This randomized phase II trial studies how well multi-epitope folate receptor alpha peptide
vaccine, sargramostim (GM-CSF), and cyclophosphamide work to prevent the recurrence of stage
1-3 triple negative breast cancer. Vaccines made from a person's white blood cells mixed with
tumor proteins may help the body build an effective immune response to kill tumor cells.
Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the
growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Giving multi-epitope folate receptor alpha peptide vaccine,
sargramostim (GM-CSF), and cyclophosphamide may work well together to prevent cancer
recurrence after surgery and other standard treatments for triple negative breast cancer.
PRIMARY OBJECTIVE:
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 OBJECTIVE:
I. To compare the safety and tolerability of metronomic cyclophosphamide followed by FRalpha
peptide vaccine with GM-CSF versus GM-CSF alone.
CORRELATIVE RESEARCH 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 cycle 1 only. Starting cycle 2, patients receive multi-epitope folate receptor alpha
peptide vaccine with sargramostim intradermally (ID) on day 1. Treatment repeats every 28
days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression
or unacceptable toxicity.
ARM II: Patients receive cyclophosphamide as in Arm I. Starting cycle 2, patients receive
placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for cycles 2-7
and every 6 months for cycles 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:
- Resected unilateral or bilateral primary carcinoma of the breast without clinical
evidence of metastatic disease (after neoadjuvant chemotherapy and/or adjuvant
chemotherapy), 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 CANCER surgeries, any radiation therapy, and any
chemotherapy, whichever is last, >= 90 days but not >= 546 days prior to randomization
- Note: Reconstructive and prophylactic surgeries are allowed after randomization
(during study treatment)
- Patient had at least one of the following:
- Biopsy or surgery-proven regional node involvement by cancer
- T1c, T2, T3, or T4 disease (with inflammatory disease allowed) identified at the
time of surgery or clinically identified prior to neoadjuvant chemotherapy
- No complete response to neoadjuvant chemotherapy (those who did achieve complete
response are still eligible if a pre-chemotherapy regional nodal biopsy
identified cancer or if the pre-chemotherapy tumor measured > 1 cm)
- 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
- 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 because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:
- 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
- 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 current receipt of treatment another
cancer (e.g., monoclonal antibody, small molecule pathway inhibitor)
- Treatment with systemic corticosteroid or immune-modulators =< 7 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
