A randomized phase II trial of adjuvant trastuzumab emtansine (T-DM1) followed by subcutaneous trastuzumab versus paclitaxel in combination with subcutaneous trastuzumab for Stage I HER2-positive breast cancer (ATEMPT 2.0)

This research study is studying how well newly diagnosed breast cancer that has tested
positive for a protein called HER2 responds using one of two different combination of
HER2-directed therapies as a treatment after surgery.

The name of the study drugs involved are:

- Trastuzumab-emtansine (T-DM1, Kadcyla)

- Trastuzumab SC (Herceptin Hylecta)

- Paclitaxel

Inclusion Criteria:

- Patients must have HER2-positive Stage I histologically confirmed invasive carcinoma
of the breast. Patients must have node-negative (N0) or micrometastases (N1mic) breast
cancer according to the AJCC 8th edition anatomic staging table.

- If the patient has had a negative sentinel node biopsy, then no further axillary
dissection is required, and the patient is determined to be node-negative. If an
axillary dissection without sentinel lymph node biopsy is performed to determine
nodal status, at least six axillary lymph nodes must be removed and analyzed, and
determined to be negative, for the patient to be considered node-negative.
Axillary nodes with single cells or tumor clusters ≤ 0.2 mm by either H&E or
immunohistochemistry (IHC) will be considered node-negative.

- Any axillary lymph node with tumor clusters between 0.02 and 0.2 cm is considered
a micrometastasis. Patients with a micrometastasis are eligible. An axillary
dissection is not required to be performed in patients with a micrometastasis
found by sentinel node evaluation. In cases where the specific pathologic size of
lymph node involvement is subject to interpretation, the principal investigator
will make the final determination as to eligibility. The investigator must
document approval in the patient medical record.

- Patients who have an area of a T1aN0, ER+ (defined as >10%), HER2-negative cancer
in addition to their primary HER2-positive tumor are eligible.

- HER2-positive by ASCO CAP 2018 guidelines, confirmed by central testing. NOTE: HER-2
status must be confirmed to be positive by central review by NeoGenomics prior to
patient starting protocol therapy. Patients previously having had HER2
immunohistochemical testing by NeoGenomics do not need to undergo retesting for
central confirmation of HER2 status.

NOTE: DCIS components will not be counted in the determination of HER2 status

- ER/PR determination is required. ER and PR assays should be performed by
immunohistochemical methods according to the local institution standard protocol.

- Bilateral breast cancers that individually meet eligibility criteria are allowed.

- Patients with multifocal or multicentric disease are eligible, as long as each tumor
individually meets eligibility criteria. Central confirmation is needed for any site
of disease that is tested to be HER2-positive by local testing (unless testing was
previously done by NeoGenomics).

- Patients with a history of ipsilateral DCIS are eligible if they were treated with
wide excision alone, without radiation therapy, or treated with a mastectomy for this
current breast cancer. Patients with a history of contralateral DCIS are not eligible.

- ≤ 90 days between the planned treatment start date and the patient's most recent
breast surgery for this breast cancer

- ≥ 18 years of age with any menopausal status.

- ECOG Performance Status 0 or 1

- All tumor should be removed by either a modified radical mastectomy or a segmental
mastectomy (lumpectomy), with either a sentinel node biopsy or axillary dissection

- All margins should be clear of invasive cancer or DCIS (i.e. no tumor on ink).
The local pathologist must document negative margins of resection in the
pathology report. If all other margins are clear, a positive posterior (deep)
margin is permitted, provided the surgeon documents that the excision was
performed down to the pectoral fascia and all tumor has been removed. Likewise,
if all other margins are clear, a positive anterior (superficial; abutting skin)
margin is permitted provided the surgeon documents that all tumor has been
removed.

- Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any
contraindications to radiation therapy. Radiation to the conserved breast is required.

- Patients may have received up to 4 weeks of tamoxifen therapy, or other hormonal
therapy, for adjuvant therapy for this cancer. Patients cannot receive adjuvant
hormonal therapy during protocol treatment for the first 12 weeks.

- Prior oophorectomy for cancer prevention is allowed.

- Patients who have undergone partial breast radiation (duration ≤ 14 days) prior to
registration are eligible. Partial breast radiation must be completed prior to 2 weeks
before starting protocol therapy. Patients who have undergone whole breast radiation
are not eligible.

- Patients who have participated in a window study (treatment with an investigational
agent prior to surgery for ≤ 2 weeks) are eligible. Patients must have discontinued
the investigational agent at least 14 days before participation.

- Adequate bone marrow function:

- ANC ≥ 1000/mm3,

- Hemoglobin ≥ 9 g/dl

- Platelets ≥ 100,000/mm3

- Adequate hepatic function:

- Total bilirubin ≤ 1.2mg/dL

- AST and ALT ≤ 1.5x Institutional ULN

- For patients with Gilbert syndrome, the direct bilirubin should be within the
institutional normal range. Serum alkaline phosphatase should be ≤ 1.5x
Institutional ULN.

- Left ventricular ejection fraction (LVEF) ≥ 50%

- Premenopausal patients must have a negative serum or urine pregnancy test, including
women who have had a tubal ligation and for women less than 12 months after the onset
of menopause.

- Women of childbearing potential and men with partners of childbearing potential must
be willing to use one highly effective form of nonhormonal contraception or two
effective forms of nonhormonal contraception by the patient and/or partner.
Contraceptive use must be continued for the duration of the study treatment and for 7
months after the last dose of study treatment. Hormonal birth control methods are not
permitted.

- Patients should have tumor tissue available, and a tissue block of sufficient size to
make 15 slides, which must be sent to DFCI for correlative research. If a tissue block
is unavailable, sites may send one H&E-stained slide and 15 unstained sections of
paraffin-embedded tissue on uncharged slides. Slide sections should be 4-5 microns in
thickness. It is also acceptable to submit 2 cores from a block of invasive tissue
using a 1.2 mm diameter coring tool. If tumor is not available, the investigator must
document why tissue is not available in the patient medical record, and that efforts
have been made to obtain tissue.

- Willing and able to sign informed consent

- Must be able to read and understand English in order to participate in the quality of
life surveys. If patient does not read and understand English, the patient is still
eligible, but cannot participate in the quality of life surveys.

Exclusion Criteria:

- Any of the following due to teratogenic potential of the study drugs:

- Pregnant women

- Nursing women

- Women of childbearing potential who are unwilling to employ adequate
contraception (condoms, diaphragms, IUDs, surgical sterilization, abstinence,
etc.).

- Men who are unwilling to employ adequate contraception (condoms, surgical
sterilization, abstinence, etc.).

- Locally advanced tumors at diagnosis, including tumors fixed to the chest wall, peau
d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny
cutaneous induration with an erysipeloid edge)

- Patients with a history of previous invasive breast cancer.

- History of prior chemotherapy in the past 5 years.

- History of paclitaxel therapy

- Patients with active liver disease, for example due to hepatitis B virus, hepatitis C
virus, autoimmune hepatic disorder, or sclerosing cholangitis

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances:

- Individuals with a history of other malignancies are eligible if they have been
disease-free for at least 5 years and are deemed by the investigator to be at low
risk for recurrence of that malignancy.

- Individuals with the following cancer are eligible regardless of when they were
diagnosed and treated: cervical cancer in situ, and non-melanoma cancer of the
skin.

- Intercurrent illness including, but not limited to: ongoing or active, unresolved
systemic infection, renal failure requiring dialysis, active cardiac disease, prior
myocardial infarction (asymptomatic changes on EKG suggestive of old MI is not an
exclusion), history of CHF, current use of any therapy specifically for CHF,
uncontrolled hypertension, significant psychiatric illness, or other conditions that
in the opinion of the investigator limit compliance with study requirements.