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

 - Sipuleucel-T is a new treatment for advanced stage prostate cancer. It takes cells from a
 person with prostate cancer and treats them in the laboratory. Then it returns the cells to
 the person to help the immune system fight the cancer. Sipuleucel-T may be combined with the
 drug CT-011 to boost its ability to kill cancer cells. The chemotherapy drug cyclophosphamide
 will also be given, either before or after the cells are collected at the start of the
 treatment.

 Objectives:

 - To test the effectiveness of Sipuleucel-T, CT-011, and cyclophosphamide for prostate
 cancer.

 Eligibility:

 - Men at least 18 years of age who have advanced prostate cancer.

 Design:

 -  Participants will be screened with a medical history, physical exam, blood and urine
 tests, and imaging studies.

 -  This study has two parts, with different participants in each part. All participants
 will be monitored with frequent blood tests and imaging studies.

 -  Part I:

 -  Participants will provide cells for the Sipuleucel-T treatment three times. The first
 time will be 3 days before the chemotherapy. The second time will be 10 days after
 chemotherapy. The third time will be 24 days after chemotherapy.

 -  Participants will have one dose of cyclophosphamide the day before the first dose of
 Sipuleucel-T.

 -  Participants will have Sipuleucel-T about 3 days after each cell donation.

 -  Part II:

 -  Participants will be in three groups: Sipuleucel-T given alone, given with CT-011, or
 given with both cyclophosphamide and CT-011.

 -  Participants will provide cells for the Sipuleucel-T treatment three times, as in Part
 I.

 -  Participants will have Sipuleucel-T about 3 days after each cell donation, and will
 receive treatment with the other drugs as directed by the study doctors.
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.