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

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ClinicalTrials.gov Identifier: NCT03632941
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : March 8, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Herbert Lyerly, Duke University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Breast Cancer HER2+ Breast Cancer Biological: VRP-HER2 Biological: Pembrolizumab Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 1, 2019
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: VRP-HER2 Vaccine
VRP-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)
Biological: VRP-HER2
VRP (alphavirus-like replicon particles) containing self amplifying replicon RNA for HER2
Other Name: AVX901

Active Comparator: Pembrolizumab
5 administrations of Pembrolizumab 200 mg every 3 weeks for 5 total IV infusions (Day 1 of each 3 week cycle x 5 cycles)
Biological: Pembrolizumab
A humanized antibody specific for the programmed cell death 1 (PD-1) receptor.
Other Name: Keytruda

Experimental: VRP-HER2 Vaccine + Pembrolizumab
VRP-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)
Biological: VRP-HER2
VRP (alphavirus-like replicon particles) containing self amplifying replicon RNA for HER2
Other Name: AVX901

Biological: Pembrolizumab
A humanized antibody specific for the programmed cell death 1 (PD-1) receptor.
Other Name: Keytruda




Primary Outcome Measures :
  1. Number of Tumor infiltrating Lymphocytes and HER2 specific antibodies [ Time Frame: 24 months ]
    The objective is to determine whether pembrolizumab increases the tumor infiltrating and HER2 specific antibodies resulting from the VRP-HER2 vaccine


Secondary Outcome Measures :
  1. Rate and severity of Adverse Events [ Time Frame: 24 months ]
    Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0


Other Outcome Measures:
  1. Clinical response rate [ Time Frame: 36 months ]
    To collect preliminary data on the clinical response rates to this concurrent therapy of agents in subjects with assessable disease based on RECIST 1.1 criteria.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03632941


Contacts
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Contact: Laura Gorski, RN 919-660-1278 laura.gorski@duke.edu
Contact: Amy Hobeika 9196846112 AMY.HOBEIKA@DUKE.EDU

Locations
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United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27710
Contact: Michael Morse, MD         
Sponsors and Collaborators
Herbert Lyerly
Merck Sharp & Dohme Corp.

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Responsible Party: Herbert Lyerly, Principal Investigator, Duke University
ClinicalTrials.gov Identifier: NCT03632941     History of Changes
Other Study ID Numbers: Pro00100093
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: March 8, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Herbert Lyerly, Duke University:
Cancer
Immunotherapy
PD-1 Antibody
HER2
T cell

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Vaccines
Pembrolizumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents