Tucatinib Combination for Breast Cancer

(BRIDGET Trial)

Recruiting at 8 trial locations

Overseen By Rae Richards

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sarah Sammons, MD

Must be taking: Trastuzumab, Pertuzumab, T-DM1, Tucatinib

Must not be taking: Lapatinib, Neratinib, Afatinib, others

Disqualifiers: Cardiopulmonary disease, Acute infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: Until disease progression or intolerable side effects

48 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with advanced HER2+ breast cancer on maintenance trastuzumab/pertuzumab or T-DM1 with 1st or 2nd intracranial disease event (brain metastases) and stable extracranial disease will be enrolled. They will receive local therapy with stereotactic radiosurgery ± surgical resection if indicated followed by enrollment. Patients will continue standard of care trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib. Hormone receptor positive patients requiring endocrine therapy should continue. Study treatment will continue until disease progression or intolerable side effects. Patients on trial with extracranial disease progression with stable intracranial disease should continue tucatinib into next line of therapy.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications. In fact, if you are on trastuzumab/pertuzumab, T-DM1, or need endocrine therapy, you should continue them while participating in the study.

What data supports the effectiveness of the drug combination including Tucatinib, Pertuzumab, and Trastuzumab Emtansine for breast cancer?

Research shows that Trastuzumab Emtansine (T-DM1) combined with Pertuzumab is effective for treating HER2-positive advanced breast cancer, offering similar progression-free survival and better tolerability compared to other treatments. Additionally, combining T-DM1 with Pertuzumab has shown enhanced antitumor activity in preclinical studies. ^{1 2 3 4 5}

Is the combination of tucatinib and other drugs safe for treating breast cancer?

The combination of trastuzumab emtansine (T-DM1) with or without pertuzumab has been studied for safety in patients with HER2-positive advanced breast cancer. These studies showed that T-DM1 generally has a better safety profile compared to some other treatments, with fewer severe side effects. However, like all treatments, it can still cause some adverse effects, which were carefully monitored in clinical trials. ^{1 3 4 5 6}

What makes the Tucatinib Combination for Breast Cancer drug unique?

The Tucatinib Combination for Breast Cancer is unique because it includes tucatinib, an oral drug that specifically targets HER2, a protein that promotes the growth of cancer cells. This combination is being developed as a novel option for patients whose cancer has progressed after standard treatments like trastuzumab, pertuzumab, and T-DM1, offering a new approach when other options are limited. ^{1 2 5 7 8}

Research Team

Carey Anders, MD

Principal Investigator

Duke Cancer Institute

Eligibility Criteria

This trial is for adults over 18 with advanced HER2+ breast cancer who have had brain metastases treated and stable disease elsewhere. They must be on specific therapies (trastuzumab/pertuzumab or T-DM1), have good organ function, and not be pregnant or breastfeeding. Contraception use is required for participants of childbearing potential.

Inclusion Criteria

My breast cancer has spread to my brain (Stage IV).

My cancer is stable or I have no cancer spread outside the brain.

I am able to get out of my bed or chair and move around.

Exclusion Criteria

You cannot have ongoing use of certain medications for brain issues, specific brain conditions, poorly controlled seizures, certain medical treatments, active infections, or recent use of experimental drugs.

I do not have an active infection needing strong medication.

I haven't taken strong CYP2C8 or CYP3A4 drugs recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Local Therapy

Participants receive local therapy with stereotactic radiosurgery ± surgical resection if indicated

3 weeks

1 visit (in-person)

Treatment

Participants continue standard of care treatment with trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib

Until disease progression or intolerable side effects

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Pertuzumab
• Trastuzumab
• Trastuzumab Emtansine (T-DM1)
• Tucatinib

Trial Overview The study tests adding tucatinib to standard care (trastuzumab/pertuzumab or T-DM1) after local therapy like surgery or radiosurgery in patients with HER2+ breast cancer that has spread to the brain. The goal is to prevent further brain metastases and manage the disease.

Participant Groups

Group I: Experimental Group Experimental Treatment 4 Interventions

Trastuzumab/pertuzumab + tucatinib or T-DM1 + tucatinib 300mg of tucatinib taken orally twice a day. Taken on Days 1-21 of a 21 Day cycle (3 Weeks). Trastuzumab/Biosimilar administered per current package insert based on site standard of care guidelines Pertuzumab or Biosimilar administered per current package insert based on site standard of care guidelines Trastuzumab Emtansine (T-DM1) administered per current package insert based on site standard of care guidelines

Pertuzumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in United States as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Canada as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Japan as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Who Is Running the Clinical Trial?

Sarah Sammons, MD

Lead Sponsor

Trials

3

Recruited

110+

Carey Anders, M.D.

Lead Sponsor

Trials

1

Recruited

50+

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

Findings from Research

In a review of six studies involving 996 patients with HER2-positive breast cancer, the addition of pertuzumab to trastuzumab emtansine (T-DM1) ± taxane did not significantly improve objective response or clinical benefit rates compared to T-DM1 alone.

While the combination treatment was associated with increased risks of certain adverse events like diarrhea and rash, it also showed a decreased risk of thrombocytopenia, indicating a complex safety profile that requires careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the addition of pertuzumab to T-DM1 ± taxane in patients with HER2-positive, locally advanced or metastatic breast cancer: a pooled analysis. Zhang, J., Li, J., Zhu, C., et al.[2022]

In a phase Ib/IIa study involving patients with HER2-positive metastatic breast cancer (MBC) and locally advanced breast cancer (LABC), the combination of trastuzumab emtansine (T-DM1) with docetaxel showed high efficacy, achieving an 80% objective response rate in MBC and a 60.3% pathologic complete response rate in LABC.

Despite the promising efficacy, nearly half of the patients experienced adverse events (AEs) that required dose modifications, with neutropenia being the most common severe AE, affecting 72% of MBC patients and 29% of LABC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. Martin, M., Fumoleau, P., Dewar, JA., et al.[2022]

In the phase III EMILIA trial, trastuzumab emtansine (T-DM1) demonstrated a significantly better safety profile compared to capecitabine plus lapatinib (CAP + LAP) in treating HER2-positive metastatic breast cancer, leading to fewer severe treatment-related adverse events.

The management of adverse events resulted in lower costs for T-DM1 (CAD 3380) compared to CAP + LAP (CAD 6901), indicating that T-DM1 not only provides effective treatment but also offers substantial savings to the Canadian public health-care system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Profile and Costs of Related Adverse Events of Trastuzumab Emtansine for the Treatment of HER2-Positive Locally Advanced or Metastatic Breast Cancer Compared to Capecitabine Plus Lapatinib from the Perspective of the Canadian Health-Care System. Piwko, C., Prady, C., Yunger, S., et al.[2019]

In the phase 3 MARIANNE trial involving 1095 patients with HER2-positive advanced breast cancer, trastuzumab emtansine (T-DM1) demonstrated similar overall survival rates compared to trastuzumab plus a taxane, while showing better tolerability and fewer severe side effects.

Patients receiving T-DM1 had a longer median overall survival when they achieved an objective tumor response, indicating that T-DM1 is a viable first-line treatment option for those unsuitable for taxane-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Perez, EA., Barrios, C., Eiermann, W., et al.[2020]

In T-DM1-resistant HER2-positive breast cancer cells, the combination of trastuzumab and pertuzumab (TRAS + PER) showed enhanced antitumor effects, significantly inhibiting cell proliferation and inducing apoptosis compared to either drug alone.

The study demonstrated that TRAS + PER effectively suppressed tumor growth in a xenograft model of T-DM1-resistant cancer, suggesting it could be a promising treatment option for patients who develop resistance to T-DM1 while maintaining HER2 expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation. Yamashita-Kashima, Y., Shu, S., Osada, M., et al.[2021]

Trastuzumab emtansine (T-DM1) has shown a favorable safety profile in 884 patients with HER2-positive metastatic breast cancer, with most adverse events being manageable and asymptomatic, such as fatigue and nausea.

The treatment demonstrated superior efficacy compared to standard therapies in previous studies, making T-DM1 a promising option for further exploration in other breast cancer settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. Diéras, V., Harbeck, N., Budd, GT., et al.[2019]

Tucatinib, when combined with T-DM1, was found to have a maximum tolerated dosage of 300 mg twice daily, showing acceptable toxicity levels in a phase 1b trial involving 57 patients with ERBB2/HER2-positive metastatic breast cancer.

The treatment demonstrated preliminary antitumor activity, with most adverse events being mild (grade 1 or 2), although some patients experienced more serious reactions like thrombocytopenia and hepatic transaminitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. Borges, VF., Ferrario, C., Aucoin, N., et al.[2019]

In a study of 325 HER2-positive metastatic breast cancer patients, the objective response rate (ORR) for treatments following trastuzumab emtansine (T-DM1) was 22.8%, indicating limited effectiveness of post-T-DM1 therapies.

The median overall survival (OS) for patients after T-DM1 was 23.7 months, suggesting that while some patients may benefit, there is a need for further research into more effective treatment options beyond T-DM1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B). Yokoe, T., Kurozumi, S., Nozawa, K., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the addition of pertuzumab to T-DM1 ± taxane in patients with HER2-positive, locally advanced or metastatic breast cancer: a pooled analysis. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Safety Profile and Costs of Related Adverse Events of Trastuzumab Emtansine for the Treatment of HER2-Positive Locally Advanced or Metastatic Breast Cancer Compared to Capecitabine Plus Lapatinib from the Perspective of the Canadian Health-Care System. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. [2019]

8. Japan pubmed.ncbi.nlm.nih.gov

Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B). [2021]