Vaccine Therapy in Treating Patients With Breast Cancer

Phase II Trial of the HER2/Neu Peptide GP2 + GM-CSF Vaccine vs GM-CSF Alone in HLA-A2+ OR the Modified HER2/Neu Peptide AE37 + GM-CSF Vaccine vs GM-CSF Alone in HLA-A2- Node-Positive and High-Risk Node-Negative Breast Cancer Patients

RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells that express HER2/neu. Biological therapies, such as GM-CSF, may stimulate the immune system in different ways and stop tumor cells from growing. It is not yet known whether vaccine therapy is more effective than GM-CSF in treating breast cancer.

PURPOSE: This randomized phase II trial is studying vaccine therapy to see how well it works compared with GM-CSF in treating patients with breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Biological: GP2 peptide + GM-CSF vaccine; Biological: GM-CSF (sargramostim); Biological: GM-CSF (sargramostim); Biological: AE37 + GM-CSF vaccine

Detailed Description

OBJECTIVES:

• To determine if the GP2 peptide/GM-CSF vaccine reduces the recurrence rate in HLA-A2-positive, HER2/neu-positive, node-positive, or high-risk node-negative breast cancer patients randomized to receive the vaccine versus the immunoadjuvant, sargramostim (GM-CSF), alone.
• To determine if the AE37 peptide/GM-CSF vaccine reduces the recurrence rate in HLA-A2-negative, HER2/neu-positive, node-positive or high-risk node-negative breast cancer patients randomized to receive the vaccine versus the immunoadjuvant, GM-CSF, alone.
• To monitor the invitro and invivo immunologic responses to the vaccines and correlate these responses with the clinical outcomes.
• To monitor for any unexpected toxicities with the vaccines.

OUTLINE: This is a multicenter study. Patients are stratified according to nodal status. Patients are randomized to 1 of 4 treatment arms.

• Arm I: HLA-A2-positive patients receive GP2 peptide/GM-CSF vaccine intradermally (ID) every 3-4 weeks for a total of up to 6 inoculations.
• Arm II: HLA-A2-positive patients receive solely GM-CSF ID
• Arm III: HLA-A2-negative patients receive AE37 peptide/GM-CSF vaccine ID every 3-4 weeks for a total of up to 6 inoculations.
• Arm IV: HLA-A2-negative patients receive solely GM-CSF ID

After completion of study therapy, patients are followed every 3 months for the first 24 months and then every 6 months for an additional 36 months.

Booster inoculations are administered at 12, 18, 24, and 30 months from the date of patients' enrollment into the study. One booster inoculation is administered at each timepoint (+/- 2 weeks) and will be the same inoculation (vaccine or GM-CSF only) as what patients received during their regular inoculation series.

• Study Type: Interventional
• Enrollment (Actual): 456
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Kirchberg
    • Landstuhl, Kirchberg, Germany, 66849
      • Landstuhl Regional Medical Center
• Greece
  • Athens, Greece, 11522
    • Saint Savas Cancer Hospital of Athens
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • MedStar Union Memorial Hospital
    • Baltimore, Maryland, United States, 21239
      • MedStar Good Samaritan Hospital Cancer Center
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Texas
    • Fort Hood, Texas, United States, 76544-4752
      • Carl R. Darnall Army Medical Center
    • Fort Sam Houston, Texas, United States, 78234-6200
      • San Antonio Army Medical Center
    • Houston, Texas, United States, 77030-4009
      • University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • STOH Clinical Research
  • Washington
    • Tacoma, Washington, United States, 98431-5000
      • Madigan Army Medical Center - Tacoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

Inclusion criteria:

1. Lymph node-positive breast cancer or high-risk lymph node-negative breast cancer. The latter is defined by any one of the following criteria:

   • T2 disease
   • Grade 3 disease
   • Lymphovascular invasion
   • Estrogen receptor- or progesterone receptor-negative disease
   • HER2/neu-expressing tumor (immunohistochemistry [IHC] 3+ and/or amplified fluorescence in situ hybridization [FISH] >2.2, or N0 (i+))
2. HER2/neu-expressing tumor (IHC 1-3+ and or positive FISH >1.2)
3. Completion of primary standard of care breast cancer therapies (i.e., surgery, chemotherapy, immunotherapy and radiation therapy as appropriate per standard of care for patients' specific cancer)
4. Clinically cancer-free (no evidence of disease)
5. Patients may be enrolled between 1-6 months from completion of standard primary breast cancer therapies
6. Good performance status (as defined in Exclusion Criteria)
7. Capable of informed consent

Exclusion criteria:

1. HER2/neu-negative breast cancers (IHC 0)
2. Clinical and/or radiographic evidence of residual or persistent breast cancer
3. Receiving immunosuppressive therapy to include chemotherapy, steroids, or methotrexate
4. In poor health (Karnofsky <60%, ECOG >/-2)
5. Total bilirubin >1.8, creatinine >2, hemoglobin <10, platelets <50,000, WBC <2,000)
6. Active interstitial lung disease; asthma requiring more than as needed bronchodilators for management; or other autoimmune lung disease
7. Pregnancy (urine hCG)
8. Breast feeding
9. History of autoimmune disease
10. Involved in other experimental protocols (except with permission of the other study PI)

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Female or male
• Menopausal status not specified
• Immunologically intact by recall anergy testing
• Negative pregnancy test

Exclusion criteria:

• Karnofsky 0-60% or ECOG ≥ 2
• Total bilirubin > 1.8 g/dL
• Creatinine > 2.0 g/dL
• Hemoglobin < 10.0 g/dL
• Platelet count < 50,000/mm³
• WBC< 2,000/mm³
• Active pulmonary disease requiring medication that includes multiple inhalers
• Pregnancy
• Breastfeeding
• History of autoimmune disease

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

• See Disease Characteristics

Exclusion criteria:

• Concurrent immunosuppressive therapy including chemotherapy, steroids, or methotrexate
• Concurrent participation in another experimental treatment (except with permission of the other study investigator)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; HLA-A2-positive patients receive GP2 peptide + GM-CSF vaccine intradermally (ID) every 3-4 weeks for a total of up to 6 inoculations.	Biological: GP2 peptide + GM-CSF vaccine; Given intradermally every 3-4 weeks for a total of up to 6 inoculations; Other Names: GM-CSF (sargramostim)
Active Comparator: Arm II; HLA-A2-positive patients receive GM-CSF ID every 3-4 weeks for a total of up to 6 inoculations.	Biological: GM-CSF (sargramostim); GM-CSF given intradermally very 3-4 weeks for a total of up to 6 inoculations; Biological: GM-CSF (sargramostim); Given intradermally every 3-4 weeks for a total of up to 6 inoculations
Experimental: Arm III; HLA-A2-negative patients receive AE37 peptide/GM-CSF vaccine ID every 3-4 weeks for a total of up to 6 inoculations.	Biological: AE37 + GM-CSF vaccine; Given intradermally every 3-4 weeks for a total of up to 6 inoculations; Other Names: GM-CSF (sargramostim)
Active Comparator: Arm IV; HLA-A2-negative patients receive GM-CSF ID ID every 3-4 weeks for a total of up to 6 inoculations	Biological: GM-CSF (sargramostim); GM-CSF given intradermally very 3-4 weeks for a total of up to 6 inoculations; Biological: GM-CSF (sargramostim); Given intradermally every 3-4 weeks for a total of up to 6 inoculations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease recurrence	The following will be compared: disease recurrence rates between HLA-A2-negative patients receiving the AE37 + GM-CSF vaccine and HLA-A2-negative patients receiving GM-CSF alone; disease recurrence rates between HLA-A2-positive patients receiving the GP2 + GM-CSF vaccine and HLA-A2-positive patients receiving GM-CSF alone; disease recurrence rates between all four arms of the trial.	Five years (from date of enrollment to the study through the end of the follow-up period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Inoculations will be immediately halted if any serious adverse reactions occur which, when based upon appropriate judgment of the PI, are determined to jeopardize the patient or require medical or surgical intervention. Any death or grade 4 adverse drug experience found to be directly related to the experimental vaccine will result in suspension of patient enrollment to the study.	Local and systemic reactions to each inoculation will be monitored every six months during the regular inoculation series and the booster series.
Immune Response	Immune response will be measured by proliferation assays, dimer assays, and ELISPOT. Delayed type hypersensitivity reactions will be compared between the vaccinated group and GM-CSF-only group.	Immune response will be measured after every monthly inoculation in the regular inoculation series and after each inoculation in the booster series

Collaborators and Investigators

• Sponsor: San Antonio Military Medical Center
• Collaborators: NuGenerex Immuno-Oncology; Norwell, Inc.
• Investigators: Principal Investigator: Elizabeth A Mittendorf, MD, FACS, UT M.D. Anderson Cancer Center; Study Director: George E Peoples, MD, FACS, Cancer Vaccine Development Program, Department of Surgery, Brooke Army Medical Center

Publications and helpful links

General Publications

• Mittendorf EA, Alatrash G, Xiao H, Clifton GT, Murray JL, Peoples GE. Breast cancer vaccines: ongoing National Cancer Institute-registered clinical trials. Expert Rev Vaccines. 2011 Jun;10(6):755-74. doi: 10.1586/erv.11.59.
• Sears AK, Perez SA, Clifton GT, Benavides LC, Gates JD, Clive KS, Holmes JP, Shumway NM, Van Echo DC, Carmichael MG, Ponniah S, Baxevanis CN, Mittendorf EA, Papamichail M, Peoples GE. AE37: a novel T-cell-eliciting vaccine for breast cancer. Expert Opin Biol Ther. 2011 Nov;11(11):1543-50. doi: 10.1517/14712598.2011.616889. Epub 2011 Sep 6.
• Jackson DO, Trappey FA, Clifton GT, Vreeland TJ, Peace KM, Hale DF, Litton JK, Murray JL, Perez SA, Papamichail M, Mittendorf EA, Peoples GE. Effects of HLA status and HER2 status on outcomes in breast cancer patients at risk for recurrence - Implications for vaccine trial design. Clin Immunol. 2018 Oct;195:28-35. doi: 10.1016/j.clim.2018.06.008. Epub 2018 Jul 17.

Helpful Links

• Clinical trial summary from the National Cancer Institute's PDQ® database

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): December 31, 2014
• Study Completion (Actual): March 31, 2017

Study Registration Dates

• First Submitted: August 31, 2007
• First Submitted That Met QC Criteria: August 31, 2007
• First Posted (Estimate): September 3, 2007

Study Record Updates

• Last Update Posted (Actual): March 30, 2020
• Last Update Submitted That Met QC Criteria: March 23, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; male breast cancer; stage II breast cancer; stage IIIC breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Vaccines; Sargramostim; Molgramostim
• Other Study ID Numbers: CDR0000562261; BAMC-C.2007.098 (Other Identifier: BAMC Institutional Review Board); WRNMMC-20225 (Other Identifier: WRNMMC Institutional Review Board)