Combination Therapy + SRS for Brain Cancer from Breast Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Baptist Health South Florida
Must not be taking: CYP3A inhibitors, CYP2C8 inhibitors, CYP3A4 inducers, Anthracyclines
Disqualifiers: Leptomeningeal metastases, Cardiac disease, HIV, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop all current medications, but you cannot use certain drugs like strong CYP3A inhibitors, CYP2C8 inhibitors, and CYP3A4 inducers. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of this treatment for brain cancer from breast cancer?
Research shows that tucatinib, when combined with trastuzumab and capecitabine, is effective for patients with advanced HER2-positive breast cancer, including those with brain metastases, improving progression-free and overall survival. Additionally, lapatinib and capecitabine have shown activity in reducing brain metastases in HER2-positive breast cancer patients.
12345Is the combination of tucatinib, trastuzumab, and capecitabine safe for treating brain metastases from breast cancer?
The combination of tucatinib, trastuzumab, and capecitabine has been approved by the FDA for treating advanced HER2-positive breast cancer with brain metastases, but important safety concerns include diarrhea and liver toxicity.
23467What makes the combination therapy of Capecitabine, Trastuzumab, and Tucatinib unique for treating brain cancer from breast cancer?
This combination therapy is unique because it targets HER2-positive breast cancer that has spread to the brain, using a mix of drugs that can cross the blood-brain barrier and potentially improve outcomes by reducing tumor size and symptoms, which is not always possible with other treatments.
128910Eligibility Criteria
This trial is for adults with HER-2 positive breast cancer that has spread to the brain. They must have 1-10 small brain metastases, good liver and kidney function, and a life expectancy of at least 12 weeks. Women who can bear children need negative pregnancy tests and must use two forms of contraception during the study.Inclusion Criteria
You are expected to live for at least 12 more weeks.
Your hemoglobin, white blood cell count, granulocyte count, and platelet count all need to be at or above certain levels.
I am a postmenopausal woman not needing contraception.
+12 more
Exclusion Criteria
You have had a bad reaction to tucatinib, capecitabine, or trastuzumab in the past.
Your heart's electrical activity (QT interval) is longer than normal when adjusted for your heart rate.
I have HIV or chronic Hepatitis B/C.
+16 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive tucatinib, trastuzumab, and capecitabine combined with stereotactic radiosurgery (SRS) for brain metastases
4 weeks
Weekly visits for drug administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of radiation-related toxicities and progression-free survival
6 months
Long-term follow-up
Participants are monitored for overall survival and long-term effects of treatment
One year
Participant Groups
The study is testing how well stereotactic radiosurgery (SRS) works when combined with tucatinib, trastuzumab, and capecitabine in controlling brain metastases from HER-2 positive breast cancer. This combination treatment approach is experimental.
1Treatment groups
Experimental Treatment
Group I: Investigational TreatmentExperimental Treatment1 Intervention
Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Xeloda for:
- Colorectal cancer
- Breast cancer
🇺🇸 Approved in United States as Xeloda for:
- Colorectal cancer
- Breast cancer
🇨🇦 Approved in Canada as Xeloda for:
- Colorectal cancer
- Breast cancer
🇯🇵 Approved in Japan as Xeloda for:
- Colorectal cancer
- Breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Miami Cancer Institute at Baptist Health, Inc.Miami, FL
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Who Is Running the Clinical Trial?
Baptist Health South FloridaLead Sponsor
PfizerIndustry Sponsor
Seagen Inc.Industry Sponsor
References
[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies]. [2018]Prevalence of brain metastases is increasing in breast cancer. Brain metastases represent a poor-prognosis disease for which local treatments continue to play a major role. In spite of the presence of a physiological blood-brain barrier limiting their activity, some systemic treatments may display a significant antitumor activity at the central nervous system level. In HER2-positive metastatic breast cancer with brain metastases not previously treated with whole brain radiotherapy, capecitabine and lapatinib combination obtains a volumetric reponse in two thirds of patients (LANDSCAPE study). If confirmed, these results could modify in selected patients the layout of therapeutic strategies. Promoting novel targeted approaches and innovative therapeutic combinations is a critical need to improve survival of breast cancer patients with brain metastases.
Phase I Study of Intermittent High-Dose Lapatinib Alternating with Capecitabine for HER2-Positive Breast Cancer Patients with Central Nervous System Metastases. [2023]Lapatinib and capecitabine cross the blood-tumor barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high-dose tyrosine kinase inhibitor has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS). We derived a rational drug scheduling of intermittent high-dose lapatinib alternating with capecitabine based on our preclinical data and Norton-Simon mathematical modeling. We tested this intermittent, sequential drug schedule in patients with breast cancer with CNS metastasis.
FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. [2022]On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.
Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. [2021]Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models.
Lapatinib plus capecitabine resolved human epidermal growth factor receptor 2-positive brain metastases. [2018]Brain metastases affect 25%-30% of women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and are associated with a high burden of disease and poor prognosis. A 55-year-old woman presented with HER2-positive, hormone receptor-positive, locally advanced infiltrating ductal carcinoma. She received 4 cycles of neoadjuvant docetaxel (75 mg/m) plus trastuzumab (6 mg/kg) on a 21-day cycle, resulting in complete pathologic response at the time of surgery. Trastuzumab (6 mg/kg every 21 days) plus anastrozole (1 mg/d) was continued for 1 year. Two years later, the patient progressed with pulmonary nodules and a large pleural effusion. Computed tomography and positron emission tomography revealed multiple lesions in the liver and thoracic spine but no evidence of brain metastases. The patient received weekly trastuzumab (2 mg/kg), paclitaxel (80 mg/m), and carboplatin (area under the curve 2) for 6 months; her symptoms resolved and her disease stabilized. Seven months later, she developed diplopia and gait difficulties, and magnetic resonance imaging revealed multiple brain lesions. Whole-brain radiotherapy (30 Gy in 10 fractions) was delivered with excellent clinical results. The patient remained progression free without symptoms for approximately 3 months. When she developed central nervous system symptoms, she was treated with lapatinib (1250 mg/d continuously) plus capecitabine (2000 mg/m given on days 1-14 of a 21-day cycle). Four months later, a brain computed tomography performed shortly before her death from progressive systemic disease revealed near complete resolution of brain metastases. Lapatinib plus capecitabine seems to have clinical activity in HER2-positive brain metastases.
Tucatinib Impresses in Breast Cancer. [2020]Recent results suggest that tucatinib, when combined with trastuzumab and capecitabine, is effective in patients with locally advanced inoperable or metastatic HER2-positive breast cancer who have received prior therapies: In a phase II trial, the drug extended overall survival and progression-free survival compared with trastuzumab and capecitabine alone, and improved progression-free survival in patients with brain metastases.
Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. [2022]Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥ 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.
Nearly Complete Response of Brain Metastases from HER2 Overexpressing Breast Cancer with Lapatinib and Capecitabine after Whole Brain Irradiation. [2022]Trastuzumab treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in HER2 overexpressing breast cancer patients. Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of HER2-positive breast cancer. We report a patient with breast cancer overexpressing HER-2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine.
Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. [2022]Brain metastases occur in 30-50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer.
[Current possibilities of targeted therapy in the treatment of breast cancer with overexpression of HER-2/neu and metastatic lesions in the brain]. [2018]Targeted therapy (lapatinib and/or trastuzumab) in combination with chemotherapy (capecitabine) is highly effective in metastatic lesions of the brain in breast cancer patients with overexpress HER-2/neu. An objective response in the brain was achieved in 19 patients (55.9%). Complete regression was observed in 5 cases (14.7%), partial regression--14 (41.2%). Stabilization of tumor process in the brain was revealed in 12 patients (35.3%). There was marked improvement in the quality of life of the majority of patients due to the regression of symptoms and good tolerability of treatment.