This Phase II trial evaluates the safety and immunogenicity of two doses of the Folate
Receptor Alpha (FRα) peptide vaccine mixed with GM-CSF as a vaccine adjuvant, with or without
a immune priming with cyclophosphamide, as a consolidation therapy after neoadjuvant or
adjuvant treatment of patients with Stage IIb-III triple negative breast cancer (TNBC).
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:
1. Female patient, age 18 years or older;
2. Completely resected unilateral or bilateral primary carcinoma of the breast
3. Written informed consent must be obtained and documented according to the local
regulatory requirements prior to beginning specific protocol procedures;
4. 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.
5. Completed primary treatment (surgery and radio/chemotherapy in adjuvant and/or
neo-adjuvant setting) <360 days prior to first vaccination.
6. Completed last cycle of chemotherapy or radiation > 60 days prior to first vaccination
7. 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
8. Karnofsky index >= 70%;
9. Life expectancy of at least 5 years, disregarding the diagnosis of cancer;
10. 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
11. 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.
12. Primary tumor is available for shipment to central laboratory for analysis of FRα
expression by IHC.
13. Patients must be, in the opinion of the Investigator, available and compliant for
treatment and follow-up.
Exclusion Criteria:
1. Clinical evidence of distant metastases per practice guidelines for breast cancer;
2. Inflammatory breast cancer or tumor with deep adherence or cutaneous invasion;
3. Known hypersensitivity reaction to the GM-CSF adjuvant; Any known contra-indication to
GM-CSF or Cyclophosphamide treatment;
4. 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;
5. 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);
6. 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;
7. 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);
8. Completed treatment with systemic corticosteroid or immune-modulators < 30 days prior
to registration;
9. Planned treatment with other experimental drugs or any other non-hormonal anti-cancer
therapy;
10. Immunocompromised patients, including patients with known HIV infection;
11. Symptomatic thyroid disease, unless negative for thyroid antibodies (TSH receptor,
TPO, thyroglobulin).
