Tucatinib Given Before Surgery to Patients with HER2 positive Cancers that have Spread to the Brain

Inclusion Criteria

• Age >= 18 years with no impairment in decision making capacity
• Patients with HER2 overexpressed/amplified/mutant metastatic breast/lung/esophagogastric/colorectal cancer (IHC, fluorescent in situ hybridation or sequencing-confirmed primary, brain, or other metastatic site) and one or more brain tumor(s) planned for neurosurgical resection. Other untreated brain metastases, and prior radiation (whole brain radiation therapy and/or stereotactic radiosurgery) to the index site are allowed
• Patients with concomitant leptomeningeal disease are eligible provided they have parenchymal brain metastases requiring resection
• Life expectancy of > 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2
• Prior treatments: * Cohort A: Clinical and or radiological CNS parenchymal progression on tucatinib as most recent line of treatment (tucatinib-resistant) in patients with HER2 overexpressed/amplified breast cancer * Cohort B: Clinical and or radiological CNS parenchymal progression with no prior tucatinib (tucatinib naive) in patients with HER2 overexpressed/amplified breast cancer * Cohort C: Clinical and or radiological CNS parenchymal progression in patients with HER2+/mutant lung/esophagogastric/colorectal cancer and HER2 mutant breast cancer
• Prior conventional dose lapatinib and neratinib are allowed in any cohort if > 6 months prior
• No limit on prior lines of systemic therapy
• Absolute neutrophil count (ANC) >= 1.0 x 10^3uL (obtained =< 7 days prior to the first day of study treatment)
• Platelet count >= 75 x 10^3/uL (obtained =< 7 days prior to the first day of study treatment)
• Hemoglobin >= 8.0 g/dL (obtained =< 7 days prior to the first day of study treatment)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to the first day of study treatment)
• Subjects with known history of Gilbert’s syndrome and normal direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are eligible: AST and ALT =< 2.5 x ULN (=< 5 x ULN if liver metastases are present) (obtained =< 7 days prior to the first day of study treatment)
• Calculated creatinine clearance >= 50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (2021) (in cohort A, in patients with elevated serum creatinine, estimated glomerular filtration rate [eGFR] can be calculated using cystatin C to confirm eligibility) (obtained =< 7 days prior to the first day of study treatment)
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless on medication known to alter INR and/or aPTT (obtained =< 7 days prior to the first day of study treatment)
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to enrollment and must agree to use adequate contraception prior to enrollment and for the duration of study participation
• Patients must be able to swallow and retain oral medication

Exclusion Criteria

• Contraindications or history of allergic reaction to tucatinib or any of its excipients
• Significant medical co-morbidities as per investigator evaluation
• Inability to comply with protocol and /or not willing or not available for follow-up assessments or any condition which in the investigator’s opinion makes the patient unsuitable for the study participation
• Have used a strong or moderate CYP2C8 inhibitor within 5 half-lives of the inhibitor or have used a strong or moderate CYP2C8 or CYP3A4 inducer within 2 weeks prior to first dose of study treatment
• Receiving concomitant CYP3A or P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities
• Concurrent pregnancy