Safety and Efficacy Study of HER2/Neu (E75) Vaccine in Breast Cancer

Breast Cancer Clinical Trial

Official title:

Phase Ib Trial of HER2/Neu Peptide (E75) Vaccine in Node Negative Breast Cancer Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00854789
• Other study ID #: 03-20012
• Status: Completed
• Phase: Phase 1
• Start date: December 2002
• Est. completion date: March 2013

Study information

• Verified date: March 2020
• Source: Walter Reed Army Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objectives of this study are the following:

1. To assess safety and document local and systemic toxicity to the peptide vaccine (E75) in node-negative breast cancer patients.

2. To determine the optimal dose of the immunoadjuvant, GM-CSF, necessary to elicit an in vivo cellular immune response to the peptide vaccine yet limit toxicity.

3. To determine the optimal inoculation schedule to elicit an in vivo cellular immune response to the peptide vaccine.

4. To correlate the efficiency of eliciting an in vivo cellular immune response to the peptide vaccine with the degree of HER2/neu expression in the patient's tumor.

Description:

Breast cancer is the most common malignancy and second most common cause of cancer-specific death among women in the United States. Despite advances in the diagnosis and treatment of breast cancer, one third of the women who develop the disease will die of the disease, accounting for approximately 46,300 deaths/year. While good primary therapies are available to treat early stage breast cancer, there is a substantial failure rate to these therapies in more advanced disease.

Advances in the understanding of the immune response to cancer have led to the genesis of immunotherapeutic approaches. Specifically, the development of anti-cancer vaccines holds promise as an adjuvant and preventive therapy for patients after primary surgical and medical treatment for breast cancer, but who are at a high risk for recurrence. While patients with hormone receptor positive tumors have the option to undergo hormonal therapy, recurrence is especially high among estrogen receptor/progesterone receptor (ER/PR) negative patients. For these patients, currently there is no good treatment option after completion of primary therapy; close surveillance and watchful waiting is the standard. It is this population of patients that we have targeted with a vaccine strategy to induce cellular immunity.

In our first vaccine study, (WU # 00-2005: Phase Ib Trial of HER2/neu Peptide (E75) Vaccine in Breast Cancer Patients at High Risk for Recurrence after Surgical and Medical Therapies) we have vaccinated node-positive, HER2/neu-positive breast cancer patients with an immunogenic peptide from the HER2/neu protein mixed with a FDA-approved immunoadjuvant, GM-CSF. The study is still enrolling patients, but to date the vaccine has been safe with very limited toxicity and has been very effective at inducing an immune response to the vaccinated peptide. However, it is too early to determine if this immunity will be protective against disease recurrence.

However, with the early immunologic success of the trial, we now intend to more thoroughly study the optimal dose and schedule of vaccinations necessary to efficiently raise immunity against the peptide. In order to study these permeations, we will need to vaccinate significantly more patients; therefore, we propose to vaccinate node-negative breast patients since 75-80% of patients present with early stage breast cancer. Furthermore, we intend to vaccinate patients regardless of their HER2/neu status in order to determine the impact of prior exposure to this antigen on our ability to raise immunity against HER2/neu. Are patients with prior exposure to HER2/neu sensitized or tolerized to this antigen? This question must be answered in order to determine the usefulness of this vaccine as truly preventive in a cancer-naïve population.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: March 2013
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Breast cancer and negative lymph nodes

2. HLA-A2+ and/or HLA-A3+ to receive the vaccine. HLA-A2-, HLA-A3- patients will be eligible to be included in the control group.

3. Immunologically intact with a good performance status (defined below).

4. Without evidence of disease.

5. Patients may enroll while receiving appropriate hormonal therapy for their disease.

6. Completion of all standard first-line therapies (but may still be on hormonal therapy)

Exclusion Criteria:

1. HLA-A2- and/or HLA-A3- patients will not be vaccinated

2. Anergic by the Mantoux panel of recall antigens

3. Receiving immunosuppressive therapy

4. In poor health (Karnofsky <60%, ECOG >2)

5. Tbili >1.5 mg/dL and creatinine>2 mg/dL

6. Pregnancy (urine HCG)

7. Active metastatic disease

8. Involved in other experimental protocols (unless approval is first obtained by the other study PI)

9. Refusal of standard therapies

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Biological:
• E75 + GM-CSF vaccine
The 1 ml by volume vaccine is administered intradermally in 0.5 ml inoculums at two different sites within 5 cm of each other on an extremity. Vaccinations will be given according to the schedule the patient has been assigned and will be administered in the same lymph node draining area (same arm or thigh). In addition, an optional booster inoculation as requested by previously vaccinated patients will be offered every 6 months for the duration of the protocol. The dose will be determined by the PI based on the patient's response to the initial vaccination series.

Locations

Country	Name	City	State
United States	Walter Reed Army Medical Center	Washington	District of Columbia
United States	Windber Medical Center	Windber	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
COL George Peoples, MD, FACS	Uniformed Services University of the Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (18)

Amin A, Benavides LC, Holmes JP, Gates JD, Carmichael MG, Hueman MT, Mittendorf EA, Storrer CE, Jama YH, Craig D, Stojadinovic A, Ponniah S, Peoples GE. Assessment of immunologic response and recurrence patterns among patients with clinical recurrence aft — View Citation

Benavides LC, Gates JD, Carmichael MG, Patil R, Holmes JP, Hueman MT, Mittendorf EA, Craig D, Stojadinovic A, Ponniah S, Peoples GE. The impact of HER2/neu expression level on response to the E75 vaccine: from U.S. Military Cancer Institute Clinical Trial — View Citation

Benavides LC, Sears AK, Gates JD, Clifton GT, Clive KS, Carmichael MG, Holmes JP, Mittendorf EA, Ponniah S, Peoples GE. Comparison of different HER2/neu vaccines in adjuvant breast cancer trials: implications for dosing of peptide vaccines. Expert Rev Vac — View Citation

Dehqanzada ZA, Storrer CE, Hueman MT, Foley RJ, Harris KA, Jama YH, Kao TC, Shriver CD, Ponniah S, Peoples GE. Correlations between serum monocyte chemotactic protein-1 levels, clinical prognostic factors, and HER-2/neu vaccine-related immunity in breast cancer patients. Clin Cancer Res. 2006 Jan 15;12(2):478-86. — View Citation

Dehqanzada ZA, Storrer CE, Hueman MT, Foley RJ, Harris KA, Jama YH, Shriver CD, Ponniah S, Peoples GE. Assessing serum cytokine profiles in breast cancer patients receiving a HER2/neu vaccine using Luminex technology. Oncol Rep. 2007 Mar;17(3):687-94. — View Citation

Holmes JP, Clifton GT, Patil R, Benavides LC, Gates JD, Stojadinovic A, Mittendorf EA, Ponniah S, Peoples GE. Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trial — View Citation

Holmes JP, Gates JD, Benavides LC, Hueman MT, Carmichael MG, Patil R, Craig D, Mittendorf EA, Stojadinovic A, Ponniah S, Peoples GE. Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Canc — View Citation

Hueman MT, Stojadinovic A, Storrer CE, Dehqanzada ZA, Gurney JM, Shriver CD, Ponniah S, Peoples GE. Analysis of naïve and memory CD4 and CD8 T cell populations in breast cancer patients receiving a HER2/neu peptide (E75) and GM-CSF vaccine. Cancer Immunol — View Citation

Hueman MT, Stojadinovic A, Storrer CE, Foley RJ, Gurney JM, Shriver CD, Ponniah S, Peoples GE. Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine. B — View Citation

Mittendorf EA, Clifton GT, Holmes JP, Clive KS, Patil R, Benavides LC, Gates JD, Sears AK, Stojadinovic A, Ponniah S, Peoples GE. Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Mili — View Citation

Mittendorf EA, Gurney JM, Storrer CE, Shriver CD, Ponniah S, Peoples GE. Vaccination with a HER2/neu peptide induces intra- and inter-antigenic epitope spreading in patients with early stage breast cancer. Surgery. 2006 Mar;139(3):407-18. — View Citation

Mittendorf EA, Holmes JP, Ponniah S, Peoples GE. The E75 HER2/neu peptide vaccine. Cancer Immunol Immunother. 2008 Oct;57(10):1511-21. doi: 10.1007/s00262-008-0540-3. Epub 2008 Jun 7. Review. — View Citation

Mittendorf EA, Storrer CE, Shriver CD, Ponniah S, Peoples GE. Investigating the combination of trastuzumab and HER2/neu peptide vaccines for the treatment of breast cancer. Ann Surg Oncol. 2006 Aug;13(8):1085-98. Epub 2006 Jul 24. — View Citation

Patil R, Clifton GT, Holmes JP, Amin A, Carmichael MG, Gates JD, Benavides LH, Hueman MT, Ponniah S, Peoples GE. Clinical and immunologic responses of HLA-A3+ breast cancer patients vaccinated with the HER2/neu-derived peptide vaccine, E75, in a phase I/I — View Citation

Peoples GE, Gurney JM, Hueman MT, Woll MM, Ryan GB, Storrer CE, Fisher C, Shriver CD, Ioannides CG, Ponniah S. Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients. J Clin Oncol. 2005 Oct 20;23(30):7 — View Citation

Peoples GE, Holmes JP, Hueman MT, Mittendorf EA, Amin A, Khoo S, Dehqanzada ZA, Gurney JM, Woll MM, Ryan GB, Storrer CE, Craig D, Ioannides CG, Ponniah S. Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high — View Citation

Stojadinovic A, Mittendorf EA, Holmes JP, Amin A, Hueman MT, Ponniah S, Peoples GE. Quantification and phenotypic characterization of circulating tumor cells for monitoring response to a preventive HER2/neu vaccine-based immunotherapy for breast cancer: a — View Citation

Woll MM, Fisher CM, Ryan GB, Gurney JM, Storrer CE, Ioannides CG, Shriver CD, Moul JW, McLeod DG, Ponniah S, Peoples GE. Direct measurement of peptide-specific CD8+ T cells using HLA-A2:Ig dimer for monitoring the in vivo immune response to a HER2/neu vaccine in breast and prostate cancer patients. J Clin Immunol. 2004 Jul;24(4):449-61. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary endpoints are the safety and optimal dosing of the vaccine to induce an in vivo peptide-specific immune response.		Time period needed to determine the maximum tolerated and optimal biologic doses (30 days after each monthly dose)
Secondary	Time to recurrence is measured as a secondary outcome measure.		30 days after each monthly vaccine, then per standard of care for breast cancer.