Tucatinib, trastuzumab, and capecitabine with stereotactic radiosurgery in patients with brain metastases from HER-2 positive breast cancer (TUTOR): Study protocol for a multicenter phase 1 clinical trial.

backgroundApproximately 30-50% of patients with HER-2 + breast cancer develop brain metastases (BM). Stereotactic radiosurgery (SRS) is frequently used for local disease control. Tucatinib, an oral HER-2-selective tyrosine kinase inhibitor, has been demonstrated to be safe and efficacious in HER-2 + breast cancer in combination with capecitabine and trastuzumab. The synergy between these three drugs and radiation may enhance DNA damage and increase apoptosis. We hypothesize that this chemoradiation regimen in patients with HER-2 + breast cancer BM (BCBM), is safe and provides superior long-term control of intracranial and systemic disease.

methodsThis is a prospective, single-arm, multicenter, ongoing, phase-1 clinical trial. Eligible patients are aged ≥ 18 years, have an Eastern Cooperative Oncology Group (ECOG) score 0-2, normal organ function, and up to ten newly diagnosed BM will be enrolled at six centers in the United States. Any number of prior systemic therapies are allowed, except prior use of tucatinib or capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BM within 5 mm of the optic chiasm/nerve. Patients receive oral tucatinib alongside SRS, followed by a two-week dose-limiting toxicity (DLT) period. Beginning in Cycle 2, they receive capecitabine (days 1-14 of each 21-day cycle) and trastuzumab (day 1 of each cycle), continuing the regimen until disease progression or intolerable toxicity. DLTs are defined by grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and grade ≥three non-hematologic toxicity. The primary study endpoint is a maximum tolerated dose (MTD) of tucatinib in combinatorial therapy. This de-escalation study starts at a 300 mg dose level DL(0), with DL(-1) 250 mg, and DL(-2) of 200 mg, based on a 3 + 3 design. Cohort expansion at the MTD is to include 40 patients. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (per investigator-assessed), extracranial PFS, overall survival, quality of life as assessed by FACT-Br, toxicity, and neurocognitive function. DISCUSSION: This trial has been approved by the Institutional Review Board (IRB) and began patient enrollment in January 2024. The trial will provide insights into the safety and effectiveness of a novel combinatorial therapy for BCBM.

trial registrationClinicalTrials.Gov identifier NCT05553522. Registered on 09-22-2022 https://clinicaltrials.gov/ct2/show/NCT05553522 .