Trastuzumab Emtansine in Treating Older Patients With Human Epidermal Growth Factor Receptor 2-Positive Stage I-III Breast Cancer

Stage IIIC Breast Cancer AJCC v7 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02414646
• Other study ID #: RU011301I
• Secondary ID: NCI-2015-00468RU
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 10, 2015
• Est. completion date: March 16, 2022

Study information

• Verified date: July 2018
• Source: Academic and Community Cancer Research United
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well trastuzumab emtansine works in treating older patients with human epidermal growth factor receptor 2 (HER2)-positive stage I-III breast cancer. HER2 is a protein found on the surface of cancer cells that helps them to grow and spread. Trastuzumab emtansine may kill cancer cells by binding to HER2-positive on the surface of the tumor cells and blocking their ability grow and spread.

Description:

PRIMARY OBJECTIVES:

I. Invasive disease-free survival (IDFS), defined as occurrence of any of the following:

ipsilateral invasive breast cancer recurrence, regional invasive breast cancer recurrence, distant recurrence, death attributable to any cause, contralateral invasive breast cancer, or second non-breast invasive cancer. Note: In-situ events are not included.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Recurrence-free survival (RFS). III. Adverse events. IV. Cardiac function/adverse events. V. Site of first recurrence.

TERTIARY OBJECTIVES:

I. The associations of adverse events and outcomes with each of the following will be examined: geriatric assessment (GA), patient reported outcomes (Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Event [PRO-CTCAE]), quality of life (QOL), and biomarkers of aging.

II. To determine whether clinician-reported CTCAEs are more accurate when PRO-CTCAE data are shared with the patient and clinician.

III. Utilize a high-throughput mutation profiling system (Oncomap) to query a large panel of cancer gene mutations in older patients with HER2-positive breast cancers.

OUTLINE:

Patients receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days for 17 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6-12 months and then yearly for 4 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 200
• Est. completion date: March 16, 2022
• Est. primary completion date: December 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

• Confirmed HER2-positive disease by local pathology, defined as immunohistochemistry (IHC) 3+ or amplification by fluorescent in situ hybridization (FISH) (HER2/chromosome 17 centromere [CEP17] ratio >= 2 or an average of >= 6 HER2 gene copies per nucleus) AND confirmed by Central Pathology Review (Mayo Clinic Rochester) prior to patient being registered to begin protocol therapy

• NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of HER2 status

• 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) of any hormone receptor subtype (document estrogen receptor/progesterone receptor [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

• 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 hematoxylin and eosin (H&E) or 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 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 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 T1b 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

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

• Baseline ejection fraction >= 50% by multi gated acquisition scan (MUGA) scan or echocardiogram performed =< 60 days prior to registration

• Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to registration

• Platelet count >= 100,000/mm^3 obtained =< 14 days prior to registration

• Hemoglobin > 9.0 g/dL obtained =< 14 days prior to registration

• Total bilirubin =< 1.5 x upper limit of normal (ULN); if patient has known Gilbert?s syndrome, direct bilirubin =< 2.0 x ULN obtained =< 14 days prior to registration

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) obtained =< 14 days prior to registration

• Alkaline phosphatase =< 2.5 x ULN obtained =< 14 days prior to registration

• International normalized ratio (INR) < 1.5 x ULN for institution unless patient is on planned therapy with anticoagulants (i.e., warfarin) with higher target planned obtained =< 14 days prior to registration; in those cases, INR up to 3.5 is acceptable

• Partial thromboplastin time (PTT) < 1.5 x ULN for institution unless patient is on planned therapy with heparin or heparin-like products obtained =< 14 days prior to registration

• Life expectancy > 5 years

• 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; 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/randomization, 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 (during the active monitoring phase of the study)

• Willing to provide blood samples for mandatory correlative research purposes

Exclusion Criteria:

• Evidence of metastatic disease

• NOTE: patients will not require baseline staging positron emission tomography (PET) or computed tomography (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

• 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 starting study if liver function tests are outside of the normal institutional range

• NOTE: patients with 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

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

• Significant cardiac disease or risk factors as indicated by MUGA or echocardiogram performed =< 60 days prior to registration and/or by presence of any of the following:

• History of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) 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 [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 randomization

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

• Evidence of transmural infarction on electrocardiogram (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 (trastuzumab emtansine) or any trastuzumab therapy

• Any neoadjuvant chemotherapy

• > 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 > 500 mg/m^2

• Epirubicin > 900 mg/m^2

• Mitoxantrone >120 mg/m^2

• Another anthracycline, or more than one anthracycline used in a cumulative dose exceeding the equivalent of doxorubicin 500 mg/m^2

• 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, lobular carcinoma in situ (LCIS) is allowed

Related Conditions & MeSH terms

• Breast Neoplasms
• Estrogen Receptor Status
• HER2 Positive Breast Carcinoma
• Progesterone Receptor Status
• Stage I Breast Cancer AJCC v7
• Stage IA Breast Cancer AJCC v7
• Stage IB Breast Cancer AJCC v7
• Stage II Breast Cancer AJCC v6 and v7
• Stage IIA Breast Cancer AJCC v6 and v7
• Stage IIB Breast Cancer AJCC v6 and v7
• Stage III Breast Cancer AJCC v7
• Stage IIIA Breast Cancer AJCC v7
• Stage IIIB Breast Cancer AJCC v7
• Stage IIIC Breast Cancer AJCC v7

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Biological:
• Trastuzumab Emtansine
Given IV

Locations

Country	Name	City	State
United States	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Columbus NCI Community Oncology Research Program	Columbus	Ohio
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	High Point Regional Hospital	High Point	North Carolina
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	FirstHealth of the Carolinas-Moore Regional Hospital	Pinehurst	North Carolina
United States	Mayo Clinic	Rochester	Minnesota
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Academic and Community Cancer Research United	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall rate of grade 3+ adverse events	Calculated using the baseline geriatric assessment measures. A score of 0 to 5 will be considered low risk, a score of 6 to 9 will be considered intermediate risk and a score of 10 to 19 will be considered high risk. A chi-square test will be done to determine if the rates of grade 3+ adverse events differ for these categories. In addition, the grade 3+ adverse event rates will be estimated for each category with a binomial estimator and corresponding 95% confidence interval and compared to the values obtained by Dr. Hurria. Occurrences of grade 3+ adverse events will be associated with geriatric assessment measurements.	Up to 12 months
Other	Change in geriatric assessment score	The average geriatric assessment score will be compared across the patient reported outcomes-Common Terminology Criteria for Adverse Events item scores using a repeated measure analysis of variance. Boxplots will be generated for each score for a particular patient reported outcomes-Common Terminology Criteria for Adverse Events item for the geriatric assessment score.	Baseline to up to 12 months
Other	Change in quality of life	The average quality of life score will be compared across the patient reported outcomes-Common Terminology Criteria for Adverse Events item scores using a repeated measure analysis of variance.	Baseline to up to 12 months
Other	Levels of inflammatory markers, coagulation, and senescence biomarkers	Boxplots will be used to summarize the biomarker values at each time point and spaghetti plots will be used to display changes in biomarker values over time for each patient. Whether each marker will be associated with grade 3+, adverse events, and disease-free survival will be determined using the appropriate model: a logistic regression model will be used for binary outcomes and cox proportional hazards model will be used for time-to-event outcomes. Changes in marker values over time will be analyzed to determine if they are associated with outcome using an appropriate linear mixed model.	Up to 12 months
Primary	Invasive disease-free survival rate	The entire invasive disease-free survival rate experience of evaluable patients will be summarized with a Kaplan-Meier curve. The 5-year invasive disease free survival landmark will be estimated from the Kaplan-Meier curve, and a 2-sided 90% confidence interval will be provided. A secondary efficacy analysis will use the log-rank test to compare the invasive disease free survival experience of this trial population with a similar population of older patients in a historical control cohort that received adjuvant chemotherapy + trastuzumab.	Up to 5 years post-treatment
Secondary	Overall survival	A Kaplan-Meier curve will be used to summarize the overall survival experience of this patient cohort.	From study enrollment to death attributable to any cause (i.e. death from breast cancer, non-breast cancer cause, or from unknown cause), assessed up to 5 years
Secondary	Recurrence-free survival	Recurrence-free survival will be summarized with a Kaplan-Meier curve.	From study enrollment to disease recurrence and will not include death as an event, assessed up to 5 years
Secondary	Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 4.0	Safety/adverse events data will be tabulated, including adverse events of all grades, in addition to cardiac dysfunction.	Up to 12 months post-treatment
Secondary	Cardiac dysfunction defined as incidence of symptomatic left ventricular systolic dysfunction, cardiac death, and incidence of decrease in ejection fraction by at least 10 percentage points below baseline or to below 50%	Safety/adverse events data will be tabulated, including adverse events of all grades, in addition to cardiac dysfunction.	Up to 12 months post-treatment
Secondary	Site of first recurrence	The site of first recurrences will be tabulated as frequencies and relative frequencies.	Up to 5 years