Tucatinib + Radiation for Breast Cancer

Recruiting at 1 trial location

Overseen By Dr. Katarzyna Jerzak

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Strong CYP2C8 inhibitors

Disqualifiers: Prior WBRT, Gastrointestinal diseases, 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: 9

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before enrolling. Specifically, you must have completed any prior chemotherapy, immunotherapy, or endocrine therapy at least 14 days before joining the study. Additionally, you cannot use strong CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers close to the start of the trial.

What data supports the effectiveness of the treatment Tucatinib + Radiation for Breast Cancer?

Research shows that trastuzumab (Herceptin), a drug used in this treatment, can make cancer cells more sensitive to radiation, potentially improving the effectiveness of the therapy. Additionally, combining radiation with HER2-targeting drugs like trastuzumab appears to be safe, with no excess toxicities reported. ^{1 2 3 4 5}

Is the combination of Tucatinib and Radiation safe for breast cancer treatment?

The safety of combining tucatinib (a type of targeted cancer therapy) with radiation is not well-studied, but similar treatments like trastuzumab with radiation have shown no excess risk of toxicity. Caution is advised when combining radiation with tyrosine kinase inhibitors like tucatinib due to limited evidence. ^{1 2 6 7 8}

What makes the drug combination of Tucatinib and Trastuzumab with radiation unique for treating HER2-positive breast cancer?

This treatment is unique because it combines Tucatinib, a selective oral HER2 tyrosine kinase inhibitor, with Trastuzumab and radiation, potentially offering a new option for patients whose cancer has progressed despite other therapies. Tucatinib has shown promise in improving survival and managing brain metastases, which are challenging to treat with standard therapies. ^{1 2 9 10 11}

What is the purpose of this trial?

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

Eligibility Criteria

This trial is for men and women over 18 with HER2+ metastatic breast cancer that has spread to the brain or spine. Participants should have an ECOG performance status of ≤2, indicating they can perform daily activities with some limitations. They must be two weeks past their last cancer therapy and recovered from its side effects (except mild neuropathy or hair loss). Heart function needs to be normal.

Inclusion Criteria

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

My heart's pumping ability is within the normal range.

My cancer has spread to my brain or spine.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiotherapy

Participants receive brain and/or spinal radiotherapy (XRT)

6 weeks

Weekly visits for radiotherapy sessions

Systemic Therapy

Participants receive systemic therapy with tucatinib, trastuzumab, and capecitabine

Up to 36 months

Every 3 weeks for treatment cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 100 months

Every 6 weeks for assessments

Treatment Details

Interventions

• Brain & Spinal Radiation
• Trastuzumab
• Tucatinib

Trial Overview The study tests the safety and effectiveness of combining radiation therapy for the brain/spine with systemic therapy using Tucatinib, Capecitabine, and Trastuzumab in patients with HER2+ metastatic breast cancer having leptomeningeal disease (LMD).

Participant Groups

Group I: Tucatinib, Transtuzumab, Capecitabine Experimental Treatment 4 Interventions

Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.

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

Approved in European Union as Herceptin for:

• Early breast cancer
• Metastatic breast cancer
• Advanced gastric cancer

Approved in United States as Herceptin for:

• Adjuvant treatment of HER2-positive breast cancer
• Metastatic breast cancer
• Advanced gastric cancer

Approved in Canada as Herceptin for:

• Early breast cancer
• Metastatic breast cancer
• Advanced gastric cancer

Approved in Japan as Herceptin for:

• Breast cancer
• Gastric cancer

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Viatris Inc.

Industry Sponsor

Trials

11

Recruited

5,600+

Biocon Biologics

Collaborator

Trials

1

Recruited

30+

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

Combining anti-HER2 monoclonal antibodies like trastuzumab and pertuzumab with radiation therapy appears to be safe, showing no significant increase in toxicity based on the reviewed literature.

However, caution is advised when combining radiation with tyrosine kinase inhibitors (like lapatinib and tucatinib) and certain antibody-drug conjugates, as the safety of these combinations is not well established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence. Debbi, K., Grellier, N., Loganadane, G., et al.[2023]

In a Phase II trial involving 19 patients with HER2-positive breast cancer, the combination of trastuzumab and radiotherapy was well tolerated, with manageable side effects and no cases of symptomatic cardiac dysfunction reported.

The treatment showed promising efficacy, with 43% of patients achieving a substantial pathologic response after surgery, significantly higher than a comparison group, and a median overall survival of 39 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial. Horton, JK., Halle, J., Ferraro, M., et al.[2022]

Trastuzumab (Herceptin) has been established as the standard treatment for HER-2/neu positive breast cancer in the adjuvant setting, demonstrating significant efficacy when combined with chemotherapy in randomized trials.

Different administration schedules of trastuzumab, either concurrently with chemotherapy or sequentially after treatment, have been studied, highlighting the need to balance efficacy with potential toxicities in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[HER-2/neu positive breast cancer: how to prescribe adjuvant trastuzumab (Herceptin)?]. Belkacémi, Y., Gligorov, J., Mauriac, L., et al.[2015]

Targeting HER2 with trastuzumab enhances the effectiveness of radiation therapy in breast cancer cells, particularly in those with high HER2 levels, by increasing apoptosis in a HER2-dependent manner.

The study suggests that the phosphatidylinositol 3-kinase (PI3-K) pathway plays a crucial role in this radiosensitization effect, as inhibiting this pathway significantly increased the sensitivity of HER2-overexpressing breast cancer cells to radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitization of breast cancer cells to radiation by trastuzumab. Liang, K., Lu, Y., Jin, W., et al.[2022]

Trastuzumab (Herceptin) is effective for treating advanced breast cancer in patients with HER-2/neu gene amplification or protein overexpression, showing improved survival when combined with chemotherapy agents like paclitaxel or docetaxel.

The success of Herceptin therapy is highly dependent on accurately identifying patients with HER-2/neu overexpression, and careful management is needed due to potential cardiac toxicity when used with certain chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives of immunotherapy in metastatic breast cancer. Lüftner, D., Pollmann, D., Schildhauer, S., et al.[2015]

Trastuzumab significantly improves treatment outcomes for women with HER2 positive breast cancer, as shown in four large randomized trials.

The main safety concerns associated with trastuzumab are serious infusion-related reactions and cardiotoxicity, highlighting the need to weigh the benefits against these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab in the adjuvant treatment of breast cancer. Svetlovska, D., Mardiak, J., Kristova, V.[2016]

In a study of 48 Japanese patients with early-stage HER2-positive breast cancer, adjuvant trastuzumab treatment showed a low incidence of cardiac events, suggesting it is a safe option for this population.

The disease-free survival rates were high, with 97.5% at 1 year and 92.9% at 2 years, indicating that trastuzumab is effective in preventing cancer recurrence in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac safety of trastuzumab as adjuvant treatment for Japanese patients with early breast cancer. Ishihara, M., Mukai, H., Nagai, S., et al.[2022]

In a study of 1,503 patients with early-stage HER-2-positive breast cancer, concurrent treatment with trastuzumab and radiotherapy did not lead to an increase in acute adverse events after surgery, indicating a favorable safety profile.

While there was a higher incidence of leukopenia in patients receiving trastuzumab compared to those who did not, the overall rates of cardiac events remained low and stable, suggesting that the combination treatment is safe in terms of cardiac health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. Halyard, MY., Pisansky, TM., Dueck, AC., 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]

Tucatinib, at a recommended phase 2 dose of 300 mg twice daily, demonstrated acceptable safety with manageable side effects, including diarrhea and nausea, in a study of 60 patients with HER2-positive breast cancer.

The combination of tucatinib with capecitabine or trastuzumab showed promising anti-tumor activity, with an objective response rate of 83% for tucatinib plus capecitabine, indicating its potential as an effective treatment option for patients who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Murthy, R., Borges, VF., Conlin, A., et al.[2022]

HER2-positive breast cancer, which makes up 20-25% of breast cancers, has seen improved management and outcomes over the last decade with the introduction of trastuzumab, a monoclonal antibody targeting the HER2 receptor.

Despite the effectiveness of trastuzumab, resistance can develop, leading to the exploration of additional therapies such as lapatinib, pertuzumab, and neratinib, which are being investigated for their potential benefits in patients who progress under trastuzumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of metastatic HER2-positive breast cancer: present and future]. Guiu, S., Coudert, B., Favier, L., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence. [2023]

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

Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial. [2022]

3. France pubmed.ncbi.nlm.nih.gov

[HER-2/neu positive breast cancer: how to prescribe adjuvant trastuzumab (Herceptin)?]. [2015]

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

Sensitization of breast cancer cells to radiation by trastuzumab. [2022]

5. Greece pubmed.ncbi.nlm.nih.gov

Perspectives of immunotherapy in metastatic breast cancer. [2015]

6. Slovakia pubmed.ncbi.nlm.nih.gov

Trastuzumab in the adjuvant treatment of breast cancer. [2016]

7. Japan pubmed.ncbi.nlm.nih.gov

Cardiac safety of trastuzumab as adjuvant treatment for Japanese patients with early breast cancer. [2022]

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

Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. [2022]

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

Tucatinib Impresses in Breast Cancer. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Management of metastatic HER2-positive breast cancer: present and future]. [2019]