Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Immune System Diseases

Prostatic Neoplasms

Hypersensitivity

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Anti-Infective Agents

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Vaccines

Metronidazole

Hormones

Nivolumab

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

* Within 60 days after the last chemo, patients will start a priming dose of PROSTVAC-V, and subsequent doses of PROSTVAC- F (weeks 0, 2, 5, 8, 11, 14, and 17). During "Treatment A" phase, subjects should receive nivolumab intravenously on Day 1 of each cycle every 3 weeks for 6 doses. Ipilimumab on Day 1 of each cycle every 3 weeks for 2 doses.
* Patients will then receive a neoantigen DNA vaccine with continuous nivolumab treatment. The vaccine will be administered starting approximately week 21 by intramuscular injection for a total of 6 treatments every 28 days +/-7 days. Each DNA vaccination will be 4 mg vaccine administered intramuscularly using a TriGrid electroporation device. Patients will receive nivolumab at 480 mg every 28 days concurrently with neoantigen DNA vaccine. This is Treatment B. In the event the DNA vaccine production is delayed, patients will receive single agent nivolumab every 4 weeks beginning week 21 until the vaccine is ready

-Replication-competent vaccinia virus which has been engineered to encode the sequences for a modified human prostate-specific antigen (PSA) and a triad of co-stimulatory molecules (TRICOM)

PROSTVAC-V

-Fowlpox virus which does not replicate in human cells and has been engineered to encode the same sequences present in PROSTVAC-V.

PROSTVAC-F

-Nivolumab is a human monoclonal antibody (mAb)

-Ipilimumab is a mAb blocking the inhibitory signal mediated by cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4), a protein receptor that downregulates the immune system.

Each DNA vaccination will be 1 mL vaccine administered intramuscularly. At each vaccination time point, patients will receive two injections at separate sites.

Neoantigen DNA vaccine

TriGrid Delivery System

-Pre-treatment, post-treatment A (optional), and end of treatment

Tumor biopsy

-At the time of pre-treatment biopsy, mid-treatment of chemo-ADT, at time of enrollment (prior to POSTVAC administration), mid-treatment A, mid-treatment B (multiple)

Peripheral blood

-Post chemo/pre-treatment A, post-treatment A, pre-treatment B, post-treatment B

Fecal samples

* Post-treatment A/pre-treatment B
* Mid-Treatment B, after Cycle 9 Day 1 and prior to Cycle 10 Day 1
* End of treatment

Leukapheresis

Russell Pachynski, M.D.

This study study aims to elucidate the immune responses to a shared antigen vaccine (PROSTVAC) and tumor specific antigens generated DNA vaccine in combination with checkpoint blockade using nivolumab (anti-PD-1), and ipilimumab (anti-CTLA-4). Additionally, the investigators will study the impact of the combination immunotherapy on peripheral T cell activation, as well as immune response in the tumor microenvironment. Finally, the investigators will evaluate the safety and tolerability to this novel personalized immunotherapy in combination with checkpoint blockade.

Neoantigen DNA Vaccine in Combination With Nivolumab/Ipilimumab and PROSTVAC in Metastatic Hormone-Sensitive Prostate Cancer

A Pilot Trial of Neoantigen DNA Vaccine in Combination With Nivolumab/Ipilimumab and PROSTVAC in Metastatic Hormone-Sensitive Prostate Cancer

-Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

-MHC tetramers made against the identified neoantigens will be used to evaluate PBMC for neoantigen-reactive T cells

-Laser capture microdissection will be performed to perform genomic studies on specific areas of tissue

-Multiparametric flow cytometry or CyTOF will be performed in parallel to evaluate for any shifts (in quality and quantity) in peripheral leukocyte subsets.

-DLT is defined as any unexpected, treatment-related grade 4 or 5 adverse event that occurs with increased severity or incidence outside of known, expected toxicities, that occur in the first 6 patients enrolled (safety lead-in cohort)

-Defined as time from day 0 of treatment to evidence of at least one of the following: biochemical failure; radiographic or clinical progression either locally, in lymph nodes, or in distant metastases; or death from prostate cancer) compared to historical controls (ADT + docetaxel). Biochemical failure is defined as three consecutive rises (at lease one week apart) in PSA levels with the date of failure being the midpoint between the PSA nadir and the first PSA rise. Radiographic progression is defined as either RECIST1.1 or PCWG3 criteria.

-Defined as the Kaplan-Meier survival probability

* Baseline PSA prior to start of treatment will be compared to PSA nadir during treatment and then the investigators can calculate how many participants hit 30% reduction from pretreatment levels
* Participants who enroll with no detectable PSA will be considered not evaluable for this outcome measure

* Baseline PSA prior to start of treatment will be compared to PSA nadir during treatment and then the investigators can calculate how many participants hit 50% reduction from pretreatment levels
* Participants who enroll with no detectable PSA will be considered not evaluable for this outcome measure

At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

* PCWG3 recommends that lymph nodes that were previously normal in size (\< 1.0 cm) or pathologic in size must have grown by at least 5 mm in the short axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have progressed. If the node progresses to ≥ 1.5 cm in the short axis, it is pathologic and measurable. Nodes that have progressed to between 1.0 and less than 1.5 cm are pathologic subject to clinical discretion and are nonmeasurable
* The date of first metastasis is the date on which an unequivocal visceral lesion by RECIST 1.1 is determined
* Documentation of radiographic evidence of metastatic disease should include the time of the unequivocal development of new sites on bone scintigraphy

-Radiographic progression-free survival (rPFS) is the time interval from baseline to the date when the first site of disease is found to progress (using a manifestation-specific definition of progression), or death, whichever occurs first. To better understand the effect of therapy on an individual site of disease, PCWG3 advises the date of progression in all specific sites be reported independently whether it is bone, nodes (pelvic or extrapelvic), visceral (lung, liver, adrenal, or CNS), or other.

Laser capture microdissection will be performed to perform genomic studies on specific areas of tissue (eg tumor core, high TIL areas, tumor-stromal interface, etc). These will be correlated with multiplexed immunofluorescence studies, as well as assays on peripheral blood.

Spots Global Cancer Trial Database for fecal samples