ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied and research doctors
are trying to find out more about it—such as the safest dose to use and the side effects it
may cause.

The purpose of this research study is to examine the long-term benefits of T-DM1 with regard
to breast cancer and take a closer look at the side effects experienced by participants
receiving T-DM1.

The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for use in patients
with stage I, II, or III breast cancer, but it has been approved for use in advanced,
previously treated, HER2-positive breast cancer.

T-DM1 is an antibody-drug conjugate; it is made up of an antibody (trastuzumab) linked to a
cytotoxic drug, DM1 (chemotherapy). T-DM1 functions as a targeted cancer therapy because it
targets HER2-positive breast cancer cells directly, limiting exposure of the rest of the body
to chemotherapy. More specifically, the trastuzumab in T-DM1 first binds to the HER2 protein
on the surface of the breast cancer cells and the DM1 then enters the cells and can cause
them to die, preventing tumor growth

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed HER2-positive disease
by local pathology, defined as immunohistochemistry (IHC) 3+ or amplification by FISH
(HER2/CEP17 ratio ≥2 or an average of ≥6 HER2 gene copies per nucleus) AND confirmed
by Central Pathology Review (Dr. Deborah Dillon at Brigham and Women's Hospital,
Boston, MA) prior to patient being registered to begin protocol therapy. See section
3.4. http://ascopubs.org/doi/full/10.1200/jco.2013.50.9984

- NOTE: DCIS components should not be counted in the determination of HER2 status.

- Age ≥60 years at the time of study registration (men and women eligible)

- Participants must have histologically or cytologically confirmed Stage I-III breast
cancer with the following criteria met:

- If node-negative or if node status unknown (because it was not assessed), tumor must
be >5 mm (T1b per AJCC 7th edition) of any hormone receptor subtype (document ER/PR
status: if some ER/PR staining is present, ER and PR negative are defined as being
positive in <10% cells [per local pathology read]).

- If node-positive (N1-N3), T1mi, T1a, T1b, T1c, T2, or T3 tumors are eligible (see
below for further details on defining node-negative disease) Definition of
node-negative disease (when node status known): If the patient has had a negative
sentinel node biopsy and/or a negative axillary dissection, then the patient is
determined to be node-negative. Axillary nodes with single cells or tumor clusters ≤
0.2 mm by either H&E or IHC will be considered node-negative. Any axillary lymph node
with tumor clusters between 0.02 and 0.2cm is considered a micrometastasis. Patients
with a micrometastasis are eligible even if their tumor is dissection is not required to be performed in patients with a positive sentinel node
and management of the axilla will be left up to the treating provider. 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. In
these special situations, the investigator must document this approval in the patient
medical record.

- ER/PR determination assays performed by IHC methods according to the local institution
standard protocol.

- Standard chemotherapy/trastuzumab declined by patient OR patient is deemed by
physician for any reason to not be a candidate for standard therapy (i.e. patient
and/or provider choose not to pursue standard trastuzumab-based chemotherapy regimen
because of concerns related to toxicity or provider/patient preference).

- For patients with bilateral or multifocal/multicentric breast cancers, one of the
following criteria must be met to enroll: (1) each cancer individually meets criteria
for enrollment (only ONE tumor has to undergo central confirmation for HER2), OR (2)
at least one tumor meets eligibility (per tumor size/nodes/subtype outlined above) and
the other foci in the ipsilateral or contralateral breast are also HER2-positive but
are too small for enrollment (e.g., a patient is eligible if a cancer is T2N0 and
HER2-positive in one breast, but the contralateral breast has a T1a HER2+ cancer that
isn't eligible on its own, OR, (3) at least one tumor meets eligibility and the other
foci in the ipsilateral or contralateral breast are HER2-negative and do not meet
criteria for adjuvant chemotherapy per provider discretion (e.g. if a patient has a
HER2-positive tumor meeting eligibility but also has a second, HER2-negative, small,
node-negative, ER+, low grade cancer present, she is still eligible for enrollment).
However, in the specific case that a second breast cancer is stage III and
HER2-negative, that patient is excluded (because the second cancer is high-risk and
likely will require non-HER2-directed therapy).

- All tumor removed by either a modified radical mastectomy or a segmental mastectomy
(lumpectomy).

- NOTE: Management of axillary lymph nodes is up to the treating provider; however, all
surgical 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.

-≤90 days from the patient's most recent breast surgery for this breast cancer.

- ECOG Performance Status (PS) 0-2. See Appendix F.

- Baseline ejection fraction ≥50% by MUGA scan or echocardiogram performed ≤60 days
prior to registration.

- The following laboratory values obtained ≤14 days prior to registration:

- Absolute neutrophil count (ANC) ≥1500/mm3

- Platelet count ≥100,000/mm3

- Hemoglobin >9.0 g/dL

- Total bilirubin ≤1.5 x upper limit of normal (ULN). If patient has known
Gilbert's syndrome, direct bilirubin ≤2.0 x ULN.

- AST and ALT ≤2.5 x ULN, alkaline phosphatase ≤2.5 x ULN

- INR <1.5 x ULN for institution unless patient is on planned therapy with
anticoagulants (i.e., warfarin) with higher target planned. In those cases, INR
up to 3.5 is acceptable.

- PTT <1.5 x ULN for institution unless patient is on planned therapy with heparin
or heparin-like products

- Life expectancy >5 years per provider's assessment

- Willing to employ adequate and appropriate birth control if applicable

- NOTE: This study is for patients aged 60 and older, and most female patients will have
entered menopause by this time; however patients should not become pregnant while on
this study because T-DM1 can affect an unborn baby. Pre-menopausal women need to use
birth control while on this study and women should not breastfeed a baby while on this
study. Any man treated on this study will also need to use contraception if his
partner is a premenopausal female. Patients should check with their health care
provider about what kind of birth control methods to use and how long to use them.

- Negative urine or serum pregnancy test done ≤7 days prior to registration, for women
of childbearing potential only

- NOTE: In the rare case that a woman enrolling on study is of childbearing potential, a
pregnancy test is required prior to enrollment on study.

- Able to provide informed written consent.

- Willing to return to consenting institution for follow-up at 6 months

- Willing to provide blood samples for mandatory correlative research purposes.

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Evidence of metastatic disease.

- Patients will not require baseline staging PET or CT chest, abdomen, pelvis or bone
scan to rule out metastatic disease prior to enrollment. Any staging scans will be
ordered at the treating provider's discretion. If metastatic disease is found on any
staging studies done, patients will not be eligible for enrollment.

- Locally advanced tumors at diagnosis (T4), including tumors fixed to the chest wall,
peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse
brawny cutaneous induration with an erysipeloid).

- Patients with stage III, HER2-negative cancer in the contralateral breast (see 3.1.6
above).

- Positive Hepatitis B (Hepatitis B surface antigen and antibody) and/or Hepatitis C
(Hepatitis C antibody test) as indicated by serologies conducted ≤3 months prior to
registration if liver function tests are outside of the normal institutional range.

- NOTE: Patients with positive Hepatitis B or C serologies indicating active infection
without known active disease must meet the eligibility requirements for ALT, AST,
total bilirubin, INR, PTT, and alkaline phosphatase on at least two consecutive
occasions, separated by at least 1 week. Patients with laboratory evidence of
vaccination to Hepatitis B (e.g., positive antibodies) are eligible.

- Active liver disease, for example, due to autoimmune hepatic disorder, or sclerosing
cholangitis.

- Significant, active cardiopulmonary dysfunction as indicated by MUGA or echocardiogram
performed ≤60 days prior to registration and/or by presence of any of the following:

- History of NCI CTCAE (Version 4.0) Grade ≥3 symptomatic congestive heart failure
(CHF) or NYHA criteria Class ≥ II

- Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not
controlled by adequate medication, severe conduction abnormality, or clinically
significant valvular disease

- High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate >
100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or
higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 [Mobitz
2] or third degree AV-block])

- Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction,
cardiac arrhythmia, or cardiac ischemia

- Myocardial infarction within 12 months prior to registration

- Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure >100 mmHg)

- Evidence of transmural infarction on ECG

- Requirement for oxygen therapy

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.

- Currently receiving any other investigational agent which would be considered as a
treatment for the primary neoplasm.

- Concurrent second malignancy or past malignancy with >30% estimated risk of relapse in
next 5 years. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the
cervix. -NOTE: If there is a history or prior malignancy, patient must not be
receiving active treatment for this malignancy cancer.

- Any prior treatment with T-DM1 or any trastuzumab therapy.

- Any neoadjuvant chemotherapy for this breast cancer.

->4 weeks of tamoxifen therapy, or other hormonal therapy, for adjuvant therapy for
this malignancy

- NOTE: If the patient has received <4 weeks of such therapy but is still receiving it
at the time of entry into the study, patient must temporarily stop the therapy. The
therapy can re-start only after 12 weeks of T-DM1 has been administered.

- History of exposure at any time to the following cumulative doses of anthracyclines:

- Doxorubicin or liposomal doxorubicin >500mg/m2.

- Epirubicin >900mg/m2.

- Mitoxantrone >120 mg/m2.

- Another anthracycline, or more than one anthracycline used in a cumulative dose
exceeding the equivalent of doxorubicin 500mg/m2.

- History of intolerance (including Grade 3 or 4 infusion reactions) to murine proteins.

- History of previous invasive breast cancer ≤5 years.

- NOTE: History of DCIS, LCIS is allowed.