Clinical Trial - NCT03587740

ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer

Recruiting

Sponsor: Dana-Farber Cancer Institute

Collaborators: Susan G. Komen Breast Cancer Foundation, Gateway for Cancer Research

Information provided by (Responsible party): Principal Investigator Dana-Farber Cancer Institute Rachel Freedman, MD, MPH Principal Investigator

ClinicalTrials.gov Identifier: NCT03587740

Protocol Info

Short Description: ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer
Long Description: ATOP TRIAL: Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer
MGH Status: Open
Sponsor: DF/HCC
Disease Program: Breast

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




Purpose

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)
Condition Title Intervention Phase
Breast Cancer T-DM1 Phase 2
Study Type Interventional
Official Title ATOP TRIAL: Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

Primary Outcome Measures

5-year invasive disease-free survival rate [Time Frame: 5 years] [Designated as safety issue: ]


Secondary Outcome Measures

Recurrence-free survival [Time Frame: 2 years] [Designated as safety issue: ]

Overall Survival [Time Frame: 2 years] [Designated as safety issue: ]

Site of first recurrence [Time Frame: 2 years] [Designated as safety issue: ]

Incidence Rate of each Toxicity (Safety) [Time Frame: 2 years] [Designated as safety issue: ]

Incidence Rate of Cardiac-Related Adverse Events (left ventricular systolic dysfunction) [Time Frame: 2 years] [Designated as safety issue: ]

Incidence Rate of Cardiac-Related Adverse Events (cardiac death) [Time Frame: 2 years] [Designated as safety issue: ]

Incidence Rate of Cardiac-Related Adverse Events (decreased ejection fraction) [Time Frame: 2 years] [Designated as safety issue: ]

Estimated Enrollment: 82
Study Start Date: August 2018
Estimated Study Completion Date: January 2025
Estimated Primary Completion Date: January 2022
Arms Assigned Interventions

Experimental:T-DM1

T-DM1 will be administered every 3 weeks intravenously, with 21 consecutive days defined as a treatment.
Drug:T-DM1
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.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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
  • 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03587740

Locations

  • United States, California
    • City of Hope Comprehensive Cancer Center Duarte, California, United States, 91010
  • United States, Connecticut
    • The Stamford Hospital Stamford, Connecticut, United States, 06904
  • United States, Maine
    • Eastern Maine Medical Center Brewer, Maine, United States, 04412
  • United States, Massachusetts
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215
    • Massachusetts General Hospital Boston, Massachusetts, United States, 02215
    • Dana-Farber Cancer Institute at St. Elizabeth's Medical Center Brighton, Massachusetts, United States, 02135
    • Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center Milford, Massachusetts, United States, 01757
    • Dana-Farber/Brigham and Women's Cancer Center in clinical affiliation with South Shore Hospital South Weymouth, Massachusetts, United States, 02190
  • United States, Minnesota
    • Mayo Clinic Rochester, Minnesota, United States, 55905
  • United States, New Hampshire
    • Dana-Farber/New Hampshire Oncology-Hematology Londonderry, New Hampshire, United States, 03053
  • United States, New York
    • Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065
  • United States, Rhode Island
    • Lifespan Cancer Institute Providence, Rhode Island, United States, 02903
  • United States, Tennessee
    • Sarah Cannon Research Institute Nashville, Tennessee, United States, 37203

Sponsors and Collaborators

Dana-Farber Cancer Institute

Susan G. Komen Breast Cancer Foundation

Gateway for Cancer Research

More Information

No publications provided

Responsible Party: Principal Investigator Dana-Farber Cancer Institute Rachel Freedman, MD, MPH Principal Investigator
ClinicalTrials.gov Identifier: NCT03587740
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Dana-Farber Cancer Institute:

Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms

Trastuzumab

Ado-trastuzumab emtansine

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019