Her2-BATS and Pembrolizumab in Metastatic Breast Cancer
Her2-BATS and Pembrolizumab in Metastatic Breast Cancer
This proposal uses HER2Bi armed activated T-cells (HER2 BATs) to target breast cancer in
 combination with pembrolizumab (PBZ) in women with metastatic breast cancer (MBC). Phase I
 will determine a safe dose of the combination of PBZ and HER2 BATs in 3 to 18 patients. In
 the phase II portion, an additional 12 patients will be treated at the selected dose to
 further evaluate the safety and preliminary efficacy.

 Study treatment includes a combination of 8 infusions of BATs using a previously established
 schedule and one to three infusions of PBZ (200 mg per dose). PBZ will be added to 8
 infusions of BATs in 3 schedules: #1) after the 8th BATs infusion; #2) after the 4th and 8th
 BATs infusions; and then, #3) before the 1st and after the 4th and 8th BATs infusions.
Once subjects are determined eligible, white blood cells (lymphocytes) are collected via
 leukapheresis procedure. Depending on arm/schedule, about 4-5 weeks later, study treatment
 will begin. For HER2 BATs, the white blood cells, specifically T cells, are then mixed with
 two proteins - OKT3 and IL-2 -- which activates the cells to multiply. After approximately 14
 days in culture, the activated T cells are coated with OKT3 and trastuzumab/Herceptin
 (HER2Bi), and washed to remove excess Herceptin in order to produce bispecific antibody armed
 T cells (BATs). Cells are then frozen and stored until scheduled to be infused.

 Follow-up appointment schedule will include clinic visits 2 weeks, 1 month, 3 months, and 6
 months after the last dose of Pembrolizumab.
Inclusion Criteria:

 1. Histologically confirmed breast cancer (infiltrating ductal or lobular breast
 carcinoma) with evidence of measurable metastatic disease. Metastatic disease must be
 biopsy proven.

 a. Since histologic type, lymphatic permeation, blood vessel invasion, and degree of
 anaplasia may be prognostic variables, appropriate slides of the primary lesion will
 be requested for future review. HER2, estrogen, and progesterone receptor positivity
 will be recorded.

 2. Measurable lesion. Patients are required to have at least one measurable non-bone
 lesion ≥10 mm that has not been irradiated.

 a. Measurable metastatic disease documented by radiograph, CT scan, PET/CT, MRI, or
 physical exam is required. Each subject will be required to have at least one
 measurable lesion that has not been irradiated with a minimum size in at least one
 diameter of ≥ 10 mm for liver lesions, lung, skin, and ≥ 15 mm lymph node metastases.
 Biopsy of recurrent site(s) is not required.

 3. Patients must have HER2 status determined by FISH or IHC. HER2 status of positive or
 negative are both eligible for the study.

 In order to be eligible for participation in this trial, the patient must also:

 4. Be female ≥ 18 years of age

 5. Be willing and able to provide written informed consent for the trial.

 6. Have a performance status (PS) ECOG 0-1

 7. Have a life expectancy ≥ 3 months

 8. Be eligible for apheresis, as determined by the Stem Cell Transplant team

 9. Demonstrate adequate organ function as defined below, all screening labs should be
 performed within 10 days prior to apheresis.

 Absolute lymphocyte count ≥ 500/mm3 Absolute neutrophil count (ANC) ≥1,500 /mcL
 Platelets ≥ 100,000 / mcL Hemoglobin ≥ 9 g/dL (or ≥5.6 mmol/L without transfusion or
 EPO dependency (within 7 days of assessment) BUN ≤ 1.5 X upper limit of normal (ULN)
 Serum creatinine OR ≤1.5 X upper limit of normal (ULN) OR Measured or calculated
 creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min
 for subject with creatinine levels > 1.5 X institutional ULN Serum total bilirubin ≤
 1.5 X ULN OR AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with
 liver metastases Albumin >2.5 mg/dL International Normalized Ratio (INR) or
 Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy
 Activated Partial Thromboplastin Time (aPTT) as long as PT or PTT is within
 therapeutic range of intended use of anticoagulants

 10. Female patients of childbearing potential should have a negative urine or serum
 pregnancy test at screening. If the urine test is positive or cannot be confirmed as
 negative, a serum pregnancy test will be required.

 11. Female patients of childbearing potential must be willing to use an adequate method of
 contraception as outlined in Section 4.5.2, for the course of the study through 120
 days after the last dose of study medication.

 12. Patients must have had two or more lines of prior therapy (chemo or hormonal) in the
 metastatic setting

 Exclusion Criteria:

 The patient must be excluded from participating in the trial if the subject:

 1. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
 other form of immunosuppressive therapy within 7 days prior to leukapheresis.

 2. Has a known history of active TB (Bacillus Tuberculosis)

 3. Hypersensitivity to PBZ or any of its excipients.

 4. Lack of recovery (i.e., ≤ Grade 1 or baseline prior to last line of cancer therapy)
 from non-laboratory adverse events except ≤ Grade 2 neuropathy

 5. Has history of another malignancy within the past 5 years. Exceptions include basal
 cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone
 potentially curative therapy or in situ cervical cancer.

 6. Has known active central nervous system (CNS) metastases and/or carcinomatous
 meningitis. Subjects with previously treated brain metastases may participate provided
 they are stable (without evidence of progression by imaging for at least four weeks
 prior to the first dose of trial treatment and any neurologic symptoms have returned
 to baseline), have no evidence of new or enlarging brain metastases, and are not using
 steroids for at least 7 days prior to leukapheresis. This exception does not include
 carcinomatous meningitis which is excluded regardless of clinical stability.

 7. Has active autoimmune disease that has required systemic treatment in the past 2 years
 (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
 drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
 replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
 form of systemic treatment.

 8. Has known history of, or any evidence of active, non-infectious pneumonitis.

 9. Has an active infection requiring systemic therapy.

 10. Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the trial, interfere with the subject's
 participation for the full duration of the trial, or is not in the best interest of
 the subject to participate, in the opinion of the treating investigator.

 11. Is pregnant or breastfeeding, or expecting to conceive children within the projected
 duration of the trial, starting with the pre-screening or screening visit through 120
 days after the last dose of trial treatment.

 12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

 13. Has Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known history of
 Hepatitis B (e.g., HBsAg reactive) or Hepatitis C antibody is detected. Note: Patients
 may be eligible if HCV antibody is detected as long as HCV viral load is undetectable
 following an FDA approved treatment regimen

 14. Has received a live vaccine within 30 days of apheresis. Note: Seasonal influenza
 vaccines for injection are generally inactivated flu vaccines and are allowed; however
 intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are
 not allowed.

 15. Has a history of significant cardiac disease, including:

 -  History of a recent myocardial infarction (within one year), a past myocardial
 infarction (more than one year ago) along with current coronary symptoms
 requiring medications and/or evidence of depressed left ventricular function
 (LVEF < 45% by MUGA or ECHO).

 -  Current history of angina/coronary symptoms requiring medications and/or evidence
 of depressed left ventricular function (LVEF < 45% by MUGA or ECHO)

 -  Clinical evidence of congestive heart failure requiring medical management
 (irrespective of ECHO results).

 16. Pt may be excluded if, in the opinion of the PI and investigator team, the pt is not
 capable of being compliant.