The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug combination to learn whether the drug
combination works in treating a specific disease. "Investigational" means that drug
combination is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Utomilumab as a treatment
for any disease.

The FDA (the U.S. Food and Drug Administration) has approved Avelumab as a treatment for
other diseases.

The FDA (the U.S. Food and Drug Administration) has approved trastuzumab as a treatment
option for this disease.

The FDA (the U.S. Food and Drug Administration) has approved vinorelbine as a treatment for
other diseases and is commonly used as a treatment option for this disease.

The immune system is the body's natural defense against disease. The immune system sends a
type of cells called T cells throughout the body to detect and fight infections and
diseases—including cancers. One way the immune system controls the activity of T cells is
through the PD-1 (programmed cell death protein-1) pathway. However, some cancer cells hide
from T-cell attack by taking control of the PD-1 pathway and this stops T cells from
attacking cancer cells. Avelumab is a type of drug, known as an antibody which is designed to
block the PD-1 pathway and helps the immune system in detecting and fighting cancer cells. An
antibody is a protein produced by the body's immune system when it detects harmful
substances. Previous studies show that the administration of antibodies which block the PD-1
pathway can lead to tumor destruction.

Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer
cells. Previous studies have shown that the administration of this type of antibody may help
to prevent tumors from growing.

In the laboratory, adding avelumab and Utomilumab to trastuzumab appears to improve
effectiveness. It is not known whether this is true in humans.

In this research study, the investigators are evaluating the activity of 3 different
combinations: (a)trastuzumab and vinorelbine combined, (b) trastuzumab, vinorelbine and
avelumab combined, and (c) trastuzumab, vinorelbine, avelumab and utomilumab combined in
participants with metastatic HER2- positive breast cancer.

Inclusion Criteria:

- Age ≥18 years or older

- Histologically confirmed breast adenocarcinoma that is unresectable loco-regionally
advanced or metastatic

- HER2-positive (immunohistochemistry score 3+) or ERBB2- amplification (Ratio
ERBB2/centromeres ≥ 2.0 or mean gene copy number ≥ 6) on primary tumor or of
metastatic or unresectable loco-regional biopsy.

- Measurable disease per RECIST v1.1 (see Section 11)

- Patients must have previous treatment with ado-trastuzumab emtansine (Kadcyla, T-DM1)
in any setting. Patients must have previously received trastuzumab and pertuzumab in
the metastatic setting or within 12 months of neoadjuvant/adjuvant treatment.

- Patient must have progressed on their most recent line of therapy. Progression must
have been demonstrated by radiological or clinical assessment.

- Left ventricular ejection fraction (LVEF) ≥ 50%

- Willingness and availability to submit FFPE tissue for central confirmation of HER2
positivity and central assessment of PD-L1 status. This can be from archival tissue
from unresectable loco-regional or metastatic disease obtained ≤ 1 year prior to
enrollment or new tissue material from a recently obtained surgical or diagnostic
biopsy. Tissue obtained for the biopsy must not have been previously irradiated. If a
patient does not have any available archival tissue ≤ 1 year old and the treating
investigator does not feel that it would be safe to perform a fresh biopsy, the
requirement for a fresh biopsy may be waived after discussion with the Principal
Investigator.

- Written informed consent for screening and trial participation procedures including
biological material transfer and handling.

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

- Hematopoietic status:

- Absolute neutrophil count ≥ 1.0 × 109/L,

- Platelet count ≥ 100 × 109/L,

- Hemoglobin ≥ 9 g/dL

- Hepatic status:

- Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known
Gilbert's syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.

- AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be
≤ 5 × ULN.

- Renal status:

- Creatinine ≤ 1.5 ×ULN or creatinine clearance > 60 ml/min

- Proteinuria < 1 g/day

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN unless
patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
range of intended use of anticoagulant.

- If female of childbearing potential, must have a negative pregnancy test within 7 days
of initiating treatment. Childbearing potential is defined by: those who have not been
surgically sterilized and/or have had a menstrual period in the past year.

- Participants of childbearing potential (as defined above) must be willing to use
effective contraception during treatment and up to 7 months after stop of trial
treatment. Acceptable methods of contraception are intrauterine devices, bilateral
tubal occlusion, vasectomized, or total abstinence. Oral, injectable, or implant
hormonal contraceptives are not allowed.

- Must not be breastfeeding/lactating.

Exclusion Criteria:

- Prior therapy with any anti-PD-1, anti-PD-L1, L2, anti-4-1BB (CD137), or anti-CTLA4
therapy

- Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

- Positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).

- History of interstitial lung disease

- Active central nervous system metastases, as indicated by clinical symptoms, cerebral
edema, and/or progressive growth (patients with history of CNS metastases or spinal
cord compression are eligible if they are clinically stable for at least 4 weeks
before first dose of investigational product and do not require high-dose steroid
treatment).

- History of clinically significant or uncontrolled cardiac disease, including
congestive heart failure (New York Heart Association functional classification ≥3),
angina, myocardial infarction or ventricular arrhythmia.

- Previous severe hypersensitivity reaction to treatment with another monoclonal
antibody.

- Active infection requiring systemic therapy.

- Chronic systemic therapy with immunosuppressive agents including corticosteroids.

- Active autoimmune disease or a documented history of autoimmune disease, or a syndrome
that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule. Patients that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the trial. Patients with hypothyroidism stable on hormone replacement or
Sjögren's syndrome will not be excluded from the trial.

- Concurrent disease or condition that would make the patient inappropriate for trial
participation or any serious medical disorder that would interfere with the patient's
safety.

- No uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest,
or chronic therapy with oxygen.

- Chemotherapy, radiotherapy, and/or biological cancer therapy within 3 weeks prior to
the first trial dose or has not recovered to CTCAE v.4 grade 1 or better from adverse
events (except alopecia).

- Unresolved or unstable, serious adverse events from prior administration of another
investigational drug.

- Live vaccines within 30 days prior to the first dose of trial therapy and during trial
treatment.