ATOP TRIAL: Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

Protocol # :
Breast Cancer
Disease Sites
Principal Investigator
Freedman, Rachel, A
Site Investigator
Block, Caroline
Briccetti, Frederick
Chi, Dorcas
Faggen, Meredith, G.
Giordano, Sara
Sinclair, Natalie, F.
Spring, Laura
Walsh, Jeanna
Site Research Nurses
Abraham, Elizabeth
Aspessi, Michael, William
Beeler, Maureen
Bowers, Jordan
Caradonna, Lisa
Caradonna, Lisa
Carrier, Amy
Cronis, Charles, Lewis
Freeman, Stefani, Danielle
Habin, Karleen, R.
Hennessy, Kerry
Hixon, Nicole, R.
Huff, Kimberly
Jeon, Maryangel, H.
Kasparian, Elizabeth
Lehnus, Jaclyn
Loeser, Wendy
Loeser, Wendy
Lundquist, Debra
Marchetti, Kelly
O'Neil, Kelly
Orechia, Meghan
Padden, Sarah
Pasquale, Kathryn, Mary
Roche, Kathleen, A.
Rutter, Morgan
Shellock, Maria
Weitz, MaryAnn

Trial Description

This research study is studying an investigational drug as a possible treatment for breast
cancer that is positive for the protein Human Epidermal Growth Factor Receptor 2, also known
as HER2-positive breast cancer.

The drug involved in this study is:

-ado-trastuzumab emtansine (T-DM1)

Eligibility Requirements

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

- 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 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), (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, (3) there is at least one qualifying tumor of >5mm but
there are other small foci of disease that are too small to test for ER/PR/HER2 and
are felt to be a part of the same tumor or similar tumor, OR (4) 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

- 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. Note:
In cases where registration will occur >90 days from surgery but within an acceptable
time frame, patient may be eligible for enrollment with approval from the PI, Rachel
Freedman MD, MPH.

- 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, 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 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 Note: In the case of longstanding ethnic neutropenia,
patient may be eligible for enrollment with approval from the PI, Rachel Freedman

- 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

- 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: 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 sclerosing

- Significant, active cardiopulmonary dysfunction (i.e. uncontrolled heart issues)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]); if adequately and safely treated, patient may be

- 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
in addition to smoldering pre-malignant or malignant conditions with minimized concern
for clinical progression during treatment such as MGUS or CLL, based on treating
provider's assessment. -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.

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

- NOTE: If the patient has received <90 days of such therapy but is still receiving it
at the time of entry into the study, patient must temporarily stop the therapy prior
to Cycle 1 Day 1. The therapy can re-start only after 6 weeks of T-DM1 have been
administered (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 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.