Clinical trial NCT00841399: Safety and Efficacy Study of HER2/Neu (E75) Vaccine in Node-Positive Breast Cancer Patients
Official title: Phase Ib Trial of HER2/Neu Peptide (E75) Vaccine in Breast Cancer Patients at Risk for Recurrence After Surgical and Medical Therapies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Keywords: Breast cancer
Lead sponsor: Walter Reed Army Medical Center
Sponsor class: FED
Collaborators: name: Uniformed Services University of the Health Sciences
First posted: 2009-02-11
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purposes of this study are the following:

1. To assess safety and document local and systemic toxicity to the peptide vaccine (E75)
2. To determine maximum tolerated dose (MTD) and optimal biologic dose (OBD) for the peptide vaccine
3. To evaluate the in vivo cellular immune response to the peptide vaccine
4. To evaluate time to recurrence in the vaccinated patients vs. matched controls

Detailed 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 lead to the genesis of immunotherapeutic approaches. Specifically, the development of anti-cancer vaccines holds promise as an adjuvant and preventive therapy for patients after both primary surgical and medical treatment for breast cancer, but who are at a high risk for recurrence. Patients with greater than four lymph nodes positive have an 87% chance of recurrence post standard surgical and medical therapies at 10 years. 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 a vaccine strategy to induce cellular immunity would target. We propose to vaccinate these patients with an immunogenic peptide from the HER2/neu protein. If successful, this vaccine strategy could be utilized as an adjuvant to currently accepted first line therapy in future clinical trials.

Eligibility criteria: Inclusion Criteria:

1. HER2/neu expressing tumor
2. HLA-A2+ and/or HLA-A3+ to receive the vaccine. HLA-A2- and/or HLA-A3- patients will be eligible to be included in the control group.
3. Immunologically intact with a good performance status
4. Identified as being high or intermediate risk for recurrence
5. Without evidence of disease
6. Completion of all standard first-line therapies (but may still be on hormonal therapy)

Exclusion Criteria:

1. Tumor does not express HER2/neu
2. Not HLA-A2+ and/or HLA-A3+
3. Anergic
4. Receiving immunosuppressive therapy
5. In poor health (Karnofsky \<60%, ECOG \>2 and Tbili \>1.5 and creatinine\>2)
6. Pregnant (beta HCG+)
7. Metastatic disease or have refused standard therapies
8. Patients enrolled in other experimental protocols may enroll to this study only with the permission of the other study PI.

Primary outcomes:
measure: The primary endpoints are the safety and optimal dosing of the vaccine to induce an in vivo peptide-specific immune response.
timeFrame: Time period needed to determine the maximum tolerated and optimal biologic doses.
Secondary outcomes:
measure: The clinical endpoint is time to disease recurrence.
timeFrame: 30 days after each monthly vaccine, then per standard of care for breast cancer.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Windber
country: United States
facility: Windber Medical Center
state: Pennsylvania
Study officials:
affiliation: Cancer Vaccine Development Program
name: George E Peoples, MD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1245/ASO.2006.03.069. Epub 2006 Jul 24.
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. doi: 10.1158/1078-0432.CCR-05-1425.
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. doi: 10.1023/B:JOCI.0000029117.10791.98.
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):7536-45. doi: 10.1200/JCO.2005.03.047. Epub 2005 Sep 12.
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. doi: 10.1016/j.surg.2005.06.059.
citation: Hueman MT, Stojadinovic A, Storrer CE, Dehqanzada ZA, Gurney JM, Shriver CD, Ponniah S, Peoples GE. Analysis of naive and memory CD4 and CD8 T cell populations in breast cancer patients receiving a HER2/neu peptide (E75) and GM-CSF vaccine. Cancer Immunol Immunother. 2007 Feb;56(2):135-46. doi: 10.1007/s00262-006-0188-9. Epub 2006 Jun 17.
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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 Trials Group Study I-01 and I-02. Clin Cancer Res. 2009 Apr 15;15(8):2895-904. doi: 10.1158/1078-0432.CCR-08-1126. Epub 2009 Apr 7.
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. Breast Cancer Res Treat. 2006 Jul;98(1):17-29. doi: 10.1007/s10549-005-9108-5. Epub 2006 Jun 7.
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