Cardiac function: ECG with no evidence of arrhythmia, conduction
abnormality or ischemia. No active coronary artery disease; no New York Heart
Association class II, III or IV disease; no arrhythmia requiring treatment.

Must willing and able to sign an informed consent document that explains the
neoplastic nature of the disease, the procedures to be followed, the experimental
nature of the treatment, alternative treatment and potential risks and toxicities.

EXCLUSION CRITERIA:

Concurrent treatment with any other cancer therapies including radiation (except
palliative radiation therapy for bone metastases), chemotherapy or other
investigational agent(s). Androgen suppression therapy will be allowed.

History of a second active malignancy in the last 2 years other than non-melanoma
skin cancers.

Patients who have active or history of autoimmune disease/symptom/conditions
including: type I diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE),
ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), ankylosing spondylitis.
Type II diabetes mellitus, vitiligo or stable hypothyroidism are not considered
exclusion criteria.

Patients being chronically treated with immunosuppressive drugs such as cyclosporin,
adrenocorticotropic hormone (ACTH).

Concurrent use of systemic glucocorticoids within 4 weeks prior to trial entry

Patients who have acquired, hereditary, or congenital immunodeficiencies including
cellular immunodeficiencies, hypogammaglobulinemia and dysgammaglobulinemia.

CNS, lung, or liver metastasis, because of the poor prognosis, and potential
inability to meet study endpoints.

Serious active infection at the time of pre-study screening.

Positive HIV or Hepatitis C antibodies or Hepatitis B anti-core antibodies, because
immunotherapies rely on intact immune systems, and toxicities may be exacerbated by
the presence of infection.