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

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

In this phase II study, participants will receive the VRP-HER2 immunizations plus pembrolizumab. 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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer; HER2+ Breast Cancer
• Intervention / Treatment: Biological: VRP-HER2; Biological: 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.

Participants will 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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
• 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 therapy or 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: AVX901; Biological: Pembrolizumab; A humanized antibody specific for the programmed cell death 1 (PD-1) receptor.; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Positive T Cell Response Based on ELISpot Results	The enzyme-linked immunosorbent spot (ELISpot) assay is a quantitative method that measures the frequency of cytokine secretion in a single cell.	up to approximately 15 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Severe Adverse Event as Assessed by CTCAE v5.0	Adverse events are graded on a scale from 1 to 5. Grade 1 adverse events are mild and generally not bothersome. Grade 2 events are bothersome and may interfere with doing some activities but are not dangerous. Grade 3 events are serious and interfere with a person's ability to do basic things like eat or get dressed. Grade 3 events may also require medical intervention. Grade 4 events are usually severe enough to require hospitalization. Grade 5 events are fatal. Reported here is the number of participants with a grade 3 adverse event.	up to approximately 15 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Stable Disease as Overall Response Based on RECIST 1.1 Criteria	RECIST (Response Evaluation Criteria in Solid Tumors) defines Stable Disease as neither partial response (>30% decrease in the sum of diameters of target lesions) or progressive disease (<20% decrease in the sum of diameters of target lesions).	up to approximately 15 weeks

Collaborators and Investigators

• Sponsor: Herbert Lyerly
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Crosby EJ, Acharya CR, Haddad AF, Rabiola CA, Lei G, Wei JP, Yang XY, Wang T, Liu CX, Wagner KU, Muller WJ, Chodosh LA, Broadwater G, Hyslop T, Shepherd JH, Hollern DP, He X, Perou CM, Chai S, Ashby BK, Vincent BG, Snyder JC, Force J, Morse MA, Lyerly HK, Hartman ZC. Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and alphaPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer. Clin Cancer Res. 2020 Sep 1;26(17):4670-4681. doi: 10.1158/1078-0432.CCR-20-0389. Epub 2020 Jul 30.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): September 3, 2023
• Study Completion (Actual): June 26, 2024

Study Registration Dates

• First Submitted: August 9, 2018
• First Submitted That Met QC Criteria: August 13, 2018
• First Posted (Actual): August 16, 2018

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Cancer; HER2; Immunotherapy; T cell; PD-1 Antibody
• Additional Relevant MeSH Terms: Neoplasms by Site; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Neoplasms; Breast Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: Pro00100093

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No