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ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer

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ClinicalTrials.gov Identifier: NCT03587740
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : December 4, 2018
Sponsor:
Collaborators:
Susan G. Komen Breast Cancer Foundation
Gateway for Cancer Research
Information provided by (Responsible Party):
Rachel Freedman, MD, MPH, Dana-Farber Cancer Institute

Brief Summary:

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 or disease Intervention/treatment Phase
Breast Cancer Drug: T-DM1 Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied and research doctors are trying to find out more about it—such as the safest dose to use and the side effects it may cause.

The purpose of this research study is to examine the long-term benefits of T-DM1 with regard to breast cancer and take a closer look at the side effects experienced by participants receiving T-DM1.

The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for use in patients with stage I, II, or III breast cancer, but it has been approved for use in advanced, previously treated, HER2-positive breast cancer.

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. More specifically, the trastuzumab in T-DM1 first binds to the HER2 protein on the surface of the breast cancer cells and the DM1 then enters the cells and can cause them to die, preventing tumor growth


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 82 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: ATOP TRIAL: Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer
Actual Study Start Date : August 22, 2018
Estimated Primary Completion Date : January 31, 2022
Estimated Study Completion Date : January 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
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.
Other Name: Kadcyla




Primary Outcome Measures :
  1. 5-year invasive disease-free survival rate [ Time Frame: 5 years ]
    To evaluate invasive disease-free survival (IDFS) for patient receiving T-DM1


Secondary Outcome Measures :
  1. Recurrence-free survival [ Time Frame: 2 years ]
    To evaluate recurrence-free survival (RFS) for patient receiving T-DM1, defined as the time from study enrollment to disease recurrence and will not include death as an event.

  2. Overall Survival [ Time Frame: 2 years ]
    To evaluate overall survival (OS) for patient receiving T-DM1, defined as the time from study enrollment to death attributable to any cause (i.e. death from breast cancer, non-breast cancer cause, or from unknown cause).

  3. Site of first recurrence [ Time Frame: 2 years ]
    To evaluate site of first recurrence for patient receiving T-DM1, which will be tabulated as frequencies and relative frequencies.

  4. Incidence Rate of each Toxicity (Safety) [ Time Frame: 2 years ]
    To evaluate adverse events for patient receiving T-DM1, defined as adverse events of all grades utilizing CTCAE v4

  5. Incidence Rate of Cardiac-Related Adverse Events (left ventricular systolic dysfunction) [ Time Frame: 2 years ]
    To evaluate cardiac-related adverse events for patients receiving T-DM1, defined as incidence of symptomatic left ventricular systolic dysfunction

  6. Incidence Rate of Cardiac-Related Adverse Events (cardiac death) [ Time Frame: 2 years ]
    To evaluate cardiac-related adverse events for patients receiving T-DM1, defined as incidence of cardiac death

  7. Incidence Rate of Cardiac-Related Adverse Events (decreased ejection fraction) [ Time Frame: 2 years ]
    To evaluate cardiac-related adverse events for patients receiving T-DM1, defined as decrease in ejection fraction by at least 10 percentage points below baseline or to below 50%.



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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 </= 5mm. 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03587740


Contacts
Contact: Rachel Freedman, MD 617-632-4587 rafreedman@partners.org

Locations
United States, Maine
Eastern Maine Medical Center Recruiting
Brewer, Maine, United States, 04412
Contact: Laurie Lewis    207-973-4249    llewis@northernlight.org   
Principal Investigator: Thomas Openshaw, MD         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Rachel Freedman, MD MPH    617-632-4587    rafreedman@partners.org   
Principal Investigator: Rachel Freedman, MD MPH         
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Laura Spring, MD    617-724-4000    Lspring2@partners.org   
Principal Investigator: Laura Spring, MD         
Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center Recruiting
Milford, Massachusetts, United States, 01757
Dana-Farber/Brigham and Women's Cancer Center in clinical affiliation with South Shore Hospital Recruiting
South Weymouth, Massachusetts, United States, 02190
United States, New Hampshire
Dana-Farber/New Hampshire Oncology-Hematology Recruiting
Londonderry, New Hampshire, United States, 03053
United States, New York
Memorial Sloan Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Institute Not yet recruiting
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Dana-Farber Cancer Institute
Susan G. Komen Breast Cancer Foundation
Gateway for Cancer Research
Investigators
Principal Investigator: Rachel Freedman, MD MPH Dana-Farber Cancer Institute

Responsible Party: Rachel Freedman, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03587740     History of Changes
Other Study ID Numbers: 18-124
First Posted: July 16, 2018    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rachel Freedman, MD, MPH, Dana-Farber Cancer Institute:
Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Ado-trastuzumab emtansine
Trastuzumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action