Multi-epitope Folate Receptor Alpha Peptide Vaccine, Sargramostim, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To show that multi-epitope folate receptor alpha peptide vaccine (folate receptor
[FR]alpha peptide vaccine) with sargramostim (GM-CSF) adjuvant will prolong the disease-free
survival (DFS) compared to GM-CSF adjuvant treatment in patients with triple negative breast
cancer.

SECONDARY OBJECTIVES:

I. To compare the safety and tolerability of metronomic cyclophosphamide followed by FRalpha
peptide vaccine with GM-CSF versus GM-CSF alone.

TERTIARY OBJECTIVES:

I. To determine whether high level of antibody and cellular immune response toward the
FRalpha measured at baseline is a prognostic factor for vaccine immune response and/or cancer
relapse.

II. To determine whether the level of tumor expression of FRalpha at baseline is a prognosis
factor for vaccine immune response and/or cancer relapse.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cyclophosphamide orally (PO) twice daily (BID) on days 1-7 and 15-21
of course 1 only. Starting course 2, patients receive multi-epitope folate receptor alpha
peptide vaccine with sargramostim intradermally (ID) on day 1. Treatment repeats every 28
days for courses 2-7 and every 6 months for courses 8-14 in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive cyclophosphamide as in Arm I. Starting course 2, patients receive
placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for courses
2-7 and every 6 months for courses 8-14 in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years.

Inclusion Criteria:

- Completely resected unilateral or bilateral primary carcinoma of the breast without
clinical evidence of disease, negative for estrogen receptor (ER) and progesterone
receptor (PR) (cut-off for positivity is > 10% positive tumor cells with nuclear
staining), and negative for HER2 as defined by one of the four situations delineated
below:

- HER2 immunohistochemistry (IHC) expression of 0 or 1+ and in-situ hybridization
non-amplified

- HER2 IHC expression of 0 or 1+ and in-situ hybridization not done

- HER2 IHC expression of 2+ and in-situ hybridization non-amplified

- IHC not done and in-situ hybridization non-amplified

- Note: central review is not required

- Note: If biopsy and surgical specimens are discordant from each other with regard
to ER, PR, and/or HER2 status, a patient will be allowed to enroll assuming at
least one of the specimens meets the above criteria and no endocrine therapy use
is planned going forward

- Completed planned breast surgeries and any radiation therapy >= 60 days prior to
randomization

- Note: Reconstructive and prophylactic surgeries are allowed after randomization
(during study treatment)

- Completed last cycle of chemotherapy (which can be given in the adjuvant and/or
neoadjuvant setting) >= 90 days but not >= 365 days prior to randomization

- Patient had at least one of the following:

- Pathologic N1-3

- Pathologic T2, T3 T4

- Neoadjuvant chemotherapy and did not achieve complete response at time of surgery
(those who did achieve complete response are still eligible if a pre-chemotherapy
regional nodal biopsy identified cancer)

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1

- Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to
randomization

- Platelet count >= 75,000/uL obtained =< 14 days prior to randomization

- Aspartate transaminase (AST) =< 3 x upper limit of normal (ULN) obtained =< 14 days
prior to randomization

- Creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization

- Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0
obtained =< 14 days prior to randomization; Note: patients discovered to have >= 2+
proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine
collection and must demonstrate =< 1 g of protein in 24 hours

- Negative serum pregnancy test done =< 14 days prior to randomization, for women of
childbearing potential only

- Provide informed written consent

- Willing to return to enrolling institution for follow-up

- Willing to provide tissue and blood samples for correlative research studies

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Women of childbearing potential who are unwilling to employ adequate
contraception

- Clinical evidence of local recurrence or distant metastases; Note: New primary tumors
are allowed, both contralaterally and ipsilaterally, but a prior breast cancer must
have been more than 5 years beforehand; also, all patients must have either 1) a
positron emission tomography (PET)/computed tomography (CT) or 2) a CT of chest,
abdomen and pelvis and a bone scan =< 1 year prior to enrollment; if one or more of
these is concerning for distant metastases, follow-up imaging and/or biopsy should be
performed to rule out distant metastases prior to randomization

- Known hypersensitivity reaction to GM-CSF

- Active autoimmune disease that has required systemic treatment =< 30 days (i.e., with
use of disease modifying agents, corticosteroids, or immunosuppressive drugs) prior to
randomization; Note: replacement therapy (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not
considered a form of systemic treatment; patients with vitiligo, Graves disease, or
psoriasis not requiring systemic treatment within the past 30 days are not excluded;
patients with Celiac disease controlled with diet modification are not excluded

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- History of other cancer < 5 years prior to consent (except non-melanoma skin cancer or
carcinoma in situ of the uterine cervix) or receiving other specific treatment for
this cancer (monoclonal antibody, small molecule pathway inhibitor)

- Treatment with systemic corticosteroid or immune-modulators =< 30 days prior to
randomization

- Concurrent treatment with other experimental drugs or any other systemic anticancer
therapy (due to unknown drug-vaccine potential interactions)

- NOTE: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, and other
medications commonly used to treat nononcologic, non-autoimmune conditions are
allowed

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy

- Prior or concurrent use of trastuzumab

- Prior or concurrent use of a PD-1 or PD-L1 checkpoint inhibitor including
pembrolizumab unless the use was >= 3 months prior to randomization