Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer
Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer
This randomized pilot trial studies vaccine therapy and pembrolizumab in treating patients
 with prostate cancer that does not respond to treatment with hormones (hormone-resistant) and
 has spread to other places in the body (metastatic). Vaccines made from deoxyribonucleic acid
 (DNA), such as pTVG-HP plasmid DNA vaccine, may help the body build an effective immune
 response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may find tumor
 cells and help kill them. Giving pTVG-HP plasmid DNA vaccine and pembrolizumab may kill more
 tumor cells.
PRIMARY OBJECTIVES:

 I. To evaluate the safety of pembrolizumab in combination with pTVG-HP (pTVG-HP plasmid DNA
 vaccine) in patients with castration-resistant, metastatic prostate cancer.

 II. To determine the 6-month progression-free survival and median time to radiographic
 progression in patients with castration-resistant metastatic prostate cancer treated with
 pembrolizumab in combination with pTVG-HP.

 III. To evaluate the anti-tumor response rates (objective response rate and prostate specific
 antigen [PSA] response rate, using Prostate Cancer Clinical Trials Working Group 2 [PCWG2]
 criteria) in patients with castration-resistant metastatic prostate cancer treated with
 pembrolizumab in combination with pTVG-HP.

 SECONDARY OBJECTIVES:

 I. To determine whether either treatment sequence, or prostatic acid phosphatase
 (PAP)-specific immune response, is associated with prolonged (6-month) radiographic
 progression-free survival.

 II. To evaluate effects of schedule (concurrent versus delayed administration of
 pembrolizumab) on the magnitude of PAP-specific T-cell responses, programmed death receptor-1
 (PD-1) expression on circulating T cells, and ligands for PD-1 (PD-L1) expression on
 circulating epithelial cells (CEC) and on tumor biopsies.

 III. To determine the median time to radiographic progression using a concurrent
 administration schedule

 TERTIARY OBJECTIVES:

 I. To evaluate effects of treatment on number of circulating tumor cells. II. To evaluate
 PAP-specific antibody responses following treatment with pembrolizumab and pTVG-HP DNA
 vaccine (pTVG-HP plasmid DNA vaccine).

 III. To determine whether either treatment sequence elicits immunologic antigen spread to
 other prostate-associated antigens.

 IV. To determine whether pre-existing or vaccine-induced PD-L1 expression on CEC or tumor
 biopsies is predictive of objective clinical response.

 V. To determine whether treatment elicits expression of other regulatory molecules on
 tumor-specific T cells (e.g. hepatitis A virus cellular receptor 2 [TIM3], B and T lymphocyte
 associated [BTLA], and lymphocyte-activation gene 3 [LAG3]) or tumor cells (e.g. tumor
 necrosis factor receptor superfamily, member 14 [HVEM], phosphatidyl serine, ligands for
 programmed death receptor-2 [PD-2] [PD-L2]).

 VI. To determine whether PD-1-regulated antigen-specific T cells identified by trans vivo
 delayed-type hypersensitivity (DTH) testing can identify patients who develop objective
 clinical responses with PD-1 blockade therapy in combination with pTVG-HP.

 VII. To determine whether changes in lymph nodes and soft tissue tumor lesions are observed
 by fluorothymidine F-18 (FLT) positron emission tomography (PET)/computed tomography (CT)
 after treatment with vaccine with or without pembrolizumab.

 VIII. To determine if PD-1 inhibitor therapy in combination with pTVG-HP will change number
 and activity (SUV) in osteoblastic metastases as measured by NaF PET/CT.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 ARM I: Patients receive pTVG-HP plasmid DNA vaccine intradermally (ID) every other week on
 days 1, 15, 29, 43, 57, and 71 and pembrolizumab intravenously (IV) over 30 minutes every 3
 weeks on days 1, 22, 43, and 64.

 ARM II: Patients receive pTVG-HP plasmid DNA vaccine ID as in Arm I and pembrolizumab IV over
 30 minutes every 3 weeks on days 85, 106, 127, and 148.

 After completion of study treatment, patients are followed up 3, 6, 9, and 12 months and then
 annually for 2 years.

 ARM III: Extended Treatment. Patients received pTVG-HP + Pembrolizumab Extended Treatment

 ARM IV: Extended Treatment. Patients receive pTVG-HP every two weeks, and Pembrolizumab every
 4 weeks
Inclusion Criteria:

 -  Histologically confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate)

 -  Metastatic disease as evidenced by the presence of soft tissue and/or bone metastases
 on imaging studies (CT of abdomen/pelvis, bone scintigraphy)

 -  Castrate-resistant disease, defined as follows:

 -  All patients must have received (and be receiving) standard of care androgen
 deprivation treatment (surgical castration versus gonadotropin-releasing hormone
 [GnRH] analogue or antagonist treatment); subjects receiving GnRH analogue or
 antagonist must continue this treatment throughout the time on this study

 -  Patients may or may not have been treated previously with a nonsteroidal
 antiandrogen; for patients previously treated with an antiandrogen, they must be
 off use of anti-androgen for at least 4 weeks (for flutamide) or 6 weeks (for
 bicalutamide or nilutamide) prior to registration; moreover, subjects who
 demonstrate an anti-androgen withdrawal response, defined as a >= 25% decline in
 PSA within 4-6 week of stopping a nonsteroidal antiandrogen, are not eligible
 until the PSA rises above the nadir observed after antiandrogen withdrawal

 -  Patients must have a castrate serum level of testosterone (< 50 ng/dL) within 6
 weeks of day 1

 -  Progressive disease while receiving androgen deprivation therapy defined by any one of
 the following as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) bone
 scan criteria or Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 during or
 after completing last therapy:

 -  PSA: at least two consecutive rises in serum PSA, obtained at a minimum of 1-week
 intervals, with the final value >= 2.0 ng/mL

 -  Measurable disease: >= 50% increase in the sum of the cross products of all
 measurable lesions or the development of new measurable lesions; the short axis
 of a target lymph node must be at least 15 mm by spiral CT to be considered a
 target lesion

 -  Non-measurable (bone) disease: the appearance of two or more new areas of uptake
 on bone scan (or fluorine F 18 sodium fluoride [NaF] PET/CT) consistent with
 metastatic disease compared to previous imaging during castration therapy; the
 increased uptake of pre-existing lesions on bone scan will not be taken to
 constitute progression, and ambiguous results must be confirmed by other imaging
 modalities (e.g. X-ray, CT or magnetic resonance imaging [MRI])

 -  Prior treatment with abiraterone or enzalutamide is permitted, but patients must have
 been off prior corticosteroid treatment for at least 3 months

 -  Life expectancy of at least 6 months

 -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
 0, 1, or 2

 -  White blood cells (WBC) >= 2000/mm^3

 -  Absolute neutrophil count (ANC) >= 1000/mm^3

 -  Hemoglobin (HgB) >= 9.0 gm/dL

 -  Platelets >= 100,000/mm^3

 -  Creatinine =< 2.0 mg/dL

 -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 x
 institutional upper limit of normal

 -  No known history of human immunodeficiency virus (HIV) 1 and 2, human T-lymphotropic
 virus (HTLV)-1, or active hepatitis B or hepatitis C

 -  Patients must be at least 4 weeks from any prior treatments and have recovered (to <
 grade 2) from acute toxicity attributed to this prior treatment, unless considered
 chronic

 -  Patients must be willing and able (in the opinion of the treating physician) to
 undergo two research biopsies for the investigational component of this trial

 -  Patients must be willing to undergo two leukapheresis procedures for the
 investigational component of this trial

 -  Patients must be willing to undergo FLT PET/CT or NaF PET/CT scans for the
 investigational component of this trial and have no known allergies to FLT or NaF

 -  For those patients who are sexually active, they must be willing to use barrier
 contraceptive methods during the period of treatment on this trial (and for four weeks
 after the last DNA immunization treatment for patients in Arm 1)

 -  Patients must be informed of the experimental nature of the study and its potential
 risks, and must sign an Institutional Review Board (IRB)-approved written informed
 consent form indicating such an understanding

 Exclusion Criteria:

 -  Small cell or other variant (non-adenocarcinoma) prostate cancer histology, unless
 there is evidence that the tumor expresses PAP

 -  Patients may not be receiving other investigational agents or be receiving concurrent
 anticancer therapy other than standard androgen deprivation therapy

 -  Concurrent bisphosphonate therapy is not excluded, however patients should not start
 bisphosphonate therapy while on this study; those patients already receiving
 bisphosphonate therapy should continue at the same dosing and schedule as prior to
 study entry

 -  Rapidly progressive symptomatic metastatic disease, as defined by the need for
 increased opioid analgesics within one month of registration for the treatment of pain
 attributed to a prostate cancer metastatic lesion; patients receiving opioids must
 receive approval from the principal investigator (PI) for eligibility

 -  Treatment with any of the following medications within 28 days of registration, or
 while on study, is prohibited:

 -  Systemic corticosteroids (at doses over the equivalent of 5 mg prednisone daily)
 - not permitted within 3 months of registration; inhaled, intranasal or topical
 corticosteroids are acceptable

 -  Prostate cancer (PC)-SPES

 -  Saw palmetto

 -  Megestrol

 -  Ketoconazole

 -  5-alpha-reductase inhibitors - patients already taking 5-alpha-reductase
 inhibitors prior to 28 days prior to registration may stay on these agents
 throughout the course of therapy, but these should not be started while patients
 are on study

 -  Diethyl stilbestrol

 -  Abiraterone

 -  Enzalutamide

 -  Radium 223 (Xofigo)

 -  Any other hormonal agent or supplement being used with the intent of cancer
 treatment

 -  External beam radiation therapy within 4 weeks of registration is prohibited, or
 anticipated need for radiation therapy (e.g. imminent pathological fracture or spinal
 cord compression) within 3 months of registration

 -  Major surgery within 4 weeks of registration is prohibited

 -  Prior cytotoxic chemotherapy (for example, but not limited to, docetaxel,
 mitoxantrone, cabazitaxel) within 6 months of registration is prohibited

 -  Patients with a history of life-threatening autoimmune disease

 -  Patients with a history of allergic reactions to filgrastim (GM-CSF) or the tetanus
 vaccine

 -  Patients who have undergone splenectomy

 -  Patients must not have other active malignancies other than non-melanoma skin cancers
 or superficial bladder cancer; subjects with a history of other cancers who have been
 adequately treated and have been recurrence-free for >= 3 years are eligible

 -  Patients with known brain metastases

 -  Any antibiotic therapy or evidence of infection within 1 week of registration

 -  Any other medical intervention or condition, which, in the opinion of the PI or
 treating physician, could compromise patient safety or adherence with the study
 requirements (including biopsies or leukapheresis procedures) over the primary 3-6
 month treatment period

 -  Patients cannot have concurrent enrollment on other phase I, II, or III
 investigational treatment studies

 NOTE: There is no exclusion for prior immune-based therapy. This includes patients
 previously treated on Arms 1 or 2 who are otherwise eligible for treatment on Arm 3 or 4.