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

K
Kathy Miller, MD

Primary Investigator

Enrolling By Invitation
18 years and older
All
Phase 3
1031 participants needed
3 Locations

Brief description of study

This phase III trial studies how well trastuzumab emtansine (T-DM1) and tucatinib work inventing breast cancer from coming back (relapsing) in patients with high risk, HER2ve breast cancer. T-DM1 is a monoclonal antibody, called trastuzumab, linked to ahemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attachesules (receptors) on the surface of cancer cells, known as HER2 receptors,d delivers DM1 to kill them. Tucatinib may stop the growth of tumor cells by blocking somehe enzymes needed for cell growth. Giving T-DM1 and tucatinib may work better inventing breast cancer from relapsing in patients with HER2 positive breast cancer comparedT-DM1 alone.

Detailed description of study

PRIMARY OBJECTIVE:
I. To determine if the invasive disease-free survival (iDFS) with T-DM1 and tucatinib isuperior to the iDFS in the control arm (T-DM1 + placebo) when administered to high riskwith HER2-positive breast cancer and residual disease after neoadjuvant HER2-directed therapy.
SECONDARY OBJECTIVES:
I. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1(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 whetherwith tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plusbo) 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 placeboy (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 14ycles 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 diseasegression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 6 months10 years.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Anatomic Stage IA 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, 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, HER2 Positive Breast Carcinoma, Invasive Breast Carcinoma, Multifocal Breast Carcinoma, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB 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, 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, Synchronous Bilateral Breast Carcinoma
  • Age: 18 Years
  • Gender: All

Inclusion Criteria:
  • HER2-positive status will be based on pretreatment biopsy material and defined as anunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH)ding to current American Society of Clinical Oncology (ASCO) College of AmericanPathologists (CAP) guidelines. Central testing is not required
    • Known hormone receptor (HR) status as defined by ASCO/CAP guidelines (based onbiopsy material). Hormone receptor positive status can be determined byher known positive estrogen receptor (ER) or known positive progesterone receptor(PR) status; hormone receptor negative status must be determined by both knowngative ER and known negative PR
  • 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/bN0umors are not eligible at initial breast cancer diagnosis are not eligible)
  • Patients with residual HR-negative, HER2 positive (+) disease in the breast and/orymph nodes per the surgical pathology report are eligible; however, patients with HR+HER2+ cancers must have node-positive residual disease per the surgical pathologyder to qualify for the study. The presence of residual invasive disease inhe breast is not mandatory for these patients
  • Patients with weakly ER-positive (1-10%) breast cancer (based on the pretreatment corebiopsy) are eligible even if they have node-negative disease per the surgicalhology report
  • The residual disease tissue (breast and/or lymph nodes) is not required to beHER2-positive, as eligibility for NCI-2020-03770 (A011801) is based on a positive HER2us at the time of the initial breast cancer diagnosis
    • Note: The presence of micrometastases in lymph nodes after preoperative therapyunts 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 theutlined above. Multifocal disease is allowed, as long as the largestbiopsied breast tumor was HER2-positive
  • Patients must have received neoadjuvant chemotherapy with one of the followinggimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin(TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P));docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P));uorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab(FAC-TH(P)), oruorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)).: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel isble
  • Prior receipt of T-DM1 in the neoadjuvant setting is not allowed.
    • Prior treatment must have consisted of >= 6 cycles of chemotherapy andHER2-directed therapy, with a total duration of >= 12 weeks, including at least 9weeks of preoperative taxane and trastuzumab with or without pertuzumab (or Foodd Drug Administration [FDA]-approved biosimilars). Patients who have received9 weeks of preoperative taxane, pertuzumab and margetuximab are alsogible if they received >= 6 cycles of systemic therapy prior to enrollment.: Patients who complete at least nine of a planned twelve doses of weeklyhree of a planned four doses of docetaxel, but discontinueurely due to toxicity are eligible. Patients receiving dose-densehemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane)d of paclitaxel or docetaxel is permitted. Prior use of subcutaneousuzumab (Hylecta) and subcutaneous trastuzumab and pertuzumab (Phesgo) iswed.
    • Patients who received neoadjuvant systemic therapy which included experimentalHER2-targeted therapy/therapies are potentially eligible, as long as thevestigational agent was not a HER2-targeted antibody-drug conjugate (e.g.T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinasehibitor (TKI) (e.g. tucatinib, lapatinib, neratinib).
  • Patients may have received =< 1 cycles of T-DM1 in the adjuvant setting. Note: These
    patients will be randomized to receive a further 14 cycles of T-DM1 anducatinib/placebo as tolerated. The most recent cycle of T-DM1 should have beendministered =< 5 weeks prior to registration
    • Note: Both of the following two criteria need to be met for the patient to begible for this study
      • An interval of no more than 12 weeks between the completion date of the lastdefinitive treatment (e.g. postoperative chemotherapy or radiation, or if neithergiven, breast surgical date) and the date of registration. Concurrent radiationherapy is permitted while receiving study treatment
      • Patients must be registered on study within =< 180 days of the date of the mostdefinitive breast cancer surgery (not including reconstructive surgery)
  • All systemic chemotherapy should have been completed preoperatively unless
    participating in EA1181 (CompassHER2 pathologic complete response [pCR]) or the BIGDECRESCENDO Trial (which is very similar to CompassHER2 pCR in terms of study design,drugs, and eligibility). However, patients who received 4 cycles of neoadjuvant THPudy can receive a further 2-4 cycles of chemotherapy postoperatively to meetgibility for A011801. Patients who participated in EA1181 or MA41 and proceeded tourgery immediately after the de-escalated trial regimen must receive postoperativehemotherapy to complete a total of >= 6 cycles of systemic treatment prior toA011801, as outlined above (e.g. 4 cycles pre-operatively, and 2 cyclesvely). The postoperative chemotherapy regimen prescribed is at thediscretion of the treating oncologist (i.e. 2-4 cycles AC or THP, other). Continuationuzumab + pertuzumab (HP) pre- or post-operatively as maintenance therapy(while awaiting a surgical date or an official pathology report) is allowed for alludy participants
  • Toxicities related to prior systemic treatment should have resolved or be at baseline,d peripheral neuropathy =< grade 1
  • Adequate excision: surgical removal of all clinically evident disease in the breastd lymph nodes as follows:
    • Breast surgery: total mastectomy with no gross residual disease at the margin ofbreast-conserving surgery with histologically negative margins of
    • For patients who undergo breast-conserving surgery, the margins of the resectedust be histologically free of invasive tumor and ductal carcinoma inu (DCIS) as determined by the local pathologist. If pathologic examinationdemonstrates tumor at the line of resection, additional operative procedures maybe performed to obtain clear margins. If tumor is still present at the resectedgin after re-excision(s), the patient must undergo total mastectomy to begible. 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 nodebiopsy or axillary lymph node dissection. If patients have a sentinel lymph nodebiopsy and sentinel nodes are negative, no further axillary treatment isy. If patients have isolated tumor cells (ITCs) in the setting ofdual breast disease, at least one of the following is required: axillaryymph node dissection (ALND) or planned nodal irradiation. If patients havedal disease, ALND and planned nodal irradiation arequired. Of note, co-enrollment on Alliance A011202 is not allowed
  • 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 permittedhieve eligibility)
  • Platelet count >= 100,000/mm^3
  • Creatinine =< 1.5 x upper limit of normal (ULN)
  • Total bilirubin =< 1.0 x upper limit of normal (ULN) or direct bilirubin within theutional normal range for patients with Gilbert's syndrome
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit(ULN)
  • Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) orultiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and nodecrease in LVEF by more than 15% absolute percentage points from the pre-chemotherapyLVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55%djuvant chemotherapy. Note: LVEF assessment may be repeatedup to 3 weeks following the initial screening assessment to assess eligibility
Exclusion Criteria:
  • No adjuvant treatment with any anti-cancer investigational drug within 28 days priorgistration
  • Not pregnant and not nursing, because this study involves an agent that has knowngenotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearingy, a negative serum pregnancy test done =< 7 days prior to registrationquired
  • Patients with known active and/or untreated hepatitis B or hepatitis C or chronicver disease are ineligible. Patients with a diagnosis of hepatitis B or C that hasbeen treated and cleared and normal liver function are eligible to participate in theudy 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 ofgistration
  • Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per theurgical pathology report
  • Evidence of recurrent disease following preoperative therapy and surgery
  • Patients for whom radiotherapy would be recommended for breast cancer treatment butwhom it is contraindicated because of medical reasons (e.g., connective tissuedisorder 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 >= 3ymptomatic congestive heart failure (CHF) or New York Heart Association (NYHA)>= II
    • Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia notd by adequate medication, severe conduction abnormality, or clinicallygnificant valvular disease
    • High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate >100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) orhigher-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,diac arrhythmia, or cardiac ischemia while or since receiving preoperativeherapy
    • History of a decrease in left ventricular ejection fraction (LVEF) to < 40% withuzumab treatment (e.g., during preoperative therapy)
    • Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolicblood pressure > 100 mmHg)
  • Current severe, uncontrolled systemic disease
  • Major surgical procedure unrelated to breast cancer or significant traumatic injurywithin 28 days prior to registration or anticipation of the need for major surgeryduring the course of study treatment
  • History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivityuzumab 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 thequirements of the protocol
  • Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4CYP2C8 inducer within 5 days prior to registration is prohibited.
    • Please note that use of sensitive CYP3A substrates should be avoided two weeksbefore registration and during study treatment. Additionally, CYP3A4 or CYP2C8ducers are prohibited as concomitant medications within 5 days followingdiscontinuation of tucatinib treatment. Patients who require medications that areknown to be sensitive substrates of CYP3A4 with a narrow therapeutic windowhould be excluded.

Updated on 01 Aug 2024. Study ID: A011801
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