Folate Receptor Alpha Peptide Vaccine With GM-CSF in Patients With Triple Negative Breast Cancer

Triple negative breast cancers (TNBCs) occur in approximately 20-25% of all patients with breast cancer and are associated with a poor prognosis. Patients with TNBCs derive no benefit from targeted therapies. Excluding those patients who demonstrate a pathologic complete response following neoadjuvant chemotherapy, which is a minor fraction (i.e. 15%), overall survival is only 45% at 7 years.

Following standard of care, there are windows of opportunity to further and safely treat patients to prevent recurrence. Stimulating the immune system to produce T cells immunity specific for tumor antigens may significantly delay recurrence and cure patients.

The proposed vaccine is intended to induce T cells to survey for the reemergence of TNBCs and to prevent recurrence in the adjuvant setting. The vaccine strategy is antigen-specific and targets the Folate Receptor Alpha (FRα). FRα is an ideal target because of its limited expression in the healthy tissues and it high expression in 86% of TNBCs. Studies have shown that it is a biologically important marker that is associated with poorer clinical outcome and is retained in metastatic lesions.

The FRα vaccine include a pool of 5 peptides that are immunogenic epitopes and safely generate tissue-surveying CD4 T cell immune responses in patients tested in a recently completed phase I clinical trial.

Inclusion criteria

• Female patient, age 18 years or older;
• Completely resected unilateral or bilateral primary carcinoma of the breast
• Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures;
• Primary tumor was negative for ER, PR (cut-off for positivity is >10% positive tumor cells with nuclear staining) and negative for Her2-neu (0 or 1+ on immunohistochemistry and/or normal gene copy number by in-situ hybridization); Central review is not required.
• Completed primary treatment (surgery and radio/chemotherapy in adjuvant and/or neo-adjuvant setting) <360 days prior to first vaccination.
• Completed last cycle of chemotherapy or radiation > 60 days prior to first vaccination
• Either clinical or pathological Stage I (T1c), II, or III according to AJCC 7th edition

• Note that patients with (i) non-invasive breast cancer (DCIS) alone, (ii) incidental (microscopic) nodal cancer without a primary tumor (pN1mi), or (iii) metastatic disease are excluded.
• Resected tumor: No evidence of gross tumor at the surgical resection margin noted in the final surgery report. No evidence of gross residual adenopathy
• Karnofsky index >= 70%;
• Life expectancy of at least 5 years, disregarding the diagnosis of cancer;
• Adequate Blood, renal and hepatic function, as determined within 28 days from registration:

• ANC ≥ 1,500 / mm3
• Platelet ≥ 100,000 / uL
• Hgb > 9 g/dL
• Creatinine ≤ 1.5 x ULN or 24-hour urine < Grade 2
• Urinalysis with < 2+ proteinuria
• Serum albumin ≥ 3 g/dL
• SGOT (AST) ≤ 3 x ULN
• Anti-nuclear antibody (ANA) negative or low-positive institutional range, as determined within 28 days from registration. Intermediate values (usually defined by a titer of ≤1:80, or as indicated by institutional range) are acceptable if there are, in the opinion of the Investigator, no early signs of an autoimmune disease.
• Primary tumor is available for shipment to central laboratory for analysis of FRα expression by IHC.
• Patients must be, in the opinion of the Investigator, available and compliant for treatment and follow-up.

Exclusion criteria

• Clinical evidence of distant metastases per practice guidelines for breast cancer;
• Inflammatory breast cancer or tumor with deep adherence or cutaneous invasion;
• Known hypersensitivity reaction to the GM-CSF adjuvant; Any known contra-indication to GM-CSF or Cyclophosphamide treatment;
• Pregnant or lactating patients. Patients of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to registration and must implement adequate contraceptive measures during study treatment;
• Active autoimmune disease requiring therapy within the past 2 years (Note: patients with vitiligo, Grave's disease or psoriasis not requiring systemic treatment within the past 2 years are not excluded);
• Other uncontrolled illness or medical condition, such as active infection, symptomatic heart failure (New York Heart Association class III or IV; moderate to severe objective evidence of cardiovascular disease), unstable angina pectoris, myocardial infarction or stroke within last 6 months, psychiatric illness that may limit compliance with study requirement or interfere with the understanding and giving of informed consent;
• Prior active secondary malignancy < 5 years prior to consent (except non-melanomatous skin cancer or carcinoma in situ of the uterine cervix) or currently receiving other specific treatment for this cancer (including monoclonal antibody or pathway inhibitor);
• Completed treatment with systemic corticosteroid or immune-modulators < 30 days prior to registration;
• Planned treatment with other experimental drugs or any other non-hormonal anti-cancer therapy;
• Immunocompromised patients, including patients with known HIV infection;
• Symptomatic thyroid disease, unless negative for thyroid antibodies (TSH receptor, TPO, thyroglobulin).