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A Study to Evaluate Concurrent VRP-HER2 Vaccination and Pembrolizumab for Patients With Breast Cancer

NCT03632941

Description:

In this phase II study, study subjects will receive the VRP-HER2 immunizations plus pembrolizumab. There will be an initial Safety Arm during which subjects will receive the VRP-HER2 immunizations plus pembrolizumab. If there is no dose limiting toxicity in the Safety Arm, then subjects will be randomized into 3 arms. They will undergo a biopsy of their tumor and peripheral blood draw for immune cell analyses and be assigned to the applicable arm of the study. Arm A will consist of the the VRP-HER2 immunizations; Arm B will consist of pembrolizumab; Arm C will consist of the VRP-HER2 immunizations plus pembrolizumab.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate Concurrent VRP-HER2 Vaccination and Pembrolizumab for Patients With Breast Cancer
  • Official Title: A Phase II Randomized Study to Evaluate the Immunologic and Antitumor Activity of Concurrent VRP-HER2 Vaccination and Pembrolizumab for Patients With Advanced HER2-overexpressing Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: Pro00100093
  • NCT ID: NCT03632941

Conditions

  • Breast Cancer
  • HER2+ Breast Cancer

Interventions

DrugSynonymsArms
VRP-HER2AVX901VRP-HER2 Vaccine
PembrolizumabKeytrudaPembrolizumab

Purpose

In this phase II study, study subjects will receive the VRP-HER2 immunizations plus pembrolizumab. There will be an initial Safety Arm during which subjects will receive the VRP-HER2 immunizations plus pembrolizumab. If there is no dose limiting toxicity in the Safety Arm, then subjects will be randomized into 3 arms. They will undergo a biopsy of their tumor and peripheral blood draw for immune cell analyses and be assigned to the applicable arm of the study. Arm A will consist of the the VRP-HER2 immunizations; Arm B will consist of pembrolizumab; Arm C will consist of the VRP-HER2 immunizations plus pembrolizumab.

Detailed Description

      The primary objective of this phase II study is to determine whether pembrolizumab increases
      the tumor infiltrating and peripheral blood immune response to the VRP-HER2 vaccine. The
      investigators hypothesize that HER2 specific T cell responses and anti-tumor immunity induced
      with HER2 vaccination will be augmented by concurrent anti-PD-1 antibody therapy.

      The investigators will additionally determine whether the administration of pembrolizumab is
      safe in patients with recurrent or metastatic HER2+ cancers who are receiving the anti-HER2
      vaccine VRP-HER2.

      There will be an initial Safety Arm (n=3) during which subjects will receive the VRP-HER2
      immunizations plus pembrolizumab and if there is no dose limiting toxicity in the Safety Arm,
      subjects will then be randomized 1:1:1 into 3 arms (n=12 per arm). Subjects with metastatic
      HER2 overexpressing breast cancer receiving trastuzumab and pertuzumab will continue these
      antibodies. They will undergo a biopsy of their tumor and peripheral blood draw for immune
      cell analyses and be assigned to the applicable arm of the study. Arm A will consist of the
      the VRP-HER2 immunizations; Arm B will consist of pembrolizumab; Arm C will consist of the
      VRP-HER2 immunizations plus pembrolizumab. Tumor biopsies and peripheral blood draws will be
      performed following the course of immunizations.
    

Trial Arms

NameTypeDescriptionInterventions
VRP-HER2 VaccineActive ComparatorVRP-HER2 Vaccine 4 x 10EE8 IU given as a single injection every 2 weeks for 3 injections total (Cycle 1: Day 1 and Day 15 Cycle 2: Day 8)
  • VRP-HER2
PembrolizumabActive Comparator5 administrations of Pembrolizumab 200 mg every 3 weeks for 5 total IV infusions (Day 1 of each 3 week cycle x 5 cycles)
  • Pembrolizumab
VRP-HER2 Vaccine + PembrolizumabExperimentalVRP-HER2 Vaccine 4 x 10EE8 IU given as a single injection every 2 weeks for 3 injections total (Cycle 1: Day 1 and Day 15 Cycle 2: Day 8)+ 5 administrations of Pembrolizumab 200 mg every 3 weeks for 5 total IV infusions (Day 1 of each 3 week cycle x 5 cycles)
  • VRP-HER2
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Have undergone treatment with trastuzumab plus pertuzumab for at least 3 weeks prior
             to initiation on this study.

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Resolution of all toxic side effects of prior chemotherapy, radiotherapy or surgical
             procedures to NCI CTCAE (version 4.03) Grade ≤ 1 (with the exception of grade 2
             alopecia, grade 2 neuropathy and grade 2 fatigue);

          -  Be >=18 years of age on day of signing informed consent.

          -  Have measurable disease based on RECIST 1.1.

          -  Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion.. Subjects for whom newly-obtained samples cannot be provided may submit
             an archived specimen only upon agreement from the Sponsor.

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  Normal cardiac function defined as either a MUGA or ECHO with LVEF in normal
             institutional range.

          -  Demonstrate adequate organ function as defined below:

        System Laboratory Value Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 /
        mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency

        Serum creatinine OR Measured or calculated creatinine clearance

          -  1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels >
             1.5 X institutional ULN

        Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
        bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR≤ 5 X ULN for subjects
        with liver metastases Albumin >2.5 mg/dL International Normalized Ratio (INR) or
        Prothrombin Time (PT)

          -  1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is
             within therapeutic range of intended use of anticoagulants

        Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
        anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of
        anticoagulants

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject.

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception.

          -  Ability to return to Duke University Medical Center for adequate follow-up as required
             by this protocol.

        Exclusion Criteria:

          -  Patients in this study, may not receive cytotoxic chemotherapy, anti-estrogen therapy,
             targeted small molecule therapy, or radiation therapy in the 3 weeks before the first
             infusion of Pembrolizumab, during the injection period for VRP-HER2 and infusion
             period for Pembrolizumab or for at least 2 weeks after booster immunization with
             VRP-HER2 (Arm 1) or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
             adverse events due to a previously administered agent.

          -  Has ER and or PR positive breast cancer.

          -  Patients may have received prior radiation including for brain metastases.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least 3 months
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment.

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapyor used an investigational
             device within 4 weeks of the first dose of treatment.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment. Prior history of autoimmune thyroiditis or vitiligo is permitted.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          -  Has active autoimmune disease that has required systemic treatment in the past 2
             years.

          -  Has history of (non-infectious) pneumonitis that required steroids or active,
             non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy or systemic use of antimicrobials
             within 72 hours prior to the first study treatment

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is
             detected).

          -  Has received a live vaccine within 30 days of planned start of study therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Tumor infiltrating Lymphocytes and HER2 specific antibodies
Time Frame:24 months
Safety Issue:
Description:The objective is to determine whether pembrolizumab increases the tumor infiltrating and HER2 specific antibodies resulting from the VRP-HER2 vaccine

Secondary Outcome Measures

Measure:Rate and severity of Adverse Events
Time Frame:24 months
Safety Issue:
Description:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Herbert Lyerly

Trial Keywords

  • Cancer
  • Immunotherapy
  • PD-1 Antibody
  • HER2
  • T cell

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