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

NCT03532217 | Completed Phase 1 DMC FDA Drug FDA Device

• 2 other identifiers: 201808043CA209-9MW
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Hormone-Sensitive Prostate Cancer

Outcome Measures

Primary Outcomes (5)

• Safety and tolerability of regimen as defined by incidence of adverse events

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

  Through 100 days after completion of treatment (estimated to be 55 weeks)

• Immune response as measured by tetramers

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

  Through completion of treatment (estimated to be 41 weeks)

• Immune response as measured by genomic studies

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

  Through completion of treatment (estimated to be 41 weeks)

• Immune response as measured by flow cytometry

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

  Through completion of treatment (estimated to be 41 weeks)

• Safety and tolerability of regimen as defined by incidence of dose-limiting toxicities (DLTs)

  -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)

  Through 100 days after completion of treatment (estimated to be 55 weeks)

Secondary Outcomes (8)

• Failure-free survival (FFS)

  Through completion of follow-up (estimated to be 65 weeks)

• Milestone survival

  Through completion of follow-up (estimated to be 65 weeks)

• Number of participants who have PSA responses at 30% reduction level

  Through completion of treatment (estimated to be 41 weeks)

• Number of participants who have PSA responses at 50% reduction level

  Through completion of treatment (estimated to be 41 weeks)

• Radiographic progression as determined by RECIST 1.1

  Through completion of treatment (estimated to be 41 weeks)

Study Arms (1)

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

EXPERIMENTAL

* 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

Biological: PROSTVAC-V; Biological: PROSTVAC-F; Drug: Nivolumab; Drug: Ipilimumab; Biological: Neoantigen DNA vaccine; Device: TriGrid Delivery System; Procedure: Tumor biopsy; Procedure: Peripheral blood; Procedure: Fecal samples; Procedure: Leukapheresis

Interventions

PROSTVAC-V BIOLOGICAL

-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/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

PROSTVAC-F BIOLOGICAL

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

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Nivolumab DRUG

-Nivolumab is a human monoclonal antibody (mAb)

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Ipilimumab DRUG

-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.

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Neoantigen DNA vaccine BIOLOGICAL

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

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

TriGrid Delivery System DEVICE

-Electroporation device

Also known as: TDS-IM

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Tumor biopsy PROCEDURE

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

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Peripheral blood PROCEDURE

-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)

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Fecal samples PROCEDURE

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

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Leukapheresis PROCEDURE

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

PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed adenocarcinoma of the prostate.
• High risk/volume metastatic disease, as defined by 4 or more sites of disease or the presence of visceral metastases.
• Must have completed an adequate course of chemo-hormonal, first line therapy for metastatic hormone-sensitive prostate cancer, as determined by the investigator. Patients must remain on stable dose of ADT with castrate levels of testosterone (defined as testosterone \< 50 ng/dL)
• At least 18 years of age.
• PSA may be undetectable after initial chemo-ADT.
• ECOG performance status ≤ 2
• Normal bone marrow and organ function as defined below:
• Leukocytes ≥ 2,000/ul
• Absolute neutrophil count ≥ 1,500/ul
• Platelets ≥ 100,000/ul
• Hemoglobin ≥ 9.0 g/ul
• Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert's syndrome who must have a total bilirubin level of ≤ 3.0 ULN)
• AST(SGOT) ≤ 3.0 x ULN
• ALT(SGPT) ≤ 3.0 x ULN
• Creatinine ≤ 1.5 x ULN OR calculated creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault formula

You may not qualify if:

• Significant small cell or neuroendocrine component or histology, as determined by the institution's reading pathologist.
• Progression of disease as defined by a rising PSA (3 sequential values, at least 1 week apart) or radiographic progression based on RECIST1.1 or PCWG3 criteria.
• Prior treatment with a checkpoint inhibitor, neoantigen vaccine, or PROSTVAC.
• Participants with active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.
• Diagnosis of atopic dermatitis or other active exfoliative skin condition
• History of concurrent second cancers requiring active, ongoing systemic treatment
• Currently receiving any other investigational agents.
• Known brain metastases. Prostate cancer patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis, and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-PD-1, anti-CTLA-4, Prostvac-VF Tricom, DNA vaccines, or other agents used in the study.
• Prior allergy or significant systemic reaction to vaccinia.
• Prior reactions to monoclonal antibodies.
• Received hematopoietic stem cell transplant \< 24 months prior to enrollment to this study, or received hematopoietic stem cell transplant ≥ 24 months prior to enrollment to this study but has graft-versus-host disease or disease relapse.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant congestive heart failure (NYHA Class III, IV), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirements.
• Immunosuppressed status (e.g. HIV/AIDS, active HCV/HBV, high dose systemic steroids, etc.) as determined by the investigator; topical or inhaled steroids are acceptable.
• History of syncopal or vasovagal episode as determined by medical record and history in the 12 month period prior to first vaccination administration.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Bristol-Myers Squibb: collaborator
• Prostate Cancer Foundation: collaborator
• The Foundation for Barnes-Jewish Hospital: collaborator
• Bavarian Nordic: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Interventions

PROSTVAC; Nivolumab; Ipilimumab; Leukapheresis

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques

Study Officials

• Russell Pachynski, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2018
• First Posted: May 22, 2018
• Study Start: September 14, 2018
• Primary Completion: April 1, 2022
• Study Completion: July 25, 2022
• Last Updated: August 5, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)