Tucatinib, Trastuzumab, and Capecitabine With SRS for Brain Metastases From HER-2 Positive Breast Cancer

Study Overview
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Brief Summary
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This research study will evaluate how well brain metastases associated with HER-2 positive breast cancer can be controlled using a type of radiation known as stereotactic radiosurgery (SRS) when combined with three therapeutic agents, tucatinib, capecitabine, and trastuzumab. The combined use of SRS with the three drugs is considered investigational.

Official Title
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Phase 1 Trial of Tucatinib, Trastuzumab, and Capecitabine With Stereotactic Radiosurgery (SRS) in Patients With Brain Metastases From HER-2 Positive Breast Cancer

Conditions
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Brain Metastases, HER2-positive Breast Cancer

Intervention / Treatment
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* Combination Product: Combined use of SRS with Tucatinib, Trastuzumab, and Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed HER-2 -positive breast cancer with newly-diagnosed brain metastases. ECOG Performance Status (PS) of 0, 1, 2 Patients with 1-10 brain metastases will be candidates for tucatinib, capecitabine, and trastuzumab with SRS at the discretion of the treating radiation oncologist. Intra-cranial brain metastasis must measure 3 cm or less in the greatest dimension Age 18 years or greater and being willing and able to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures Life expectancy at least 12 weeks Any number of prior systemic therapies will be allowed, except tucatinib and capecitabine. Hemoglobin ≥9g/dL, White blood count ≥3.0 x 10^9/ L , Absolute Granulocyte count ≥1.5x 10^9/ L and platelet count ≥100 × 10^9/ L. Serum bilirubin ≤ 1.5 x ULN AST and / or ALT <= 2 ULN (≤ 5 x ULN when clearly attributable to the presence of liver metastases) Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance > 60ml/min Ability to comply with study procedures and monitoring For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to the start of therapy Male or female patients of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 120 days after last dose of tucatinib, capecitabine and trastuzumab. Highly effective and acceptable forms of contraception are: Male condom plus spermicide Cap plus spermicide Diaphragm plus spermicide Copper T Progesterone T Levonorgestrel-releasing intrauterine system (e.g., Mirena®) Implants Hormone shot or injection Combined pill Mini-pill Patch Postmenopausal woman on the study (that will not need contraception) is defined as: Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments LH and FSH levels in the postmenopausal range for women under 50 Radiation-induced oophorectomy with last menses > 1 year ago Chemotherapy-induced menopause with >1 year interval since last menses Surgical sterilization (bilateral oophorectomy or hysterectomy). Men and women and members of all races and ethnic groups are eligible for this trial. Exclusion Criteria: Patients with leptomeningeal metastases documented by MRI or CSF evaluation Evidence of intra-tumoral or peri-tumoral hemorrhage deemed significant by the treating physician Brain metastases within 5 mm of the optic chiasm or optic nerve Metastases in the brainstem (midbrain, pons, or medulla) Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Crohn's disease, malabsorption, or CTCAE grade >2 diarrhea of any etiology at baseline History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, New York Heart Association (NYHA) functional classification of 3 or 4 Unable to undergo brain MRI Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C All toxicities from prior therapies must have resolved to CTCAE v 5.0 grade 1 or better by the time of study enrollment Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes, second active malignancy) that could cause unacceptable safety risks or compromise compliance with the protocol Currently receiving other investigational cancer therapy within 4 weeks prior to start of study treatment with the exception of continuing therapy with GnRH analogues Mean QT interval corrected heart rate (QTc) ≥ 470ms calculated from 3 electrocardiograms using Frediricia's Correction Left ventricular ejection fraction (LVEF) <50% Concomitant use of strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor Concomitant use of strong CYP3A4 inducers (e.g. phenytoin, rifampicin, carbamazepine, St. John's Wort) within 5 days prior to the first dose of study treatment Concomitant use of potent CYP2C8 inhibitors within 5 days prior to the first dose of study treatment History of hypersensitivity to tucatinib, capecitabine, and trastuzumab any of its excipients History and/or confirmed corneal ulceration Pregnant or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Treatment<br> | Combination Product: Combined use of SRS with Tucatinib, Trastuzumab, and Capecitabine<br>* SRS and oral tucatinib for 2 wk, followed by oral tucatinib, oral capecitabine, and intravenous (IV) trastuzumab maintenance during 21-d cycles until tumor progression, participant withdrawal, a severe adverse event deemed related to the study drug, or the treating physician discontinues the drug. There are three dosing levels of tucatinib (Dose Level 0, Dose Level -1, or Dose Level -2) using a dose de-escalation scheme. Dosing of capectabine (1000 mg/m2 BID Days 1-14) and trastuzumab (6 mg/kg once per 21 days; 8 mg/kg initial loading dose) per cycle will remain the same regardless of tucatinib dosing. Dose Level 0: 300 mg twice a day (BID) continuously for 2 wk post SRS, then 300 mg BID continuously per cycle. Dose Level -1: 250 mg twice a day (BID) continuously for 2 wk post SRS, then 250 mg BID continuously per cycle. Dose Level -2: 200 mg twice a day (BID) continuously for 2 wk post SRS, then 200 mg BID continuously per cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Toxicities will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). DLTs are defined as any of the following events: Grade 3 or 4 thrombocytopenia Grade 4 anemia Grade 4 neutropenia lasting more than 7 days Febrile neutropenia Any non-hematologic toxicity of grade 3 or greater (excluding alopecia) despite maximal medical therapy Grade 4 radiation-induced skin changes Any episode of noninfectious pneumonitis. | During first 4 weeks following SRS | 
| Incidence of radiation-related toxicities | Toxicities presumed to be due to radiation are defined as: Acute, < 90 days from treatment start: Expected toxicities include hair loss (for lesions abutting skull), erythema of the scalp (for lesions abutting skull), headache, nausea, and vomiting. Reactions in the ear canals and on the ear should be observed and treated symptomatically. Pin site infection, pin site pain, facial swelling/bruising, and scalp numbness are other common acute effects. Acute toxicity is defined by CTCAE v5.0. Both acute and delayed, > or = 90 days from treatment start (lethargy, transient worsening of existing neurological deficits) or late (radiation necrosis, cognitive dysfunction, accelerated atherosclerosis, radiation-induced neoplasms) effects of radiotherapy are to be recorded and included in the toxicity evaluation. Late or delayed toxicity is defined by CTCAE v5.0. | 30 days of progression or last dose of drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Time from first dose of study drug until the first date of disease progression or death due any cause. The date of disease progression will be defined as the earliest date of disease progression based on central review. For participants whose disease has not progressed at the time of the analysis, censoring will be performed using the date of the last valid disease assessment. The data will be analyzed by the Kaplan-Meier method. PFS will be considered when there is progression just intracranially, as well as when there is progression intracranially or extracranially. | Six months | 
| Overall survival | Time from the beginning of study drug treatment until death due to any cause. For participants who have not died at the time of the analysis, censoring will be performed using the date the patient was last known to be alive. The data will be analyzed by the Kaplan-Meier method. | One year | 
| Overall response rate (ORR) | Proportion of participants with a complete response (CR) or partial response (PR) as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. For ORR analysis in all the treated population, participants with an CR or PR will be counted as successes and all other participants (including those with missing response information) will be counted as failures. ORR will be considered for intracranial and extracranial tumors. | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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brain metastases, HER2-positive breast cancer