CTNI-32. A MULTICENTER PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER2 POSITIVE BREAST CANCER (TUTOR)

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Abstract BACKGROUND Nearly 20-40% of HER2+ breast cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard-for-care for local control. Tucatinib, an oral HER2-selective TKI, is safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs (TCT) and radiation may enhance DNA damage. This phase 1 trial aims to evaluate TCT plus SRS for HER2+ breast cancer BMs (BCBM). METHODS TUTOR is a pre-registered (NCT05553522), single-arm, multicenter, ongoing, phase 1 trial that aims to determine the safety and efficacy of TCT+SRS in HER2+ BCBM patients. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and ≤10 newly-diagnosed BMs are being enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BMs ≤5 mm of optic chiasm/nerve. Primary endpoint is maximum tolerated dose (MTD) of tucatinib, in this 3 + 3 de-escalation study starting at dose level (DL) 300 mg BID. DL-1 is 250 mg BID, and DL-2 is 200 mg BID. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are assessed using Hopkins Verbal Learning, Controlled Oral Word Association, Trail Making, and Grooved Pegboard Tests. Toxicities are assessed using CTCAE v5.0. Quality of life is assessed using Functional Assessment of Cancer Therapy with Brain Tumor module. Patients are administered tucatinib with SRS as per treating radiation oncologist, followed by tucatinib for two weeks, i.e. dose-limiting toxicity (DLT) period, followed by TCT until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting >7 days, febrile neutropenia, and any non-hematologic toxicity of grade ≥3 (excluding alopecia). Cohort expansion at MTD to 40 patients is planned. Patient enrollment started in February 2023 and remains ongoing.

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