Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD

Study Overview
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Brief Summary
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A phase 2 non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab with capecitabine for the treatment of leptomeningeal metastases in HER2-neu positive breast cancer.

Detailed Description
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The purpose of this study is to evaluate a new treatment for patients with HER2+ metastatic breast cancer (MBC) with leptomeningeal disease (LMD). This is a rare and fast-growing form of cancer. Leptomeningeal disease refers to the seeding of tumor cells to the leptomeninges and dissemination in the cerebrospinal fluid. Currently, there are is no standard of care treatment for LMD. However, we think the combination therapy will be safe and well-tolerated and may also improve survival. Blood and spinal fluid samples will be collected to evaluate the effects on the body and the cancer, which will help provide greater understanding to therapy response in patients. The study has a two-stage design with the first stage including 15 subjects from up to ten institutions nationwide. If it advances to the second stage based on the number of successes, another 15 subjects will be enrolled.

Official Title
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A Phase II Non-randomized Study to Assess the Safety and Efficacy of the Combination of Tucatinib and Trastuzumab and Capecitabine for Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer

Conditions
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Metastatic Breast Cancer, Leptomeningeal Disease

Intervention / Treatment
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* Drug: Tucatinib
* Drug: Trastuzumab
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, age ≥18 years at time of consent Histologically proven metastatic infiltrating carcinoma of the breast that is HER2 positive - Immunohistochemistry (IHC) 3+ and/or Fluorescence in situ hybridization (FISH) ratio >2.0, or average HER2 copy number >6.0 signals per cell or per current ASCO-CAP (American Society of Clinical Oncology - College of American Pathologists) or NCCN (National Comprehensive Cancer Network) guidelines. (NOTE: HER2 testing may be performed on primary and/or metastatic site; Any estrogen and progesterone [ER/PR] status is allowed.) Evidence of leptomeningeal disease (LMD) as diagnosed by a) presence of malignant cells in CSF (+CSF cytology) and/or b) Magnetic Resonance Imaging (MRI) evidence of LMD, plus clinical signs and/or symptoms. NOTE: Measurable extra-CNS disease is not required. Note: Patients who have MRI evidence of focal LMD with negative cytology and no symptoms are not eligible for enrollment. Karnofsky Performance Status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≤ 3 Patient is able and willing to undergo study-required testing including: Contrast-enhanced MRI Note: If patient has implants in place that are MRI incompatible, these must be removed prior to enrollment. Placement of an Ommaya reservoir (ventricular access device). Note: This is mandatory for the first 15 patients enrolled onto the protocol (first stage). In the second stage, this is strongly recommended per protocol. If a patient cannot or chooses not to undergo Ommaya placement in the second stage, the patient will be allowed to enroll. Evaluation by medical oncologist at baseline and at every cycle (required) Evaluation by neurologist/neuro-oncologist at baseline and at every cycle (strongly recommended); if this is not possible at a site, a medical oncologist may per perform the protocol specified evaluations at each visit. Patients who are on steroids due to CNS disease or LMD diagnosis should be on a stable dose for at least 5 days prior to registration. Prior treatment allowances are as follows: >14 days since last dose of any previous endocrine therapy, chemotherapy, trastuzumab or other antibody-based therapy. NOTE: If patients have been previously receiving trastuzumab on a weekly basis (at a dose of 2mg/kg), only a 7 day washout will be required. >14 days or five half-lives since previous treatment with any experimental agent, whichever is greater Cumulative dose of doxorubicin >360 mg/m2 or previous treatment with another anthracycline with cumulative dose equivalent to >360 mg/m2 doxorubicin is not allowed. Patients must not have received any therapy specifically directed at LMD, including prior systemic or intrathecal therapy for LMD. Radiotherapy: Patients must not have received radiotherapy to the neuroaxis following diagnosis of LMD for the purpose of treating LMD, and may not receive radiotherapy to the neuroaxis concurrently with the study drug; Patients must not have received whole brain radiotherapy for parenchymal metastases within the last 2 weeks (14 days) or focal CNS radiotherapy within 1 week (7 days) prior to first dose of study drug. Note: Radiation for the purpose of palliation in the setting of a painful bone or dural metastasis can be allowed at the discretion of the treating physicians. All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2; and CHF, which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely. Must be without significant systemic illness (e.g. infection unresponsive to treatment after 7 days) Adequate hematologic, liver, and renal function, as follows: Hemoglobin ≥ 9 g/dL ANC ≥ 1000 cells/μL Platelets ≥ 100,000/μ Total bilirubin ≤ 1.5 X upper limit of normal (ULN), unless a known history of Gilbert's disease (≤ 3 X ULN) Transaminases (AST/SGOT and ALT/SGPT) ≤ 2.5X ULN (< 5 X ULN if liver metastases are present) International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN Creatinine clearance (CrCL) ≥ 50 mL/min Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 4 weeks prior to enrollment on the study. Able to understand the study requirements and document informed consent indicating his/her awareness of the investigational nature and the risks of this study. Exclusion Criteria: Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures. Patient is pregnant or is breastfeeding. Note: If female and of child-bearing potential (females who are not surgically sterile or who have had a period in the last 12 months), has negative pregnancy test within 21 days prior to treatment. If a sexually active male or a sexually active female of child- bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose. History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (Group A only), trastuzumab or tucatinib, except for a history of Grade 1 or Grade 2 infusion related reaction to trastuzumab, that has been successfully managed. Known to be HIV positive, or a carrier for Hepatitis B and/or Hepatitis C (whether active disease or not) Known liver disease, autoimmune hepatitis, or sclerosing cholangitis Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications Use of a strong CYP2C8/CYP3A4 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment. Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy or congestive heart failure. Note: Patients with hypertension must have controlled disease defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on antihypertensive medications. Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug. Patient with known dihydropyrimidine dehydrogenase deficiency Previous treatment with tucatinib Previous treatment with capecitabine within 12 months prior to study registration Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years.

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
Interventional Model Description: Subjects will receive combination treatment with tucatinib + trastuzumab + capecitabine every 21 days, which is one cycle. Evaluation will be done every two cycles with an MRI of the brain and spine. Cycles 3 and beyond will be at the discretion of the physician. A scan will be done every four cycles.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tucatinib + Trastuzumab + Capecitabine<br>Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles. | Drug: Tucatinib<br>* Tucatinib study drug is given in tablet form and taken daily.<br>* Other names: ONT-380;Drug: Trastuzumab<br>* Trastuzumab is approved by the FDA and is available commercially. Trastuzumab must be prepared and is administered intravenously.<br>Drug: Capecitabine<br>* Capecitabine is approved by the FDA and is available commercially as an oral drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Subject Survival After Starting Study Treatment | Number of participants alive. A Gehan-like trial design with an interim futility analysis will be used. | Through study completions, an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | Adverse event reporting will be graded following the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Subjects who receive at least one dose of the drug combination will be evaluable for toxicity from the time of the first dose. | Baseline up to 3 years or until disease progression or unacceptable toxicity or death. | 
| Progression Free Survival | From the start of treatment to 12 weeks | Baseline to 12 weeks | 
| Objective Response in the Central Nervous System (CNS) | Data from subjects who have received at least one cycle of therapy and disease re-evaluation for CNS tumors by imaging, cytopathology, and clinical evaluation will be accumulated until disease progression. | Baseline up to 3 years | 
| Clinical Benefit Rate (CBR) in CNS | The overall survival from the combination therapy is compared to the historical control. Clinical benefit is observed with a ratio of successes and corresponding confidence interval. | Baseline to 3 years | 
| Objective Response in Extra-CNS Disease | Data from subjects who have received at least one cycle of therapy and disease re-evaluation for extra-CNS tumors by imaging, cytopathology, and clinical evaluation will be accumulated until disease progression. Extra-CNS response will be classified per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Baseline up to 3 years | 
| Clinical Benefit Rate (CBR) in Extra-CNS Disease | The overall survival from the combination therapy is compared to the historical control. Clinical benefit is observed with a ratio of successes and corresponding confidence interval. | Baseline to 3 years | 
| Symptom Burden | The M.D. Anderson Symptom Inventory Brain Tumor (MDASI -BT) module questionnaire will collect data at each study time point and evaluate changes of symptom burden. | Beginning at baseline and every 21 days until the end of study up to three years | 
| Quality of Life Assessment | The Linear Analog Scale Assessment Quality of Life will be used to evaluate changes in the quality of life at restaging visits. | Beginning at baseline and every 42 days until the end of study up to three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2+, metastatic breast cancer, leptomeningeal disease, tucatinib, trastuzumab, capecitabine