Adjuvant Therapy With an Alpha-lactalbumin Vaccine in Triple-Negative Breast Cancer

Inclusion Criteria:

Triple Negative Cohort:

* Histologically proven invasive breast cancer.
* Primary tumor must be ER-negative (ER in \<1% of cells), PR-negative (PR in \<1% of cells), and HER2-negative (0-1+ by IHC or FISH ratio\<2.0 with signal number \<6/cell), or consistent with contemporary NCCN guidelines (https://www.nccn.org/).
* Patients must be high risk, defined as either:
* Pathologic stage IIA, IIB, IIIA, IIIB, or IIIC by AJCC 8, or
* Residual invasive cancer in breast or regional nodes following preoperative chemotherapy.
* Patients must have no convincing evidence of recurrent disease based on one of the following:
* bone scan and imaging scans of the chest/abdomen/pelvis or
* FDG PET scan.
* ≥1 months since last active therapy (chemotherapy, radiation therapy, or surgery) and ≤ 36 months since the initiation of treatment for the current cancer, based on the period of highest risk for patients with Stages I-III triplenegative breast cancer \[33, 34\].
* Treatment prior to enrollment must be consistent with NCCN guidelines extant at the time treatment was given, found at: https://www.nccn.org/.
* Age greater than or equal to 18 years.
* ECOG Performance Status 0-1.
* Adequate major organ function, defined as:

WBC ≥ 3,000/mcl, hemoglobin ≥ 10.0 gm/dL, platelets ≥ 100,000/mcL, total bilirubin within normal limits, ALT/AST \<3 x upper limits of normal (ULN), serum creatinine ≤ 1.5 x ULN.

* Serum prolactin level must be ≤ upper limits of normal (ULN).
* Subjects must have the ability to understand and the willingness to sign and provide a written informed consent document.
* Subjects must have archival tissue available for potential correlative studies (e.g., assays for α-lactalbumin expression or tumor infiltrating lymphocytes), but tumors will not be required to exhibit overexpression of α-lactalbumin for enrollment.
* Subject agrees not to use alternative therapies from the time of informed consent through 30 days following the last vaccine injection. ). Patients may be asked to complete a "wash out" period prior to the first dose of vaccine at the PI's discretion to ensure the absence of all alternative therapies.

Prevention Cohort:

* Participant must have a high risk for developing triple-negative breast cancer, defined as: carrying a deleterious mutation in BRCA1, PALB2 or BRCA2
* Patients must have no evidence of breast cancer based on both of the following: Negative mammography or breast MRI within 180 days, Negative breast examination by a physician or advanced practice practitioner within 30 days
* Age ≥ 18 years
* ECOG Performance Status 0-1.
* Adequate major organ function, defined as: WBC ≥ 3,000/mcl, hemoglobin ≥ 10.0 gm/dL, platelets \>100,000/mcL, total bilirubin within normal limits, ALT/AST \<3 x upper limits of normal (ULN), serum creatinine ≤ 1.5 x ULN.
* Serum prolactin level must be ≤ upper limits of normal (ULN)
* Subjects must have the ability to understand and the willingness to sign and provide a written informed consent document.
* Subject agrees not to use alternative therapies from the time of informed consent through 30 days following the last vaccine injection. Patients may be asked to complete a "wash out" period prior to the first dose of vaccine at the PI's discretion to ensure the absence of all alternative therapies.

Pembrolizumab Cohort:

* Histologically proven invasive breast cancer.
* Primary tumor must be ER-negative (ER in \<1% of cells), PR-negative (PR in \<1% of cells), and HER2-negative (0-1+ by IHC or FISH ratio \<2.0 with signal number \<6/cell), or consistent with contemporary NCCN guidelines (https://www.nccn.org/).
* Patients must be high risk, defined as having residual invasive cancer in breast or regional nodes following pre-operative chemotherapy.
* Patients must have no convincing evidence of recurrent disease based on one of the following: Bone scan and imaging scans of the chest/abdomen/pelvis, or: FDG PET scan.
* \>1 months since last active therapy with chemotherapy (excluding Xeloda/capecitabine), radiation therapy, or surgery and at least 6 weeks of pembrolizumab therapy planned after the first dose of alpha-lactalbumin vaccine.
* Treatment prior to enrollment must be consistent with NCCN guidelines extant at the time treatment was given, found at: https://www.nccn.org/.
* Age \>18 years.
* ECOG Performance Status 0-1.
* Adequate major organ function, defined as: WBC \> 3,000/mcl, hemoglobin \> 10.0 gm/dL, platelets \> 100,000/mcL, total bilirubin within normal limits, ALT/AST \<3 x upper limits of normal (ULN), serum creatinine \< 1.5 x ULN.
* Serum prolactin level must be \< upper limits of normal (ULN).
* Subjects must have the ability to understand and the willingness to sign and provide a written informed consent document.
* Subjects must have archival tissue available for potential correlative studies (e.g., assays for α-lactalbumin expression or tumor infiltrating lymphocytes), but tumors will not be required to exhibit overexpression of α-lactalbumin for enrollment.
* Subject agrees not to use alternative therapies from the time of informed consent through 30 days following the last vaccine injection. Patients may be asked to complete a "wash out" period prior to the first dose of vaccine at the PI's discretion to ensure the absence of all alternative therapies.

Exclusion Criteria:

Triple Negative Cohort:

* Receipt of cytotoxic chemotherapy within 4 weeks of study entry (except for capecitabine in subjects enrolled in the pembrolizumab cohort).
* Radiation therapy within 4 weeks of study entry.
* Failure to recover from the toxicity of the previous therapy to CTCAE Grade 0-1, except for alopecia and grade 2 neuropathy.
* Need for systemic corticosteroid use (except as physiologic replacement, defined as prednisone 10 mg/day or equivalent).
* Need for immunosuppression (e.g., for a history of organ transplantation).
* Known HIV infection.
* Active or planned lactation or pregnancy.
* Patients taking or planning to take oral contraceptives will be excluded, as there is some evidence that such agents can induce lactational foci. This includes patients using hormone containing IUD's.
* Refusal to use effective non-hormonal contraception. Acceptable contraception methods include but may not be limited to barrier contraception (diaphragm or condom), non-hormonal intrauterine device, vasectomy of male partner.
* Subjects receiving any other investigational agents within the last 4 weeks.
* Subjects with any known recurrence or metastasis.
* Subjects with a history of another active invasive malignancy within 5 years of study entry.
* History of allergic reactions to α-lactalbumin, human milk (excluding lactose intolerance), zymosan, or other agents used in this study.
* Subjects with 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.
* Subjects with known hyperprolactinemia.
* Subjects being treated with drugs known to cause hyperprolactinemia
* Subjects diagnosed with TNBC while pregnant.
* Subjects having lactated within 6 months of study start (first dose of vaccine).

Prevention Cohort:

* Receipt of cytotoxic chemotherapy within 4 weeks of study entry (including for benign indications).
* Radiation therapy within 4 weeks of study entry (including for benign indications)
* Need for systemic corticosteroid use (except as physiologic replacement, defined as prednisone 10 mg/day or equivalent).
* Need for immunosuppression (e.g., for a history of organ transplantation).
* Known HIV infection.
* Active or planned lactation or pregnancy.
* Patients taking or planning to take oral contraceptives will be excluded, as there is some evidence that such agents can induce lactational foci. This includes patients using hormone containing IUD's.
* Refusal to use effective non-hormonal contraception. Acceptable contraception methods include but may not be limited to barrier contraception (diaphragm or condom), non-hormonal intrauterine device, vasectomy of male partner.
* Subjects receiving any other investigational agents within the last 4 weeks.
* Subjects with a history of invasive malignancy within 5 years of study entry.
* History of allergic reactions to α-lactalbumin, human milk (excluding lactose intolerance), zymosan, or other agents used in this study.
* Subjects with 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
* Subjects with known hyperprolactinemia
* Subjects being treated with drugs known to cause hyperprolactinemia
* Subjects having lactated within 6 months of study start (first dose of vaccine).

Pembrolizumab Cohort:

* All exclusion criteria for the pembrolizumab cohort will be the same as the TNBC cohort as outlined above, with the exception of: Failure to recover from the toxicity of the previous therapy to CTCAE Grade 0-1, except for:

  * Alopecia
  * Grade 2 neuropathy, or,
  * Grade 2 or 3 decreased lymphocyte count/lymphopenia (only in the pembrolizumab cohort in patients having received radiation therapy within 6 months of study enrollment)