ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed HER2-positivedisease by local pathology, defined as immunohistochemistry (IHC) 3+ oramplification by FISH (HER2/CEP17 ratio ≥2 or an average of ≥6 HER2 gene copies pernucleus) AND confirmed by Central Pathology Review (Dr. Deborah Dillon at Brighamand Women's Hospital, Boston, MA) prior to patient being registered to beginprotocol 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 breastcancer with the following criteria met:

• If node-negative or if node status unknown (because it was not assessed), tumor mustbe >5 mm of any hormone receptor subtype (document ER/PR status: if some ER/PRstaining 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 (seebelow for further details on defining node-negative disease) Definition ofnode-negative disease (when node status known): If the patient has had a negativesentinel node biopsy and/or a negative axillary dissection, then the patient isdetermined 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 lymphnode with tumor clusters between 0.02 and 0.2cm is considered a micrometastasis.Patients with a micrometastasis are eligible even if their tumor is </= 5mm. Anaxillary dissection is not required to be performed in patients with a positivesentinel 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 tointerpretation, the principal investigator will make the final determination as toeligibility. In these special situations, the investigator must document thisapproval in the patient medical record.

• ER/PR determination assays performed by IHC methods according to the localinstitution standard protocol.

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

• For patients with bilateral or multifocal/multicentric breast cancers, one of thefollowing criteria must be met to enroll: (1) each cancer individually meetscriteria for enrollment (only ONE tumor has to undergo central confirmation forHER2), (2) at least one tumor meets eligibility (per tumor size/nodes/subtypeoutlined above) and the other foci in the ipsilateral or contralateral breast arealso HER2-positive but are too small for enrollment (e.g., a patient is eligible ifa cancer is T2N0 and HER2-positive in one breast, but the contralateral breast has aT1a HER2+ cancer that isn't eligible on its own, (3) there is at least onequalifying tumor of >5mm but there are other small foci of disease that are toosmall to test for ER/PR/HER2 and are felt to be a part of the same tumor or similartumor, OR (4) at least one tumor meets eligibility and the other foci in theipsilateral or contralateral breast are HER2-negative and do not meet criteria foradjuvant chemotherapy per provider discretion (e.g. if a patient has a HER2-positivetumor 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 andHER2-negative, that patient is excluded (because the second cancer is high-risk andlikely 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 onink). The local pathologist must document negative margins of resection in thepathology report. If all other margins are clear, a positive posterior (deep) marginis permitted, provided the surgeon documents that the excision was performed down tothe pectoral fascia and all tumor has been removed. Likewise, if all other marginsare clear, a positive anterior (superficial; abutting skin) margin is permittedprovided the surgeon documents that all tumor has been removed.

-≤90 days from the patient's most recent breast surgery for this breast cancer.Note: In cases where registration will occur >90 days from surgery but within anacceptable time frame, patient may be eligible for enrollment with approval from thePI, Rachel Freedman MD, MPH.

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

• Baseline ejection fraction ≥50% by MUGA scan or echocardiogram performed ≤60 daysprior 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 knownGilbert's syndrome, the suggested threshold for treatment is a total bilirubin ≤2.0 x ULN, but will be left to the treating providers discretion.

• 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 withanticoagulants (i.e., warfarin) with higher target planned. In those cases, INRup to 3.5 is acceptable.

• PTT <1.5 x ULN for institution unless patient is on planned therapy withheparin or heparin-like products Note: In the case of longstanding ethnicneutropenia, patient may be eligible for enrollment with approval from the PI,Rachel Freedman MD, MPH.

• 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 willhave entered menopause by this time; however patients should not become pregnantwhile on this study because T-DM1 can affect an unborn baby. Pre-menopausal womenneed to use birth control while on this study and women should not breastfeed a babywhile on this study. Any man treated on this study will also need to usecontraception if his partner is a premenopausal female. Patients should check withtheir health care provider about what kind of birth control methods to use and howlong to use them.

• Negative urine or serum pregnancy test done ≤7 days prior to registration, for womenof 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 consentdocument

Exclusion Criteria:

• Evidence of metastatic disease.

• Patients will not require baseline staging PET or CT chest, abdomen, pelvis or bonescan to rule out metastatic disease prior to enrollment. Any staging scans will beordered at the treating provider's discretion. If metastatic disease is found on anystaging 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 (diffusebrawny cutaneous induration with an erysipeloid).

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

• 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 toregistration if liver function tests are outside of the normal institutional range.

NOTE: A hepatitis panel is required of all participants as part of screening. 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 sclerosingcholangitis.

• Significant, active cardiopulmonary dysfunction (i.e. uncontrolled heart issues)asindicated by MUGA or echocardiogram performed ≤60 days prior to registration and/orby presence of any of the following:

• History of NCI CTCAE (Version 4.0) Grade ≥3 symptomatic congestive heartfailure (CHF) or NYHA criteria Class ≥ II

• Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmianot controlled by adequate medication, severe conduction abnormality, orclinically significant valvular disease

• High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia [ventriculartachycardia], or higher-grade atrioventricular [AV]-block [second degreeAV-block Type 2 [Mobitz 2] or third degree AV-block]); if adequately and safelytreated, patient may be eligible.

• 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 diastolicblood pressure >100 mmHg)

• Evidence of transmural infarction on ECG

• Requirement for oxygen therapy

• Co-morbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection or psychiatric illness/social situations that would limit compliance withstudy requirements.

• Currently receiving any other investigational agent which would be considered as atreatment for the primary neoplasm.

• Concurrent second malignancy or past malignancy with >30% estimated risk of relapsein next 5 years. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of thecervix in addition to smoldering pre-malignant or malignant conditions withminimized concern for clinical progression during treatment such as MGUS or CLL,based on treating provider's assessment. -NOTE: If there is a history or priormalignancy, patient must not be receiving active treatment for this malignancycancer.

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

• Any neoadjuvant chemotherapy for this breast cancer.

->90 days of tamoxifen therapy, or other hormonal therapy, for adjuvant therapy forthis malignancy

• NOTE: If the patient has received <90 days of such therapy but is still receiving itat the time of entry into the study, patient must temporarily stop the therapy priorto Cycle 1 Day 1. The therapy can re-start only after 6 weeks of T-DM1 have beenadministered (anytime after C3D1).

• 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 doseexceeding the equivalent of doxorubicin 500mg/m2.

• History of intolerance (including Grade 3 or 4 infusion reactions) to murineproteins.

• History of previous invasive breast cancer ≤5 years.

• NOTE: History of DCIS, LCIS is allowed.