Clinical Trials /

Perioperative Atezolizumab With MVA-BN-Brachyury and PROSTVAC For Intermediate-Risk And High-Risk Localized Prostate Cancer

NCT04020094

Description:

This study is a prospective, open label, single arm phase II trial. A total of 22 patients will be treated with atezolizumab, PROSTVAC, and pre-operative MVA-BN-Brachyury to confirm the efficacy of prostatic combination immunotherapy and to measure the relative change in the number of tumor infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Perioperative Atezolizumab With MVA-BN-Brachyury and PROSTVAC For Intermediate-Risk And High-Risk Localized Prostate Cancer
  • Official Title: Perioperative Atezolizumab With MVA-BN-Brachyury and PROSTVAC For Intermediate-Risk And High-Risk Localized Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: HCI121075
  • NCT ID: NCT04020094

Conditions

  • Prostate Adenocarcinoma

Purpose

This study is a prospective, open label, single arm phase II trial. A total of 22 patients will be treated with atezolizumab, PROSTVAC, and pre-operative MVA-BN-Brachyury to confirm the efficacy of prostatic combination immunotherapy and to measure the relative change in the number of tumor infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens.

Detailed Description

      Here we propose to use a combination of both checkpoint therapy with dual vaccine therapy.
      Patients will be treated with an intraprostatic injection of MVA-BN-Brachyury and
      subcutaneous PROSTVAC therapy. MVA-BN-Brachyury is a replication-deficient, attenuated
      vaccinia virus (Ankara strain) expressing both a CD8+ T-cell epitope from the brachyury
      protein and a triad of T-cell co-stimulatory molecules (B7.1, ICAM-1 and LFA-3).
      MVA-brachury-TRICOM, upon infection of cells, causes innate and then adaptive immune
      responses, antigen cascade, and improved T cell trafficking to the tumor. Vaccine therapy is
      one strategy that might increase immune infiltration into the tumor microenvironment.
      Prostate cancer is known to have minimal lymphocyte infiltration within the microenvironment.

      This vaccine strategy of direct injection into the tumor in combination with checkpoint
      inhibitors has previously been performed in early phase clinical trials.6 Furthermore, this
      approach of potent vaccine vector use can induce systemic effects as seen in a recent
      clinical trial of 12 patients with metastatic melanoma.12 In that study, responses were also
      observed in non-target lesions. In this case, MVA-BN-Brachyury is preferred as in
      intralesional injection agent over other vaccines due to the increased immunogenicity of MVA
      compared with fowlpox and improved safety profile for direct injection when compared with
      vaccinia, due to replication incompetence. In the prior study with MVA-BN-Brachyury no
      patients were observed to have replication of the virus.

      T cell mediated tumor cell killing is dependent on specific T cell recognition of a tumor
      target antigen, localization of those specific T cells to the tumor, and those T cells
      properly functioning within the tumor microenvironment. We hypothesize that these three
      primary issues comprise the major causes of most patients receiving no benefit from
      checkpoint inhibitor therapy or with vaccine monotherapy. We hypothesize that these issues
      can be addressed with an active intratumoral virus administration approach combined with the
      use of a subcutaneously administered vaccine (PROSTVAC) to induce PSA-specific T cell
      activation in combination with a checkpoint inhibitor. Combination viral based vaccine plus
      immune checkpoint inhibitor therapy will result in exposure of cancer specific antigens and
      induce inflammation at the site of the cancer ultimately resulting in significant clinical
      antitumor effect. Additionally, we hypothesize that the concurrent administration of
      anti-PD-1 moncolonal antibody therapy is necessary to allow those active T cells to achieve
      tumor cell killing, and significant overall clinical efficacy.

      The addition of atezolizumab is likely to provide additional efficacy over vaccine therapy
      alone. This is suggested by the induction of PD-1+ T-cells with vaccines.17 Additionally,
      PD-1 inhibition with nivolumab18 and pembrolizumab19 have shown clinical activity in
      metastatic prostate cancer. We suggest that the combination will provide even greater
      efficacy.

      Multiple studies have demonstrated a strong correlation between density of lymphocytes and
      prognosis, including overall survival.13-16 Given the very low density of infiltrating
      lymphocytes historically in prostate cancer, (Kaur HB, Hum Path 2019) we suggest that the
      primary endpoint of the change in CD8+ density is a reasonable pharmacodynamic endpoint for
      this exploratory, hypothesis generating study. However, as this study will be the first to
      date of the treatment combination, safety will also serve as a co-primary endpoint. The
      secondary objectives of PSA responses will help confirm the clinical utility of this approach
      in this target population.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment: all patientsExperimental

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Male subjects aged ≥ 18 years.
    
              -  Clinical staged unfavorable intermediate, high-risk or very high-risk prostate cancer
                 per NCCN guidelines.
    
              -  Histologically proven prostate adenocarcinoma
    
              -  Patient must be a surgical candidate
    
              -  ECOG Performance Status ≤ 1.
    
              -  Adequate organ function as defined as:
    
                   -  Hematologic:
    
              -  Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (without granulocyte colony-stimulation
                 factor support within 2 weeks of screening)
    
              -  Platelet count ≥ 100 × 109/L (without platelet transfusion within 2 weeks of
                 screening)
    
              -  Hemoglobin ≥ 9 g/dL (may not have been transfused within 2 weeks of study treatment
                 initiation)
    
              -  White blood cell count (WBC) ≥ 2.5 × 109/L.
    
                   -  Hepatic:
    
              -  Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) (≤ 3 × ULN for subjects
                 with Gilbert's disease)
    
              -  AST and ALT levels ≤ 2.5 × ULN. Patient with a history of unconjugated
                 hyperbilirubinemia with otherwise acceptable liver enzyme levels (as per above
                 criteria) may have higher bilirubin levels.
    
                   -  Renal:
    
              -  Urine protein/creatinine ratio (UPCR) ≤ 2 mg/mg (≤ 113.2 mg/mmol) UPCR can be
                 calculated with either a random spot urine test or a 24 hour test. The 24 urine
                 collection test is more clinically validated, so it is the determining test if there
                 is a discrepancy.
    
              -  Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5
                 mL/sec) using the Cockcroft-Gault equation.
    
              -  Highly effective contraception for male subjects throughout the study and for at least
                 6 months after last study treatment administration if the risk of conception exists.
    
              -  Patients must have archival prostate biopsy tissue available with identified prostate
                 cancer. If none is available, a repeat prostate biopsy is mandatory to be eligible for
                 this study. The repeat biopsy if performed must have documented prostate
                 adenocarcinoma. The archival tissue must not have been obtained more than 4 months
                 before enrollment.
    
              -  Able to provide informed consent and willing to sign an approved consent form that
                 conforms to federal and institutional guidelines.
    
              -  Prostate MRI must be performed within the past 8 months.
    
            Exclusion Criteria:
    
              -  Prostate cancer histology other than adenocarcinoma.
    
              -  Previous treatment for prostate cancer.
    
              -  Metastatic disease on imaging (CT, MRI, or NM bone scan) or through tissue biopsy.
                 This includes nodal metastatic disease. A biopsy is not required to rule out
                 metastasis.
    
              -  Use of immunosuppressive medication within 28 days of study treatment initiation,
                 EXCEPT for the following:
    
                   -  Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
                      intra-articular injection);
    
                   -  Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
                      equivalent;
    
                   -  Steroids as premedication for hypersensitivity reactions (e.g. CT scan
                      premedication).
    
              -  Known history of and/or active autoimmune disease requiring systemic treatment.
                 Patients with diabetes mellitus, thyroid disease, vitiligo, or other diseases
                 determined to be not clinically meaningful (per the treating physician) will not be
                 excluded for these conditions.
    
              -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
                 agent per treating physician's clinical judgment. Subjects with diabetes type I,
                 vitiligo, psoriasis, hypo- or hyperthyroid diseases, or other conditions are eligible
                 as per 5.2.5.
    
              -  The subject has uncontrolled, significant intercurrent or recent illness including,
                 but not limited to, the following conditions:
    
                 o Cardiovascular disorders:
    
              -  Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
                 pectoris, serious cardiac arrhythmias within 3 months of study enrollment.
    
              -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 180 mm Hg
                 systolic or > 120 mm Hg diastolic despite optimal antihypertensive treatment within 2
                 weeks of starting treatment.
    
              -  Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or
                 other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary
                 embolism) within 3 months before first dose.
    
                   -  Uncontrolled tumor-related pain.
    
                   -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
                      recurrent drainage procedures (once monthly or more frequently).
    
                   -  Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium
                      > 12 mg/dL or corrected serum calcium >ULN).
    
                   -  Active Tuberculosis
    
              -  Prior allogeneic stem cell or solid organ transplantation.
    
              -  Known history of acquired immunodeficiency syndrome.
    
              -  Prior or concurrent malignancy whose natural history or treatment, in the opinion of
                 the enrolling investigator, may have the potential to interfere with the safety or
                 efficacy assessment of the investigational regimen.
    
              -  Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening.
                 Patients with a history of HBV or HCV infection are eligible if the viral load is
                 documented as undetectable at screening. Screening tests for HBV, HCV or HIV are not
                 mandatory by the study but will be performed per the discretion of the study
                 investigators.
    
              -  Known history of atopic dermatitis or active skin condition (acute chronic, or
                 exfoliative) that disrupts the epidermis that is clinically meaningful within the past
                 6 months.
    
              -  Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
                 bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or
                 evidence of active pneumonitis on screening chest computed tomography (CT) scan.
    
              -  Known history of severe allergic anaphylactic reactions to chimeric or humanized
                 antibodies or fusion proteins.
    
              -  Active and inactive vaccinations within 28 days of study treatment initiation. Active
                 vaccinations are prohibited for the duration of the study. Inactive vaccinations are
                 acceptable after the prostatectomy is performed but cannot be given within 1 week of
                 the study vaccine administration.
    
              -  Known prior severe hypersensitivity to investigational product or any component in its
                 formulations, including known severe hypersensitivity reactions to monoclonal
                 antibodies (NCI CTCAE v 5.0 Grade ≥ 3).
    
              -  Known allergy to eggs, egg products, or aminoglycoside antibiotics (for example
                 gentamicin or tobramycin).
    
              -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of
                 the atezolizumab formulation.
    
              -  Known allergy or hypersensitivity to any component of the PROSTVAC or MVA-BN-Brachyury
                 formulation.
    
              -  Subjects taking prohibited medications as described in Section 6.6. A washout period
                 of prohibited medications for a period of at least 14 days or as clinically indicated
                 should occur prior to the start of treatment.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Male
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:To measure the relative change in the number of infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens.
    Time Frame:Within 8 weeks after cycle2 day 1 visit
    Safety Issue:
    Description:CD8+ lymphocytes in diagnostic biopsy and prostatectomy tissue samples will be quantified by immunohistochemistry (IHC) and analyzed using digital quantification. The relative change will be reported.

    Secondary Outcome Measures

    Measure:To assess the undetectable PSA rate
    Time Frame:6 and 12 months
    Safety Issue:
    Description:Undetectable PSA rates at 6 months and 12 months post-prostatectomy. This will be compared with Huntsman Cancer Institute (HCI) historical controls. Matching will be based on NCCN risk categories, age and follow up time.
    Measure:Assess clinical activity of perioperative combination immunotherapy.
    Time Frame:PSA evaluation will occur every 3 months after completion of the adjuvant treatment period. PSA relapse-free survival will be calculated and compared to HCI matched historical controls. Patients will be followed for 2 years after prostatectomy.
    Safety Issue:
    Description:PSA evaluation will occur every 3 months after completion of the adjuvant treatment period. PSA relapse-free survival will be calculated and compared to HCI matched historical controls. Patients will be followed for 2 years after prostatectomy. PSA progression will be defined based on Prostate Cancer Working Group 3 (PCWG3) criteria.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:University of Utah

    Trial Keywords

    • intermediate-risk prostate cancer
    • high-risk prostate cancer
    • very high-risk prostate cancer

    Last Updated