Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD
Metastatic Breast Cancer, Leptomeningeal Disease
About this trial
This is an interventional treatment trial for Metastatic Breast Cancer focused on measuring HER2+, metastatic breast cancer, leptomeningeal disease, tucatinib, trastuzumab, capecitabine
Eligibility Criteria
Inclusion Criteria:
- Men and women, age ≥18 years at time of consent
- Histologically proven metastatic infiltrating carcinoma of the breast that is HER2 positive - Immunohistochemistry (IHC) 3+ and/or Fluorescence in situ hybridization (FISH) ratio >2.0, or average HER2 copy number >6.0 signals per cell or per current ASCO-CAP (American Society of Clinical Oncology - College of American Pathologists) or NCCN (National Comprehensive Cancer Network) guidelines. (NOTE: HER2 testing may be performed on primary and/or metastatic site; Any estrogen and progesterone [ER/PR] status is allowed.)
- Evidence of leptomeningeal disease (LMD) as diagnosed by a) presence of malignant cells in CSF (+CSF cytology) and/or b) Magnetic Resonance Imaging (MRI) evidence of LMD, plus clinical signs and/or symptoms. NOTE: Measurable extra-CNS disease is not required. Note: Patients who have MRI evidence of focal LMD with negative cytology and no symptoms are not eligible for enrollment.
- Karnofsky Performance Status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≤ 3
Patient is able and willing to undergo study-required testing including:
- Contrast-enhanced MRI Note: If patient has implants in place that are MRI incompatible, these must be removed prior to enrollment.
- Placement of an Ommaya reservoir (ventricular access device). Note: This is mandatory for the first 15 patients enrolled onto the protocol (first stage). In the second stage, this is strongly recommended per protocol. If a patient cannot or chooses not to undergo Ommaya placement in the second stage, the patient will be allowed to enroll.
- Evaluation by medical oncologist at baseline and at every cycle (required)
- Evaluation by neurologist/neuro-oncologist at baseline and at every cycle (strongly recommended); if this is not possible at a site, a medical oncologist may per perform the protocol specified evaluations at each visit.
- Patients who are on steroids due to CNS disease or LMD diagnosis should be on a stable dose for at least 5 days prior to registration.
Prior treatment allowances are as follows:
- >14 days since last dose of any previous endocrine therapy, chemotherapy, trastuzumab or other antibody-based therapy. NOTE: If patients have been previously receiving trastuzumab on a weekly basis (at a dose of 2mg/kg), only a 7 day washout will be required.
- >14 days or five half-lives since previous treatment with any experimental agent, whichever is greater
- Cumulative dose of doxorubicin >360 mg/m2 or previous treatment with another anthracycline with cumulative dose equivalent to >360 mg/m2 doxorubicin is not allowed.
- Patients must not have received any therapy specifically directed at LMD, including prior systemic or intrathecal therapy for LMD.
Radiotherapy:
Patients must not have received radiotherapy to the neuroaxis following diagnosis of LMD for the purpose of treating LMD, and may not receive
- radiotherapy to the neuroaxis concurrently with the study drug;
- Patients must not have received whole brain radiotherapy for parenchymal metastases within the last 2 weeks (14 days) or focal CNS radiotherapy within 1 week (7 days) prior to first dose of study drug. Note: Radiation for the purpose of palliation in the setting of a painful bone or dural metastasis can be allowed at the discretion of the treating physicians.
- All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2; and CHF, which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely. Must be without significant systemic illness (e.g. infection unresponsive to treatment after 7 days)
Adequate hematologic, liver, and renal function, as follows:
- Hemoglobin ≥ 9 g/dL
- ANC ≥ 1000 cells/μL
- Platelets ≥ 100,000/μ
- Total bilirubin ≤ 1.5 X upper limit of normal (ULN), unless a known history of Gilbert's disease (≤ 3 X ULN)
- Transaminases (AST/SGOT and ALT/SGPT) ≤ 2.5X ULN (< 5 X ULN if liver metastases are present)
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN
- Creatinine clearance (CrCL) ≥ 50 mL/min
- Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 4 weeks prior to enrollment on the study.
- Able to understand the study requirements and document informed consent indicating his/her awareness of the investigational nature and the risks of this study.
Exclusion Criteria:
- Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures.
- Patient is pregnant or is breastfeeding. Note: If female and of child-bearing potential (females who are not surgically sterile or who have had a period in the last 12 months), has negative pregnancy test within 21 days prior to treatment. If a sexually active male or a sexually active female of child- bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose.
- History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (Group A only), trastuzumab or tucatinib, except for a history of Grade 1 or Grade 2 infusion related reaction to trastuzumab, that has been successfully managed.
- Known to be HIV positive, or a carrier for Hepatitis B and/or Hepatitis C (whether active disease or not)
- Known liver disease, autoimmune hepatitis, or sclerosing cholangitis
- Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications
- Use of a strong CYP2C8/CYP3A4 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment.
- Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy or congestive heart failure. Note: Patients with hypertension must have controlled disease defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on antihypertensive medications.
- Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug.
- Patient with known dihydropyrimidine dehydrogenase deficiency
- Previous treatment with tucatinib
- Previous treatment with capecitabine within 12 months prior to study registration
- Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years.
Sites / Locations
- University of Alabama at Birmingham
- UCSF-Mission Bay
- MedStar Georgetown University-Lombardi CCC
- University of Chicago
- Indiana University-Melvin and Bren Simon cancer center
- Dana Farber/Harvard Cancer Center-
- University of Michigan-
- University of Texas MD Anderson Cancer Center
- University of Washington Medical Center-Montlake
Arms of the Study
Arm 1
Experimental
Tucatinib + Trastuzumab + Capecitabine
Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles.