T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer the CompassHER2 RD Trial

  • End date
    May 17, 2035
  • participants needed
  • sponsor
    Alliance for Clinical Trials in Oncology
Updated on 17 October 2021


This phase III trial studies how well trastuzumab emtansine (T-DM1) and tucatinib work in preventing breast cancer from coming back (relapsing) in patients with high risk, HER2 positive breast cancer. T-DM1 is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors, and delivers DM1 to kill them. Tucatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving T-DM1 and tucatinib may work better in preventing breast cancer from relapsing in patients with HER2 positive breast cancer compared to T-DM1 alone.



I. To determine if the invasive disease-free survival (iDFS) with T-DM1 and tucatinib is superior to the iDFS in the control arm (T-DM1 + placebo) when administered to high risk patients with HER2-positive breast cancer and residual disease after neoadjuvant HER2-directed therapy.


I. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus placebo) improves the following:

Ia. Breast cancer free survival (BCFS). Ib. Distant recurrence-free survival (DRFS). Ic. Brain metastases-free survival (BMFS). Id. Overall survival (OS). II. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus placebo) reduces the incidence of brain metastases.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive T-DM1 intravenously (IV) over 30-90 minutes on day 1 and placebo orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 6 months for 10 years.

Condition HER2 Positive Breast Cancer, Invasive Breast Carcinoma, Invasive Breast Cancer, HER2 Positive Breast Carcinoma, Multifocal Breast Carcinoma, Synchronous Bilateral Breast Carcinoma, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, multifocal breast cancer, her2/neu-positive breast cancer, her2-positive breast cancer
Treatment questionnaire administration, quality-of-life assessment, Trastuzumab Emtansine, Placebo Administration, Tucatinib
Clinical Study IdentifierNCT04457596
SponsorAlliance for Clinical Trials in Oncology
Last Modified on17 October 2021


Yes No Not Sure

Inclusion Criteria

HER2-positive status will be based on pretreatment biopsy material and defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) according to current American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines. Central testing is not required
Known hormone receptor (HR) status as defined by ASCO/CAP guidelines. Hormone receptor positive status can be determined by either known positive estrogen receptor (ER) or known positive progesterone receptor (PR) status; hormone receptor negative status must be determined by both known negative ER and known negative PR
Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or lymph nodes per the surgical pathology report are eligible; however, patients with HR+ HER2+ cancers must have node-positive residual disease per the surgical pathology report in order to qualify for the study. The presence of residual invasive disease in the breast is not mandatory for these patients. Note: The presence of micrometastases in lymph nodes after preoperative therapy counts as residual disease, whereas the presence of isolated tumor cells does not
Patients with synchronous bilateral invasive disease are eligible provided both lesions were confirmed to be HER2-positive, and at least one of the lesions meets the criteria outlined above. Multifocal disease is allowed, as long as the largest biopsied breast tumor was HER2-positive
Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0 tumors are not eligible)
Patients must have received neoadjuvant chemotherapy with one of the following regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin (TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P)); docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P)); fluorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FAC-TH(P)), or fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)). Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is acceptable
Patients may have received =< 1 cycle of T-DM1 in the adjuvant setting. Note: These patients will be randomized to receive a further 14 cycles of T-DM1 and tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been administered =< 5 weeks prior to registration
N.B: Both of the following two criteria need to be met for the patient to be eligible for this study
An interval of no more than 12 weeks between the completion date of the last definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither given, breast surgical date) and the date of registration
Patients must be registered on study within =< 180 days of the date of the most recent definitive breast cancer surgery (not including reconstructive surgery)
All systemic chemotherapy should have been completed preoperatively unless participating in EA1181 (CompassHER2 pathologic complete response [pCR])
Toxicities related to prior systemic treatment should have resolved or be at baseline, apart from alopecia and peripheral neuropathy =< grade 1
Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as follows
Breast surgery: total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision
For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection
Lymph node surgery The axilla needs to be evaluated with either sentinel node biopsy or axillary lymph node dissection. If patients have a sentinel lymph node biopsy and sentinel nodes are negative, no further axillary treatment is necessary. If patients have isolated tumor cells (ITCs) in the setting of residual breast disease, at least one of the following is required: axillary lymph node dissection (ALND) or planned nodal irradiation. If patients have micro- or macro-metastatic nodal disease, an ALND is required
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Absolute neutrophil count (ANC) >= 1,000/mm^3
Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted to achieve eligibility)
Platelet count >= 100,000/mm^3
Creatinine =< 1.5 x upper limit of normal (ULN)
Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin within the institutional normal range for patients with Gilbert's syndrome
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55% after completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated once up to 3 weeks following the initial screening assessment to assess eligibility

Exclusion Criteria

Prior receipt of T-DM1 in the neoadjuvant setting is not allowed
Systemic therapy must have consisted of at least 9 weeks of preoperative taxane and trastuzumab (or Food and Drug Administration [FDA]-approved biosimilar) with or without pertuzumab. Patients who have received at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also eligible. Note: Patients who complete at least nine of a planned twelve doses of weekly paclitaxel, or three of a planned four doses of docetaxel, but discontinue prematurely due to toxicity (i.e. peripheral neuropathy =< grade 1) are eligible. Patients receiving dose-dense chemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane) instead of paclitaxel or docetaxel is permitted. Prior use of subcutaneous trastuzumab (Hylecta) is also allowed
Patients who received neoadjuvant systemic therapy which included experimental HER2-targeted therapy/therapies are potentially eligible, as long as the investigational agent was not a HER2-targeted antibody-drug conjugate (e.g. T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib)
No adjuvant treatment with any anti-cancer investigational drug within 28 days prior to registration
Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum pregnancy test done =< 7 days prior to registration is required
Patients with known active and/or untreated hepatitis B or hepatitis C or chronic liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has been treated and cleared and normal liver function are eligible to participate in the study if the other eligibility parameters are met
Stage IV (metastatic) breast cancer
History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of registration
Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the surgical pathology report
Evidence of recurrent disease following preoperative therapy and surgery
Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation)
History of exposure to the following cumulative doses of anthracyclines: doxorubicin > 240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2. For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2
Cardiopulmonary dysfunction as defined by any of the following
History of National Cancer Institute (NCI) CTCAE version (v) 5.0 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 block (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 while or since receiving preoperative therapy
History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with prior trastuzumab treatment (e.g., during preoperative therapy)
Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg)
Current severe, uncontrolled systemic disease
Major surgical procedure unrelated to breast cancer or significant traumatic injury within 28 days prior to registration or anticipation of the need for major surgery during the course of study treatment
History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product
Peripheral neuropathy of any etiology that exceeds grade 1
Assessment by the investigator as being unable or unwilling to comply with the requirements of the protocol
Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to registration is prohibited. Please note that use of sensitive CYP3A substrates should be avoided two weeks before registration and during study treatment. Additionally, CYP3A4 or CYP2C8 inducers are prohibited as concomitant medications within 5 days following discontinuation of tucatinib treatment
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