Docetaxel and PROSTVAC for Metastatic Castration-Sensitive Prostate Cancer

Background: Metastatic castrate-sensitive prostate cancer is cancer that has spread beyond the prostate area. It can be controlled by lowering the amount of testosterone in the body. This is called androgen deprivation therapy (ADT). The vaccine PROSTVAC might help the immune system kill cancer cells. Researchers want to add PROSTVAC and docetaxel chemotherapy to ADT. They think this may work better against prostate cancer than ADT alone. Objective: To test if adding PROSTVAC and docetaxel to ADT works better against prostate cancer than ADT alone. Eligibility: Men ages 18 years and over with metastatic castrate-sensitive prostate cancer Design: Participants will be screened with: Physical exam Medical history Blood tests Possible computed tomography (CT), magnetic resonance imaging (MRI), or bone scan: Participants lie in a machine. The machine takes pictures of the body. Electrocardiogram: Soft electrodes are stuck to the skin to record heart signals. Participants will have 2 optional tumor biopsies during the study. Participants will join 1 of 2 groups. Both groups will get: ADT Docetaxel by vein Steroids by mouth or vein before each docetaxel infusion PROSTVAC injection Both groups first have ADT. One to 4 months after, they have: Group A: Docetaxel every 3 weeks for 6 cycles PROSTVAC 3 weeks after the last infusion Booster injections 2 weeks later and then every 3 weeks, for 6 boosters total Group B: PROSTVAC Booster 2 weeks later Docetaxel hours later Docetaxel and the booster every 3 weeks for 6 cycles Participants will have a visit 4-5 weeks after the last treatment. They will then have visits every 12 weeks. Participants will be followed for up to 15 years. This includes physical exams every year for 5 years.

Background: A phase III trial demonstrated that combining docetaxel and androgen deprivation therapy (ADT) significantly improved survival (57.6 vs 44.0 months (hazard ration (HR)=0.56, (0.44-0.70), p <0.0001) for men with metastatic castration sensitive prostate cancer (mCSPC). PROSTVAC (developed by the National Cancer Institute [NCI] and licensed to Bavarian Nordic Immunotherapeutics, Mountain View, California (CA) is a therapeutic cancer vaccine for prostate cancer. Preclinical and clinical studies support the potential synergy in the combination of docetaxel and PROSTVAC. The potential to combine docetaxel with vaccine in mCSPC could improve upon the survival advantage that has been previously seen. Objectives: Primary -To determine if PROSTVAC combined with docetaxel is able to induce greater antigen spreading (i.e. a broader immune response) with greater associated response score compared to docetaxel alone after 19 weeks. Key Eligibility Criteria: Must have castrate sensitive prostate cancer (rising PSA and testosterone over 100) or is within 134 days of starting ADT (Arm A or B) or within 28 days of start ADT (Arm C) Histopathological confirmation of prostate cancer Patients must have metastatic disease Patients must have a performance status of 0 to 2 according to the Eastern Cooperative Oncology Group (ECOG) criteria Patients must have adequate bone marrow, hepatic, and renal function Design This is a randomized trial of ADT followed by simultaneous docetaxel 75 mg/m(2) every (q)3 weeks x 6 cycles + PROSTVAC q3 weeks x 6 cycles versus ADT followed by sequential docetaxel 75 mg/m(2) q3 weeks x 6 cycles followed by PROSTVAC q3 weeks x 6 cycles in men with newly diagnosed mCSPC. Patients who have not started ADT or who have been on ADT 28 days or fewer will be assigned to treatment with PROSTVAC for 4 - 6 injections followed by docetaxel 75 mg/m^2 q3 weeks x 6 cycles.

Standard androgen deprivation therapy (ADT) followed by prostvac, then docetaxel. No ADT for less than 28 days, prostvac prior to docetaxel.

It is a recombinant vaccinia virus vector vaccine containing the genes for human prostate-specific antigen (PSA) and three co-stimulatory molecules (cluster of differentiation 80 (B7.1), intercellular adhesion molecule 1 (ICAM-1), and lymphocyte function-associated antigen 3 (LFA-3). It will be given subcutaneously, 2x10(8) infectious units.

It is a recombinant fowlpox virus vector vaccine containing the genes for human prostate-specific antigen (PSA) and three co-stimulatory molecules (cluster of differentiation 80 (B7.1), intercellular adhesion molecule 1 (ICAM-1), and lymphocyte function-associated antigen 3 (LFA-3). It will be given subcutaneously, 1x10(9) infectious units.

Antigen Spreading (i.e., a Broader Immune Response) With Greater Associated Response Score Compared to Docetaxel Alone After 19 Weeks

Antigen spreading as measured by antigen spread score. The antigen spreading score denotes the presence of a T-cell (cluster of differentiation(CD8)+ and/or cluster of differentiation 4(CD4+) immune response against 2 tumor associated antigens that were not targeted by PROSTVAC:Mucin 1(MUC-1) & carcinoembryonic antigen(CEA). Antigen-specific T-cell responses were determined using intracellular cytokine staining of 4 established markers (Lysosome-associated membrane proteins h-LAMP1, interferon gamma, interleukin-2& tumor necrosis factor) in both CD4+& CD8+T-cells, giving a total of 8 measures of activation per antigen. Numbers of activation markers per antigen were totaled & multiplied by 1.5 to give higher weighting to T-cell responses to antigens that were not targeted by PROSTVAC;& the scores for both MUC-1 & CEA were totaled per participant, with a possible range of 0-24 (0 is a negative result whereas 1.5-24 are positive results). The higher level of response, the better outcome.

Response score denotes the presence of a T-cell (cluster of differentiation 8(CD8+) and/or cluster of differentiation 4(CD4+) response against 3 tumor associated antigens: prostate-specific antigen(PSA), mucin 1(MUC-1) and carcinoembryonic antigen(CEA). Antigen-specific T-cell immune responses were determined using intracellular cytokine staining of 4 established markers (Lysosome-associated membrane proteins h-LAMP1, interferon gamma, interleukin-2& tumor necrosis factor in both CD4+ & CD8+T-cells, a total of 8 measures of activation per antigen. The number of activation markers for PSA were totaled for a maximum score of 8. Numbers of activation markers for MUC-1 & CEA were totaled & multiplied by 1.5 to give higher weighting to T-cell responses to antigens that were not targeted by PROSTVAC. The scores for PSA, MUC-1 & CEA were totaled per participant, with a possible range of 0-32 (0 is a negative result whereas 1-32 are positive results). Higher level of response, better outcome.

PSA-specific immune responses T-cell responses were assessed using nonparametric methods. The value denotes the number of participants with T-cell immune responses towards PSA. The higher level of response, the better outcome.

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Date treatment consent signed to date off study, approximately 70 months and 4 days for Arm A, 38 months and 28 days for Arm B, and 43 months and 29 days for Arm C.

INCLUSION CRITERIA: Documented histopathological confirmation of prostate cancer-from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Patients must have metastatic disease, defined as at least one lesion on bone scan or at least one lesion that are measurable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Patients who have metastatic disease by these criteria prior to ADT, but then have changes after androgen deprivation therapy (ADT) that diminish the size of these lesions or changes on bone scan are still eligible.) Patients must have a performance status of 0 to 2 according to the Eastern Cooperative Oncology Group (ECOG) criteria Patients must have adequate bone marrow, hepatic, and renal function with: Absolute neutrophil count (ANC) greater than or equal to 1500/microL, without cerebrospinal fluid (CSF) support Platelets greater than or equal to 100,000/microL Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) less than or equal to 2.5 times upper limit of normal (ULN); Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5 times upper limit of normal (ULN); Total serum bilirubin less than or equal to 1.5 times upper limit of normal (ULN), OR in patients with Gilbert's syndrome, a total bilirubin less than or equal to 3.0) Serum albumin greater than or equal to 2.8 g/dL Lipase < 2.0 times the upper limit of normal and no radiologic or clinical evidence of pancreatitis Creatinine less than or equal to 1.5 times institutional upper limits of normal OR Creatinine clearance of greater than or equal to 50 ml/min/1.73 m(2) for patients with creatinine levels above institutional normal by 24-hour urine. Willing to travel to the National Institutes of Health (NIH) for follow-up visits 18 years of age or older. Able to understand and sign informed consent. May have had up to 24 months of ADT (testosterone suppression therapy in the nonmetastatic setting) and are at least 12 months removed from treatment Men treated or enrolled on this protocol must also agree to use adequate contraception, prior to the study, for the duration of study participation, and 4 months after completion. Sexually active subjects and their female partners must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must also agree to use both a barrier method and a second method of birth control during the course on the study and for 4 months after the last dose of study drug(s). Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Must have started ADT for metastatic disease within 134 days (for Arm A and B) or within 28 days (for Arm C). EXCLUSION CRITERIA: Immunocompromised status due to: Human immunodeficiency virus (HIV) positivity. Active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematosus, Sjogren's syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome or active Grave's disease. Patients with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including central nervous system (CNS), heart, lungs, kidneys, skin, and gastrointestinal (GI) tract will be allowed. Other immunodeficiency diseases Chronic administration (defined as daily or every other day for continued use > 14 days) of corticosteroids deemed systemic by investigator within 28 days before the first planned dose of PROSTVAC. Use of inhaled steroids, nasal sprays, and topical creams for small body areas is allowed. Evidence of rising prostate-specific antigen (PSA) on ADT Serious intercurrent medical illness that, in the judgment of the investigator, would interfere with patient's ability to carry out the treatment program. Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (e.g. phytoestrogens and saw palmetto) History of allergic reactions attributed to compounds of similar chemical or biologic composition to poxviral vaccines (e.g., vaccinia vaccine) Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or tobramycin). History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis Previous serious adverse reactions to smallpox vaccination Unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczemoid skin disorders, or (d) immunocompromised individuals, such as those with human immunodeficiency virus (HIV). Receipt of an investigational agent within 28 days (or 60 days for an antibody-based therapy) before the first planned dose of study drugs. Patients who test positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) Uncontrolled hypertension (systolic blood pressure (SBP)>170/ diastolic blood pressure (DBP)>105) Patients who have had prior chemotherapy for prostate cancer. The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment (with the exception of nonmelanoma skin cancers or carcinoma in situ of the bladder). The subject has active brain metastases or epidural disease. Patients with greater than or equal to grade 2 peripheral neuropathy at baseline. Patients with history of splenectomy

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. All collected IPD will be shared with collaborators under the terms of collaborative agreements.

Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).