Clinical Trials /

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

NCT03532217

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 201808043
  • SECONDARY ID: CA209-9MW
  • NCT ID: NCT03532217

Conditions

  • Metastatic Hormone-Sensitive Prostate Cancer

Interventions

DrugSynonymsArms
PROSTVAC-VPROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine
PROSTVAC-FPROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine
NivolumabPROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine
IpilimumabPROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine
Neoantigen DNA vaccinePROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccine

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
PROSTVAC/Ipilimumab/Nivolumab/Neoantigen DNA vaccineExperimentalWithin 60 days after the last dose of standard of care docetaxel, patients will start a priming dose of PROSTVAC-V as a single agent, and subsequent doses of PROSTVAC- F in combination with ipilimumab (1mg/kg every 3 weeks for 2 doses), and nivolumab (3 mg/kg every 3 weeks for 6 doses), taking a total of approximately 17 weeks to complete. This is called Treatment A. Patients will then receive a neoantigen DNA vaccine with continuous nivolumab treatment. The vaccine will be administered by intramuscular injection for a total of 6 treatments every 28 days +/-7 days with at least 21 days between injection 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 called Treatment B.
  • PROSTVAC-V
  • PROSTVAC-F
  • Nivolumab
  • Ipilimumab
  • Neoantigen DNA vaccine

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  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

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

          -  Must have a biopsy of a metastatic site of disease (may be archival) available and
             adequate for evaluation and determination of neoantigens by genomic analyses.

          -  Must have all AEs resolved to baseline prior to chemo-ADT, or if treatment related,
             resolved to grade 1 prior to enrollment.

        Exclusion Criteria:

          -  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

          -  Prior malignancy active within the previous 3 years with the exception of basal cell
             or squamous cell carcinoma of the skin which were treated with local resection only,
             superficial bladder cancer or carcinoma in situ of cervix or breast.

          -  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.

          -  Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue
             for eligible injection sites (left and right medial deltoid region) exceeds 40 mm.

          -  Individuals in whom the ability to observe possible local reactions at the eligible
             injection sites (deltoid region) is, in the opinion of the investigator, unacceptably
             obscured due to a physical condition or permanent body art.

          -  Therapeutic or traumatic metal implant in the skin or muscle of either deltoid region.

          -  Any chronic or active neurologic disorder, including seizures and epilepsy, excluding
             a single febrile seizure as a child.

          -  Current use of any electronic stimulation device, such as cardiac demand pacemakers,
             automatic implantable cardiac defibrillator, nerve stimulators, or deep brain
             stimulators.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of regimen as defined by incidence of adverse events
Time Frame:Through 100 days after completion of treatment (estimated to be 55 weeks)
Safety Issue:
Description:-Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Secondary Outcome Measures

Measure:Failure-free survival (FFS)
Time Frame:2 years
Safety Issue:
Description:-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.
Measure:Milestone survival
Time Frame:3 years
Safety Issue:
Description:-Defined as the Kaplan-Meier survival probability
Measure:Number of participants who have PSA responses at 30% reduction level
Time Frame:Through completion of treatment (estimated to be 41 weeks)
Safety Issue:
Description: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
Measure:Number of participants who have PSA responses at 50% reduction level
Time Frame:Through completion of treatment (estimated to be 41 weeks)
Safety Issue:
Description: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
Measure:Radiographic progression as determined by RECIST 1.1
Time Frame:Through completion of treatment (estimated to be 41 weeks)
Safety Issue:
Description: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).
Measure:Radiographic progression as determined by Prostate Cancer Working Group 3 (PCWG3)
Time Frame:Through completion of treatment (estimated to be 41 weeks)
Safety Issue:
Description: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
Measure:Radiographic progression free survival (rPFS)
Time Frame:Through completion of treatment (estimated to be 41 weeks)
Safety Issue:
Description:-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.
Measure:Comparison of the immune correlates on matched tumor tissue and peripheral blood
Time Frame:Pre- and post-treatment (estimated to be 41 weeks)
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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