Clinical Trials /

ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer

NCT03587740

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)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer
  • 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 IDs

  • ORG STUDY ID: 18-124
  • NCT ID: NCT03587740

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
T-DM1KadcylaT-DM1

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)

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
    

Trial Arms

NameTypeDescriptionInterventions
T-DM1ExperimentalT-DM1 will be administered every 3 weeks intravenously, with 21 consecutive days defined as a treatment.
  • T-DM1

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:5-year invasive disease-free survival rate
Time Frame:5 years
Safety Issue:
Description:To evaluate invasive disease-free survival (IDFS) for patient receiving T-DM1

Secondary Outcome Measures

Measure:Recurrence-free survival
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description: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).
Measure:Site of first recurrence
Time Frame:2 years
Safety Issue:
Description:To evaluate site of first recurrence for patient receiving T-DM1, which will be tabulated as frequencies and relative frequencies.
Measure:Incidence Rate of each Toxicity (Safety)
Time Frame:2 years
Safety Issue:
Description:To evaluate adverse events for patient receiving T-DM1, defined as adverse events of all grades utilizing CTCAE v4
Measure:Incidence Rate of Cardiac-Related Adverse Events (left ventricular systolic dysfunction)
Time Frame:2 years
Safety Issue:
Description:To evaluate cardiac-related adverse events for patients receiving T-DM1, defined as incidence of symptomatic left ventricular systolic dysfunction
Measure:Incidence Rate of Cardiac-Related Adverse Events (cardiac death)
Time Frame:2 years
Safety Issue:
Description:To evaluate cardiac-related adverse events for patients receiving T-DM1, defined as incidence of cardiac death
Measure:Incidence Rate of Cardiac-Related Adverse Events (decreased ejection fraction)
Time Frame:2 years
Safety Issue:
Description: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%.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Breast Cancer

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