Protocol # :
Anatomic Stage IA Breast Cancer AJCC v8
Anatomic Stage II Breast Cancer AJCC v8
Anatomic Stage IIA Breast Cancer AJCC v8
Anatomic Stage IIB Breast Cancer AJCC v8
Anatomic Stage III Breast Cancer AJCC v8
Anatomic Stage IIIA Breast Cancer AJCC v8
Anatomic Stage IIIB Breast Cancer AJCC v8
Anatomic Stage IIIC Breast Cancer AJCC v8
HER2 Positive Breast Carcinoma
Invasive Breast Carcinoma
Multifocal Breast Carcinoma
Prognostic Stage I Breast Cancer AJCC v8
Prognostic Stage IA Breast Cancer AJCC v8
Prognostic Stage IB Breast Cancer AJCC v8
Prognostic Stage II Breast Cancer AJCC v8
Prognostic Stage IIA Breast Cancer AJCC v8
Prognostic Stage IIB Breast Cancer AJCC v8
Prognostic Stage III Breast Cancer AJCC v8
Prognostic Stage IIIA Breast Cancer AJCC v8
Prognostic Stage IIIB Breast Cancer AJCC v8
Prognostic Stage IIIC Breast Cancer AJCC v8
Synchronous Bilateral Breast Carcinoma
Disease Sites
Principal Investigator
Waks, Adrienne
Site Research Nurses
Brule, Maurice, N.
Campbell, Margaret
Caradonna, Lisa
Cung, Connie
Fleming, Norah, Michelle
Freeman, Stefani, Danielle
Gentile, Alissa
Hixon, Nicole, R.
Houghton, Nicole
Jeon, Maryangel, H.
Kasparian, Elizabeth
Kosinski, Michelle
Loeser, Wendy
Macauley, Colleen
Patel, Nikita
Piper, Audrey, L.
Roche, Kathleen, A.
Rutter, Morgan
Sheehan, Susan

Trial Description

This phase III trial studies how well trastuzumab emtansine (T-DM1) and tucatinib work in
preventing breast cancer from coming back (relapsing) in patients with high risk, HER2
positive breast cancer. T-DM1 is a monoclonal antibody, called trastuzumab, linked to a
chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches
to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors,
and delivers DM1 to kill them. Tucatinib may stop the growth of tumor cells by blocking some
of the enzymes needed for cell growth. Giving T-DM1 and tucatinib may work better in
preventing breast cancer from relapsing in patients with HER2 positive breast cancer compared
to T-DM1 alone.

Eligibility Requirements

Inclusion Criteria:

- HER2-positive status will be based on pretreatment biopsy material and defined as an
immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH)
according to current American Society of Clinical Oncology (ASCO) College of American
Pathologists (CAP) guidelines. Central testing is not required

* Known hormone receptor (HR) status as defined by ASCO/CAP guidelines (based on
pretreatment biopsy material). Hormone receptor positive status can be determined by
either known positive estrogen receptor (ER) or known positive progesterone receptor
(PR) status; hormone receptor negative status must be determined by both known
negative ER and known negative PR

- Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive
disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0
tumors are not eligible at initial breast cancer diagnosis are not eligible)

- Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or
lymph nodes per the surgical pathology report are eligible; however, patients with HR+
HER2+ cancers must have node-positive residual disease per the surgical pathology
report in order to qualify for the study. The presence of residual invasive disease in
the breast is not mandatory for these patients

- Patients with weakly ER-positive (1-10%) breast cancer (based on the pretreatment core
biopsy) are eligible even if they have node-negative disease per the surgical
pathology report

- The residual disease tissue (breast and/or lymph nodes) is not required to be
HER2-positive, as eligibility for NCI-2020-03770 (A011801) is based on a positive HER2
status at the time of the initial breast cancer diagnosis

* Note: The presence of micrometastases in lymph nodes after preoperative therapy
counts as residual disease, whereas the presence of isolated tumor cells does not

- Patients with synchronous bilateral invasive disease are eligible provided both
lesions were confirmed to be HER2-positive, and at least one of the lesions meets the
criteria outlined above. Multifocal disease is allowed, as long as the largest
biopsied breast tumor was HER2-positive

- Patients must have received neoadjuvant chemotherapy with one of the following
regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin
(TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P));
docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P));
(FAC-TH(P)), or
fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)).
Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is

- Prior receipt of T-DM1 in the neoadjuvant setting is not allowed.

- Prior treatment must have consisted of >= 6 cycles of chemotherapy and
HER2-directed therapy, with a total duration of >= 12 weeks, including at least 9
weeks of preoperative taxane and trastuzumab with or without pertuzumab (or Food
and Drug Administration [FDA]-approved biosimilars). Patients who have received
at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also
eligible if they received >= 6 cycles of systemic therapy prior to enrollment.
Note: Patients who complete at least nine of a planned twelve doses of weekly
paclitaxel, or three of a planned four doses of docetaxel, but discontinue
prematurely due to toxicity are eligible. Patients receiving dose-dense
chemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane)
instead of paclitaxel or docetaxel is permitted. Prior use of subcutaneous
trastuzumab (Hylecta) and subcutaneous trastuzumab and pertuzumab (Phesgo) is
also allowed.

- Patients who received neoadjuvant systemic therapy which included experimental
HER2-targeted therapy/therapies are potentially eligible, as long as the
investigational agent was not a HER2-targeted antibody-drug conjugate (e.g.
T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase
inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib).

- Patients may have received =< 1 cycles of T-DM1 in the adjuvant setting. Note: These
patients will be randomized to receive a further 14 cycles of T-DM1 and
tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been
administered =< 5 weeks prior to registration

* Note: Both of the following two criteria need to be met for the patient to be
eligible for this study

- An interval of no more than 12 weeks between the completion date of the last
definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither
given, breast surgical date) and the date of registration. Concurrent radiation
therapy is permitted while receiving study treatment

- Patients must be registered on study within =< 180 days of the date of the most
recent definitive breast cancer surgery (not including reconstructive surgery)

- All systemic chemotherapy should have been completed preoperatively unless
participating in EA1181 (CompassHER2 pathologic complete response [pCR]) or the BIG
DECRESCENDO Trial (which is very similar to CompassHER2 pCR in terms of study design,
drugs, and eligibility). However, patients who received 4 cycles of neoadjuvant THP
off study can receive a further 2-4 cycles of chemotherapy postoperatively to meet
eligibility for A011801. Patients who participated in EA1181 or MA41 and proceeded to
surgery immediately after the de-escalated trial regimen must receive postoperative
chemotherapy to complete a total of >= 6 cycles of systemic treatment prior to
enrollment on A011801, as outlined above (e.g. 4 cycles pre-operatively, and 2 cycles
post-operatively). The postoperative chemotherapy regimen prescribed is at the
discretion of the treating oncologist (i.e. 2-4 cycles AC or THP, other). Continuation
of trastuzumab + pertuzumab (HP) pre- or post-operatively as maintenance therapy
(while awaiting a surgical date or an official pathology report) is allowed for all
study participants

- Toxicities related to prior systemic treatment should have resolved or be at baseline,
apart from alopecia and peripheral neuropathy =< grade 1

- Adequate excision: surgical removal of all clinically evident disease in the breast
and lymph nodes as follows:

- Breast surgery: total mastectomy with no gross residual disease at the margin of
resection, or breast-conserving surgery with histologically negative margins of

- For patients who undergo breast-conserving surgery, the margins of the resected
specimen must be histologically free of invasive tumor and ductal carcinoma in
situ (DCIS) as determined by the local pathologist. If pathologic examination
demonstrates tumor at the line of resection, additional operative procedures may
be performed to obtain clear margins. If tumor is still present at the resected
margin after re-excision(s), the patient must undergo total mastectomy to be
eligible. Patients with margins positive for classic lobular carcinoma in situ
(LCIS) are eligible without additional resection

- Lymph node surgery ** The axilla needs to be evaluated with either sentinel node
biopsy or axillary lymph node dissection. If patients have a sentinel lymph node
biopsy and sentinel nodes are negative, no further axillary treatment is
necessary. If patients have isolated tumor cells (ITCs) in the setting of
residual breast disease, at least one of the following is required: axillary
lymph node dissection (ALND) or planned nodal irradiation. If patients have
micro- or macro-metastatic nodal disease, ALND and planned nodal irradiation are
required. Of note, co-enrollment on Alliance A011202 is not allowed

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

- Absolute neutrophil count (ANC) >= 1,000/mm^3

- Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted
to achieve eligibility)

- Platelet count >= 100,000/mm^3

- Creatinine =< 1.5 x upper limit of normal (ULN)

- Total bilirubin =< 1.0 x upper limit of normal (ULN) or direct bilirubin within the
institutional normal range for patients with Gilbert's syndrome

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN)

- Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or
multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no
decrease in LVEF by more than 15% absolute percentage points from the pre-chemotherapy
LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55%
after completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated
once up to 3 weeks following the initial screening assessment to assess eligibility

Exclusion Criteria:

- No adjuvant treatment with any anti-cancer investigational drug within 28 days prior
to registration

- Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing
potential only, a negative serum pregnancy test done =< 7 days prior to registration
is required

- Patients with known active and/or untreated hepatitis B or hepatitis C or chronic
liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has
been treated and cleared and normal liver function are eligible to participate in the
study if the other eligibility parameters are met

- Stage IV (metastatic) breast cancer

- History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of

- Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the
surgical pathology report

- Evidence of recurrent disease following preoperative therapy and surgery

- Patients for whom radiotherapy would be recommended for breast cancer treatment but
for whom it is contraindicated because of medical reasons (e.g., connective tissue
disorder or prior ipsilateral breast radiation)

- History of exposure to the following cumulative doses of anthracyclines: doxorubicin >
240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2.
For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2

- Cardiopulmonary dysfunction as defined by any of the following:

- History of National Cancer Institute (NCI) CTCAE version (v) 5.0 grade >= 3
symptomatic congestive heart failure (CHF) or New York Heart Association (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 block (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 while or since receiving preoperative

- History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with
prior trastuzumab treatment (e.g., during preoperative therapy)

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

- Current severe, uncontrolled systemic disease

- Major surgical procedure unrelated to breast cancer or significant traumatic injury
within 28 days prior to registration or anticipation of the need for major surgery
during the course of study treatment

- History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity
to trastuzumab or murine proteins or any components of the product

- Peripheral neuropathy of any etiology that exceeds grade 1

- Assessment by the investigator as being unable or unwilling to comply with the
requirements of the protocol

- Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4
or CYP2C8 inducer within 5 days prior to registration is prohibited.

- Please note that use of sensitive CYP3A substrates should be avoided two weeks
before registration and during study treatment. Additionally, CYP3A4 or CYP2C8
inducers are prohibited as concomitant medications within 5 days following
discontinuation of tucatinib treatment. Patients who require medications that are
known to be sensitive substrates of CYP3A4 with a narrow therapeutic window
should be excluded.