Trastuzumab Emtansine Followed by Trastuzumab versus Paclitaxel in Combination with Trastuzumab for the Treatment of HER2-Positive Stage I Breast Cancer, ATEMPT 2.0 Trial
This phase II trial studies the effects of trastuzumab emtansine followed by trastuzumab versus paclitaxel with trastuzumab in treating patients with HER2-positive stage I breast cancer. Trastuzumab emtansine is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug called emtansine. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers emtansine to kill them. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab is a monoclonal antibody, which are disease-fighting proteins made by cloned immune cells. Giving trastuzumab emtansine followed by trastuzumab may have less side-effects than traditional HER2-positive breast cancer treatment of trastuzumab and paclitaxel.
Inclusion Criteria
- Patients must have HER2-positive stage I histologically confirmed invasive carcinoma of the breast. Patients must have node-negative (N0) or micrometastases (N1mic) breast cancer according to the American Joint Committee on Cancer (AJCC) 8th edition anatomic staging table * If the patient has had a negative sentinel node biopsy, then no further axillary dissection is required, and the patient is determined to be node-negative. If an axillary dissection without sentinel lymph node biopsy is performed to determine nodal status, at least six axillary lymph nodes must be removed and analyzed, and determined to be negative, for the patient to be considered node-negative. Axillary nodes with single cells or tumor clusters =< 0.2 mm by either hematoxylin and eosin (H&E) or immunohistochemistry (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 micrometastasis found by sentinel node evaluation. 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. The investigator must document approval in the patient medical record * Patients who have an area of a T1aN0, ER+ (defined as > 10%), HER2-negative cancer in addition to their primary HER2-positive tumor are eligible
- HER2-positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2018 guidelines, confirmed by central testing. * NOTE: HER-2 status must be confirmed to be positive by central review by NeoGenomics prior to patient starting protocol therapy. Patients previously having had HER2 immunohistochemical testing by NeoGenomics do not need to undergo retesting for central confirmation of HER2 status * NOTE: Ductal carcinoma in situ (DCIS) components will not be counted in the determination of HER2 status
- Estrogen receptor (ER)/progesterone receptor (PR) determination is required. ER and PR assays should be performed by immunohistochemical methods according to the local institution standard protocol
- Bilateral breast cancers that individually meet eligibility criteria are allowed
- Patients with multifocal or multicentric disease are eligible, as long as each tumor individually meets eligibility criteria. Central confirmation is needed for any site of disease that is tested to be HER2-positive by local testing (unless testing was previously done by NeoGenomics)
- Patients with a history of ipsilateral DCIS are eligible if they were treated with wide excision alone, without radiation therapy, or treated with a mastectomy for this current breast cancer. Patients with a history of contralateral DCIS are not eligible
- =< 90 days between the planned treatment start date and the patient’s most recent breast surgery for this breast cancer
- >= 18 years of age with any menopausal status
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy (lumpectomy), with either a sentinel node biopsy or axillary dissection * All 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
- Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy. Radiation to the conserved breast is required
- Patients may have received up to 4 weeks of tamoxifen therapy, or other hormonal therapy, for adjuvant therapy for this cancer. Patients cannot receive adjuvant hormonal therapy during protocol treatment for the first 12 weeks
- Prior oophorectomy for cancer prevention is allowed
- Patients who have undergone partial or whole breast radiation (duration =< 14 days) prior to registration are eligible. Partial or whole breast radiation must be completed prior to 2 weeks before starting protocol therapy
- Patients who have participated in a window study (treatment with an investigational agent prior to surgery for =< 2 weeks) are eligible. Patients must have discontinued the investigational agent at least 14 days before participation
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Hemoglobin >= 9 g/dl
- Platelets >= 100,000/mm^3
- Total bilirubin =< 1.2 mg/dL
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x Institutional upper limit of normal (ULN)
- For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range. Serum alkaline phosphatase should be =< 1.5 x Institutional ULN
- Left ventricular ejection fraction (LVEF) >= 50%
- Premenopausal patients must have a negative serum or urine pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause
- Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of contraception or two effective forms of contraception by the patient and/or partner. Contraceptive use must be continued for the duration of the study treatment and for 7 months after the last dose of study treatment.
- Patients should have tumor tissue available, and a tissue block of sufficient size to make 15 slides, which must be sent to Dana Farber Cancer Institute (DFCI) for correlative research. If a tissue block is unavailable, sites may send one H&E-stained slide and 15 unstained sections of paraffin-embedded tissue on charged slides. Slide sections should be 4-5 microns in thickness. It is also acceptable to submit 2 cores from a block of invasive tissue using a 1.2 mm diameter coring tool. If tumor is not available, the investigator must document why tissue is not available in the patient medical record, and that efforts have been made to obtain tissue
- Willing and able to sign informed consent
- Participants that do not read and understand English are eligible to participate, but will be exempt from the patient-completed questionnaires that are only available in English
Exclusion Criteria
- Any of the following due to teratogenic potential of the study drugs: * Pregnant women * Nursing women * Women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragms, intrauterine devices [IUDs], surgical sterilization, abstinence, etc.) * Men who are unwilling to employ adequate contraception (condoms, surgical sterilization, abstinence, etc.)
- Locally advanced tumors at diagnosis, including tumors fixed to the chest wall, peau d’orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)
- Patients with a history of previous invasive breast cancer
- History of prior chemotherapy in the past 5 years
- History of paclitaxel therapy
- Patients with active liver disease, for example due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis
- Individuals with a history of a different malignancy are ineligible except for the following circumstances: * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy * Individuals with the following cancer are eligible regardless of when they were diagnosed and treated: cervical cancer in situ, and non-melanoma cancer of the skin
- Intercurrent illness including, but not limited to: ongoing or active, unresolved systemic infection, renal failure requiring dialysis, active cardiac disease, prior myocardial infarction (asymptomatic changes on electrocardiogram (EKG) suggestive of old MI is not an exclusion), history of congestive heart failure (CHF), current use of any therapy specifically for CHF, uncontrolled hypertension, significant psychiatric illness, or other conditions that in the opinion of the investigator limit compliance with study requirements
Additional locations may be listed on ClinicalTrials.gov for NCT04893109.
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PRIMARY OBJECTIVES:
I. To compare the incidence of clinically relevant toxicities (CRT) in patients with stage I HER2-positive breast cancer treated with trastuzumab emtansine followed by trastuzumab subcutaneous (SC) to the incidence in those treated with paclitaxel in combination with trastuzumab SC.
II. To evaluate disease-free survival (DFS) in patients with stage I HER2-positive breast cancer treated with trastuzumab emtansine followed by trastuzumab SC.
SECONDARY OBJECTIVES:
I. Compare the incidence of all grade 3 and 4 adverse events in patients treated with adjuvant trastuzumab emtansine followed by trastuzumab SC to the incidence in those receiving paclitaxel in combination with trastuzumab SC.
II. Compare quality of life (QOL) in patients receiving trastuzumab emtansine followed by trastuzumab SC to that experienced by patients receiving paclitaxel in combination with trastuzumab SC using Functional Assessment of Cancer Therapy-Breast (FACT-B).
III. Evaluate symptoms related to therapy in patients receiving trastuzumab emtansine followed by trastuzumab SC compared to those receiving paclitaxel in combination with trastuzumab SC using the Rotterdam Symptom Checklist (RSCL) and Patient Neurotoxicity Questionnaire (PNQ)
IV. Evaluate effects of therapy on work productivity and activity using the Work Productivity and Activity Impairment Questionnaire (WPAI-SHP) in patients receiving trastuzumab emtansine followed by trastuzumab SC compared to those receiving paclitaxel in combination with trastuzumab SC.
V. Evaluate the effects of alopecia on patients receiving paclitaxel in combination with trastuzumab SC using an alopecia questionnaire and using Patient Reported Outcome (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) alopecia.
VI. Compare incidence of sensory neuropathy, headache, arthralgia and myalgia using PRO-CTCAE criteria in patients receiving trastuzumab emtansine followed by trastuzumab SC to that experienced by patients receiving paclitaxel in combination with trastuzumab SC.
VII. Describe DFS in patient groups defined by tumor size (=< 1 cm or > 1 cm) and hormone receptor status who are treated with trastuzumab emtansine followed by trastuzumab SC.
VIII. Evaluate the incidence of grade 3-4 cardiac left ventricular dysfunction in patients treated with adjuvant trastuzumab emtansine followed by trastuzumab SC compared to those receiving paclitaxel with trastuzumab SC.
IX. Evaluate the incidence of trastuzumab-emtansine-induced grade 2-4 thrombocytopenia.
X. Investigate the percentage of patients with amenorrhea at various time points after the start of treatment in premenopausal women receiving treatment with trastuzumab emtansine followed by trastuzumab SC and paclitaxel with trastuzumab SC.
XI. Evaluate gene biomarkers predictive of trastuzumab-emtansine-induced grade 2-4 thrombocytopenia.
XII. Utilize genomic profiling to query a large panel of cancer gene mutations and gene expression in patients with stage I HER2-positive breast cancer.
XIII. Evaluate the incidence of toxicities attributed to radiation therapy when given concurrently with trastuzumab SC after receipt of either trastuzumab emtansine or paclitaxel.
XIV. Describe overall survival in patients with stage I HER2-positive breast cancer treated with trastuzumab emtansine followed by trastuzumab SC.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression of unacceptable toxicity. Beginning 12 weeks after trastuzumab emtansine, patients undergo radiation therapy. Patients then receive trastuzumab subcutaneously (SC) over 2-5 minutes on day 1. Treatment repeats every 21 days for 11 cycles in the absence of disease progression of unacceptable toxicity. Patients who discontinue trastuzumab emtansine early receive additional trastuzumab SC for up to 1 year. Patients undergo blood sample collection, breast ultrasound, mammography and multigated acquisition scan (MUGA) or echocardiography throughout study.
ARM II: Patients receive paclitaxel IV over 30-180 minutes weekly and trastuzumab SC over 2-5 minutes or IV over 3 minutes on day 1. Cycles repeat every 21 days for 4 cycles in the absence of disease progression of unacceptable toxicity. After completion of paclitaxel therapy, patients undergo radiation therapy. Patients then receive trastuzumab SC over 2-5 minutes or IV over 3 minutes on day 1. Treatment repeats every 21 days for 13 cycles in the absence of disease progression of unacceptable toxicity. Patients undergo blood sample collection, breast ultrasound, mammography and MUGA or echocardiography throughout study.
After completion of study treatment, patients are followed up every 6 months for 2 years and at progression, every 12 months for 3 years or until progression.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorSara Michell Tolaney
- Primary ID21-159
- Secondary IDsNCI-2021-06637
- ClinicalTrials.gov IDNCT04893109