Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD

Study Overview
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Brief Summary
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The proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy among patients with HER2+ metastatic breast cancer and LMD

Detailed Description
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Breast cancer is the most common cancer among women worldwide, and the second leading cause of brain metastases (BrM). Despite recent treatment advances, the prognosis of patients with breast cancer BrM remains poor, and the prognosis among those with leptomeningeal disease (LMD) is particularly dire with a median survival of only 2-4 months. Patients with HER2+ metastatic breast cancer have a high life-time risk of central nervous system (CNS) metastases, with an approximately 50% lifetime risk. Although the cause of death among patients with breast cancer BrM is challenging to ascertain, approximately 50% of patients with HER2+ BrM are thought to die from central nervous system (CNS) disease involvement. Among patients with LMD specifically, the cause of death is most commonly related to CNS disease. In an analysis of 430 patients (96 of whom had breast cancer) treated for LMD in the National Cancer Database between 2005 and 2014, those patients treated with chemotherapy plus radiotherapy had a longer median overall survival of 5 months (3.5 - 6.5 months) compared to patients treated with XRT or chemotherapy alone. In addition, a majority (n=18/26, 69%) of observational studies irrespective of primary tumor site have shown an improvement or likely improvement in survival with the use of XRT for LMD, either alone or in combination with systemic therapy. Hence, this proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy (which is considered standard of care) among patients with HER2+ metastatic breast cancer and LMD.

Official Title
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Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study

Conditions
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LMD, HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Tucatinib 150 MG
* Drug: Trastuzumab
* Drug: Capecitabine
* Radiation: Brain & Spinal Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1 Men or women with HER2+ metastatic breast cancer. Evidence of LMD in the brain and/or spine Age 18+ at time of consent; ECOG ≤ 2; If applicable, the last dose of prior chemotherapy, immunotherapy, endocrine therapy therapy must have been completed 14 days prior to study enrollment. More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater; All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 prior to enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2. Phase 2: Inclusion Criteria Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 2 weeks prior to starting systemic therapy on the study; Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows: Hemoglobin ≥ 9 g/dL ANC ≥ 1 x109/L Platelets ≥ 100 x109/L Total bilirubin ≤ 1.5 X upper limit of normal (ULN) AST and ALT ≤ 2.5X ULN International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN Creatinine clearance (CrCL) ≥ 50 mL/min Exclusion Criteria: Phase 1 Prior WBRT for brain metastases Prior therapy specifically directed at LMD Inability to comply with MRI-based surveillance of CNS disease. Inability to swallow pills or any significant gastrointestinal diseases such as inflammatory bowel disease. Presently known dihydropyrimidine dehydrogenase deficiency; Diagnosed with Hereditary fructose intolerance; Diagnosed with Gilbert's disease; Prior history of other cancer with evidence of disease within the last 5 years; Prior use of tucatinib at any time prior to enrollment. Phase 2: Currently pregnant or breastfeeding; Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of systemic therapy Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy. Blood product transfusions in order to meet eligibility criteria

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: Tucatinib, Transtuzumab, Capecitabine<br>Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease. | Drug: Tucatinib 150 MG<br>* Tucatinib is a potent, selective, adenosine triphosphate-competitive small-molecule inhibitor of the receptor tyrosine kinase HER2. The molecular formula for tubatinib is C26H24N8O2 and it has a molecular weight of 480.52 g/mol.<br>* Other names: Tukysa;Drug: Trastuzumab<br>* MYL-1401O contains the active substance trastuzumab, which is an IgG1 monoclonal antibody. The molecular size of the intact molecule is around 148 kDa. Each vial of MYL-1401O contains 150 mg of lyophilized proposed active biosimilar substance trastuzumab as well as 3.36 mg L-Histidine Hydrochloride, 2.16 mg L-Histidine, 115.2 mg sorbitol and 33.6 mg PEG-3350 (Macrogol 3350). Sorbitol and PEG-3350 substitute the α- trehalose dehydrate and polysorbate-20, which are used as excipients in the EU-approved and US-licensed Herceptin formulations.<br>Drug: Capecitabine<br>* Capecitabine is a tumour-activated antineoplastic agent (antimetabolite). The molecular formula for capecitabine is C15H22FN3O6 and has a molecular weight of 359.35 g/mol.<br>Radiation: Brain & Spinal Radiation<br>* Brain & Spinal XRT is a treatment for patients with HER2+ metastatic breast cancer and leptomeningeal disease,<br>* Other names: Brain & Spinal XRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival status from the start of XRT • Survival status from the start of XRT | To assess overall survival (OS) from the start of XRT. | From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to CNS progression from the start of XRT | To determine the time for CNS symptoms progresses from start of XRT in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Safety and tolerability (CTCAE v.5.0) | To determine the safety & tolerability of systemic therapy (tucatinib, trastuzumab and capecitabine) in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Progression free survival from the start of XRT | To determine progression from the start of XRT in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| CNS specific objective response (RANO-BM) | To determine the CNS objective response in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | Every 6 weeks through study completion, an average of 5 years | 
| Extracranial objective response (RECIST v1.1) | To determine the extracranial objective response in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | Every 6 weeks through study completion, an average of 5 years | 
| Neurologic-specific QoL (FACT-BR version 4) | To determine the neurologic-specific QoL's in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit | 
| Overall QoL (EORTC QLQ-C30 version 3) | To determine the Overall QoL in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD). | Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2+, Breast Cancer, Leptomeningeal disease, Tucanitib