Combination Therapy + SRS for Brain Cancer from Breast Cancer

Overseen By Daylen Santana

Age: 18+

Sex: Any

Trial Phase: Phase 1

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating brain tumors that have spread from HER-2 positive breast cancer. It combines stereotactic radiosurgery (SRS), a focused radiation type, with three drugs: tucatinib, capecitabine (Xeloda), and trastuzumab (Herceptin). Researchers aim to determine if this combination can control tumors more effectively. Suitable candidates have been diagnosed with HER-2 positive breast cancer and have 1-10 small, newly diagnosed brain metastases measuring 3 cm or less. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatment combination being tested—capecitabine, trastuzumab, tucatinib, and stereotactic radiosurgery (SRS)—has promising safety results from separate studies. Capecitabine is generally well-tolerated when combined with radiation for brain metastases, offering good local control and a low risk of serious side effects. Trastuzumab has a manageable safety profile, with studies indicating better outcomes for patients with brain metastases. Tucatinib, when used with trastuzumab and capecitabine, significantly slowed disease progression in patients with brain metastases and maintained an acceptable safety profile. SRS, the type of radiation used in this trial, has also shown a low rate of severe side effects, making it a safe option for treating brain metastases. Each of these treatments has individually demonstrated good tolerance, but their combined use is still under study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Capecitabine, Trastuzumab, and Tucatinib for treating brain cancer that stems from breast cancer because this approach brings some unique advantages. Unlike standard treatments that often rely solely on surgery or radiation, this combination therapy targets the cancer cells more precisely. Tucatinib specifically inhibits the HER2 protein, which can be overactive in certain breast cancers, providing a more targeted attack on cancer cells. Additionally, combining these drugs with SRS (stereotactic radiosurgery) could enhance their effectiveness by delivering a one-two punch—targeting the cancer directly with radiation while simultaneously using medications that work at a molecular level. This multifaceted approach has the potential to improve outcomes and reduce side effects compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for brain cancer from breast cancer?

Research has shown that the combination of treatments in this trial holds promise for treating brain metastases from HER2-positive breast cancer. Participants will receive a combination that includes Capecitabine, which has demonstrated strong anticancer effects, with some patients achieving a complete response, meaning no detectable cancer. Trastuzumab, another component, has been linked to a significant increase in survival for patients with brain metastases, indicating its effectiveness even after the cancer has spread to the brain. Tucatinib, also part of the trial, has shown clear improvements in survival rates for patients with HER2-positive breast cancer that has spread to the brain. Additionally, Stereotactic Radiosurgery (SRS), a precise type of radiation treatment included in the trial, has proven both effective and safe for managing brain metastases from breast cancer. This combination of therapies aims to leverage the strengths of each treatment to better control brain metastases. ^{1 2 4 6 7}

Who Is on the Research Team?

Manmeet Ahluwalia, MD

Principal Investigator

Miami Cancer Institute/Baptist Health South Florida

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Stereotactic Radiosurgery
• Trastuzumab
• Tucatinib

Trial Overview 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.

How Is the Trial Designed?

Group I: Investigational Treatment Experimental Treatment 1 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

Who Is Running the Clinical Trial?

Baptist Health South Florida

Lead Sponsor

Trials

54

Recruited

8,100+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

Published Research Related to This Trial

In a phase 2 study involving 45 patients with untreated brain metastases from HER2-positive breast cancer, the combination of lapatinib and capecitabine resulted in a significant objective CNS response rate of 65.9%, indicating its potential efficacy as a first-line treatment.

While 49% of patients experienced grade 3 or 4 treatment-related adverse events, including diarrhea and hand-foot syndrome, there were no toxic deaths, suggesting that the treatment is relatively safe despite the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Bachelot, T., Romieu, G., Campone, M., et al.[2022]

A phase I trial involving 11 patients with HER2-positive breast cancer and CNS metastasis demonstrated that an intermittent high-dose regimen of lapatinib, combined with capecitabine, is tolerable and can lead to antitumor activity in both CNS and non-CNS sites.

The maximum tolerated dose (MTD) of lapatinib was established at 1,500 mg BID, with some patients remaining on therapy for over 6 months, indicating potential for prolonged treatment benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Intermittent High-Dose Lapatinib Alternating with Capecitabine for HER2-Positive Breast Cancer Patients with Central Nervous System Metastases. Morikawa, A., de Stanchina, E., Pentsova, E., et al.[2023]

In the LANDSCAPE study, a combination of capecitabine and lapatinib showed a significant volumetric response in about two-thirds of HER2-positive breast cancer patients with untreated brain metastases, indicating promising efficacy despite the challenges posed by the blood-brain barrier.

These findings suggest that targeted therapies like capecitabine and lapatinib could change treatment strategies for selected patients with brain metastases, highlighting the need for innovative approaches to improve survival rates in this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies]. Bachelot, T., Le Rhun, E., Labidi-Gally, I., et al.[2018]

Tucatinib, approved by the FDA for advanced HER2-positive breast cancer, significantly improved progression-free survival (PFS) and overall survival (OS) compared to placebo, particularly benefiting patients with brain metastases, who comprised 48% of the study population.

The HER2CLIMB trial demonstrated a favorable benefit-risk profile for tucatinib, although it is associated with safety concerns such as diarrhea and hepatotoxicity, which are important to monitor during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. Shah, M., Wedam, S., Cheng, J., et al.[2022]

In a study of breast cancer patients with HER-2/neu overexpression, targeted therapy using lapatinib and/or trastuzumab combined with chemotherapy (capecitabine) resulted in a 55.9% objective response rate in brain metastases.

The treatment led to complete regression in 14.7% of cases and partial regression in 41.2%, along with significant improvements in patients' quality of life due to symptom relief and good tolerability of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current possibilities of targeted therapy in the treatment of breast cancer with overexpression of HER-2/neu and metastatic lesions in the brain]. Naskhletashvili, DR., Gorbunova, VA., Moskvina, EA.[2018]

Trastuzumab, a common treatment for HER2-positive breast cancer, does not prevent the spread of cancer to the brain and is ineffective against existing brain metastases.

A combination therapy of lapatinib and capecitabine, along with radiation, showed successful treatment of brain metastases in a patient with HER2-positive breast cancer, suggesting a potential effective alternative for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nearly Complete Response of Brain Metastases from HER2 Overexpressing Breast Cancer with Lapatinib and Capecitabine after Whole Brain Irradiation. Oktay, E., Yersal, O., Meydan, N., et al.[2022]

In a phase II trial, tucatinib combined with trastuzumab and capecitabine significantly improved overall survival and progression-free survival in patients with locally advanced or metastatic HER2-positive breast cancer who had previously undergone treatment.

The combination therapy also showed enhanced progression-free survival specifically in patients with brain metastases, indicating its potential effectiveness in a challenging subset of breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib Impresses in Breast Cancer. [2020]

In a study of patients with HER2-positive breast cancer and progressive brain metastases, the combination of lapatinib and capecitabine showed a promising objective response rate of 38%, indicating potential efficacy in treating CNS lesions.

However, the combination of lapatinib and topotecan was found to be ineffective and associated with excessive toxicity, leading to the early closure of the study after only 22 of the planned 110 patients were enrolled.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. Lin, NU., Eierman, W., Greil, R., et al.[2022]

A 55-year-old woman with HER2-positive breast cancer showed significant clinical improvement and stabilization of her disease after receiving a combination of trastuzumab, paclitaxel, and carboplatin, followed by whole-brain radiotherapy for brain metastases.

The treatment with lapatinib and capecitabine demonstrated near complete resolution of brain metastases, suggesting that this combination may be an effective option for patients with HER2-positive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lapatinib plus capecitabine resolved human epidermal growth factor receptor 2-positive brain metastases. Glück, S., Castrellon, A.[2018]

In a phase I study involving 41 patients with HER2-positive brain metastases, the combination of tucatinib and trastuzumab was found to be tolerable, with a maximum tolerated dose of 300 mg twice daily or 750 mg once daily, and common side effects including elevated liver enzymes.

The treatment showed preliminary efficacy, with a clinical benefit rate of 35% in the twice-daily cohort and 53% in the once-daily cohort, indicating potential effectiveness in managing brain metastases in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. Metzger Filho, O., Leone, JP., Li, T., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10898896/

Activity of capecitabine for central nervous system metastases ... Survival curves of the present study show that many patients present early disease progression and outcomes are overall poor.

2. asco.org asco.org/abstracts-presentations/ABSTRACT114672

Outcomes of patients with HER2-negative breast cancer ... The median time to brain metastasis was 3.1 years (min-max; 0.5-15.5). Thirty (51%) patients were hormone positive, and twenty-nine (49%) were triple-negative.

3. ascopubs.org ascopubs.org/doi/10.1200/jco.2009.27.15_suppl.1102

Capecitabine monotherapy for patients with brain ... Our small study suggests that capecitabine has pronounced anticancer activity in patients with brain metastases from breast cancer with reasonable tolerability.

4. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-021-08302-9

Capecitabine and stereotactic radiation in the management of ... Among patients with brain metastases, progression-free survival (PFS) at 1 year was 25% in the tucatinib-combination group and 0% in the placebo ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/17611719/

Capecitabine therapy of central nervous system ... Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR ...

6. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2813582

Brain Radiotherapy With Pyrotinib and Capecitabine in ... This nonrandomized trial examines the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ...

7. redjournal.org redjournal.org/article/S0360-3016(20)33459-3/fulltext

Clinical Outcomes of Breast Cancer Brain Metastases ... We demonstrate that stereotactic radiation and capecitabine is a well-tolerated treatment for BCBM with high LC and a low associated risk for symptomatic ...