Triple Drug Combo for Advanced Breast Cancer

Recruiting at 5 trial locations

Overseen By Felicitas Ambrose

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Criterium, Inc.

Must not be taking: Warfarin, Coumarin, others

Disqualifiers: Eribulin, Anthracyclines, Cardiopulmonary disease, 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: 21

Duration: 2 years

30 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently on warfarin or other coumarin derivatives, or if you have used strong CYP3A4 or CYP2C8 inhibitors or inducers recently. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the triple drug combo for advanced breast cancer?

The combination of HER2-targeted drugs like trastuzumab (Herceptin) and tucatinib (Tukysa) has shown to significantly improve outcomes for patients with HER2-positive advanced breast cancer. Additionally, eribulin has been proven to extend overall survival in patients with advanced breast cancer who have undergone multiple prior treatments. ^{1 2 3 4 5}

Is the triple drug combo for advanced breast cancer safe?

The combination of eribulin and trastuzumab has been shown to be generally safe and well-tolerated in patients with advanced HER2-positive breast cancer. Common side effects include neutropenia (low white blood cell count), which is manageable, and no severe heart issues were observed. However, regular monitoring of heart function is recommended. ^{6 7 8 9 10}

What makes the triple drug combo of Eribulin, Trastuzumab, and Tucatinib unique for advanced breast cancer?

This triple drug combo is unique because it combines Eribulin, which is promising in combination with Trastuzumab for HER2-positive breast cancer, with Tucatinib, a newer drug that specifically targets HER2, potentially offering a more comprehensive treatment approach for advanced cases. ^{11 12 13 14 15}

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and efficacy of the three-drug combination of tucatinib, trastuzumab, and eribulin in patients with de novo and recurrent unresectable metastatic HER-2/neu positive breast cancer as assessed by ORR, PFS and OS after prior treatment with a taxane, trastuzumab, and T-DM1.

Research Team

Hank Kaplan, MD

Principal Investigator

[e-mail]

Eligibility Criteria

This trial is for adults with HER2+ breast cancer that's advanced and can't be surgically removed. Participants must have had prior treatments including trastuzumab and a taxane, but not necessarily tucatinib. They should be in relatively good health otherwise, able to follow the study plan, and women of childbearing age must test negative for pregnancy.

Inclusion Criteria

My liver is functioning well.

I agree to use effective birth control during the study.

Have a life expectancy of at least 6 months, in the opinion of the site investigator

Exclusion Criteria

I have chronic Hepatitis B, C, or another long-term liver disease.

All side effects from my previous cancer treatments are mild.

You have been diagnosed with HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tucatinib, trastuzumab, and eribulin in 21-day cycles

2 years

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Eribulin
• Trastuzumab
• Tucatinib

Trial Overview The trial tests how safe and effective the combination of tucatinib, trastuzumab, and eribulin is in treating patients who've already received certain other breast cancer treatments. The effectiveness will be measured by tumor response rate, progression-free survival (PFS), and overall survival (OS).

Participant Groups

Group I: Tucatinib/Eribulin/Trastuzumab Experimental Treatment 3 Interventions

* The initial dose of trastuzumab will be given as a loading dose of 8 mg/kg intravenously (IV), unless trastuzumab was administered within the prior 4 weeks, then the initial dose of trastuzumab will be administered at a dose of 6 mg/kg. Each trastuzumab dose is given once every 21 days, except in specific circumstances where it may be given weekly to compensate for modifications in treatment schedule * Tucatinib 300 mg orally twice daily (PO BID) every day (Days 1-21) of each 21-day cycle using a modified schedule of events. Subcutaneous trastuzumab is given only once every three weeks as there is no allowance for weekly dosing. * Eribulin will be given at a dose of 1.4 mg/M2 intravenously over a 2-5 minute period on days 1 and 8 of each 21-day cycle.

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

Approved in European Union as Halaven for:

• Locally advanced or metastatic breast cancer

Approved in United States as Halaven for:

• Metastatic breast cancer
• Liposarcoma

Approved in Japan as Halaven for:

• Breast cancer
• Soft tissue sarcoma

Approved in Canada as Halaven for:

• Metastatic breast cancer

Who Is Running the Clinical Trial?

Criterium, Inc.

Lead Sponsor

Trials

18

Recruited

730+

Findings from Research

HER2 overexpression is a significant factor in 20% of breast cancers, leading to poor patient prognosis, but targeted therapies like trastuzumab, lapatinib, and pertuzumab have been shown to significantly improve outcomes for HER2-positive patients.

The FDA has recently approved the combination of trastuzumab, pertuzumab, and docetaxel as a first-line treatment for metastatic breast cancer, along with trastuzumab emtansine (T-DM1), highlighting the ongoing advancements in HER2-targeted therapies and the need to address challenges like drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-directed therapy for metastatic breast cancer. Jelovac, D., Emens, LA.[2014]

HER2-positive breast cancer, which affects about 20% of patients, has seen improved outcomes with new targeted therapies like trastuzumab and pertuzumab, especially in first-line treatment.

Emerging therapies such as tucatinib and fam-trastuzumab deruxtecan are expanding treatment options for advanced HER2-positive breast cancer, with ongoing research into biomarkers to enhance patient selection and address specific needs like brain metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Future Management of HER2-Positive Metastatic Breast Cancer. Martínez-Sáez, O., Prat, A.[2022]

HER2-positive breast cancer, which historically had a poor prognosis, can now be effectively treated with a variety of anti-HER2 therapies, significantly improving patient survival rates.

Newly developed treatments, including trastuzumab deruxtecan and trastuzumab emtansine, along with ongoing clinical trials, are expanding options for patients with advanced HER2-positive breast cancer, raising important questions about the best treatment sequences and combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. Stanowicka-Grada, M., Senkus, E.[2023]

In a trial involving 81 patients with early-stage breast cancer, the feasibility of using eribulin as adjuvant therapy was 72.9% in the group without prophylactic growth factors, which did not meet the target of over 80%.

The most common side effects of eribulin included fatigue (75.9%), peripheral neuropathy (54.4%), and neutropenia (35.4%), but no unexpected adverse events were reported, indicating that while the treatment was challenging, it was generally safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Eribulin Mesylate With or Without Prophylactic Growth Factor for Adjuvant Treatment of Early-Stage Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer. Cadoo, KA., Kaufman, PA., Seidman, AD., et al.[2023]

Eribulin mesylate (Halaven) was approved by the FDA for treating refractory metastatic breast cancer based on a study of 762 patients, showing a significant increase in overall survival (OS) of 13.1 months compared to 10.6 months for the control group.

While eribulin improved overall survival, it did not significantly affect progression-free survival, suggesting that OS should be prioritized as a primary endpoint in future clinical trials for advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eribulin mesylate for the treatment of patients with refractory metastatic breast cancer: use of a "physician's choice" control arm in a randomized approval trial. Donoghue, M., Lemery, SJ., Yuan, W., et al.[2016]

The ERI-TRA chemotherapy regimen combining eribulin and trastuzumab has been shown to be well-tolerated for long-term use in patients with HER2-positive breast cancer, as demonstrated in a Phase I study involving three patients who completed up to 27 cycles without new adverse events.

Long-term treatment did not increase the risk of serious side effects like cardiomyopathy or worsen peripheral neuropathy, and any neutropenia experienced was manageable, suggesting that ERI-TRA could be a safe and effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Saeki, T., Araki, K., Shimada, K., et al.[2020]

A feasibility study of a non-taxane triple therapy (pertuzumab, trastuzumab, and eribulin mesylate) for advanced HER2-positive breast cancer showed promising results, with no Grade 4 or 5 adverse events reported among the 10 enrolled patients.

The therapy led to significant increases in the CD8+ T cell/CD4+Foxp3+ regulatory T cell ratio, suggesting an immune response, and showed an improving trend in quality of life as measured by the FACT-B score at 3 months, indicating potential efficacy and safety for patients who cannot tolerate taxanes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers. Tono, Y., Ishihara, M., Miyahara, Y., et al.[2019]

In a study involving 12 Japanese patients with advanced HER2+ breast cancer, the combination of eribulin mesylate and trastuzumab was found to be well tolerated, with no dose-limiting toxicities observed, and the recommended dose of eribulin was established at 1.4 mg/m².

Common side effects included neutropenia, leukopenia, anemia, and alopecia, but these were manageable; however, cardiac function should be monitored due to transient decreases in ejection fraction in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer. Mukai, H., Saeki, T., Shimada, K., et al.[2021]

In a phase II study involving patients with previously treated HER2+ metastatic breast cancer, the combination of eribulin mesylate and trastuzumab-pertuzumab (HP) showed a modest objective response rate of 26.3% in patients who had not previously received pertuzumab, indicating potential efficacy in this group.

The study also found that patients who did not benefit from the treatment had more frequent alterations in the TP53 gene, suggesting that genomic alterations may help predict responses to therapy, although this finding requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer. Balch, SM., Vaz-Luis, I., Li, T., et al.[2021]

In a phase II study involving 52 patients with locally recurrent or metastatic HER2+ breast cancer, the combination of eribulin and trastuzumab resulted in a high overall response rate (ORR) of 71.2%, indicating significant efficacy as a first-line treatment.

The treatment demonstrated a median progression-free survival (PFS) of 11.6 months and an acceptable safety profile, with the most common severe side effects being neutropenia and peripheral neuropathy, suggesting it is a viable option for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. Wilks, S., Puhalla, S., O'Shaughnessy, J., et al.[2022]

A young patient with metastatic breast cancer (MBC) showed long-term clinical benefit from eribulin, both alone and in combination with trastuzumab, after HER2 amplification was detected in liver metastases.

This case suggests that eribulin combined with trastuzumab may be an effective treatment option for MBC, but further Phase III trials are needed to validate its efficacy and safety in broader patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of a third-line treatment with eribulin plus trastuzumab in a young breast cancer patient. Scavelli, C., Gallù, F.[2016]

In a study of 152 patients with HER2-positive metastatic breast cancer, the combination of taxanes with trastuzumab and pertuzumab showed a significant progression-free survival (PFS) advantage over vinorelbine in patients with newly diagnosed metastatic disease, indicating a potential benefit for this specific group.

Overall, there was no significant difference in overall survival (OS) between the two treatment groups, suggesting that both taxanes and vinorelbine are viable options when combined with trastuzumab and pertuzumab for first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study. Reinhorn, D., Kuchuk, I., Shochat, T., et al.[2021]

In a phase II trial involving 30 HER2-positive advanced breast cancer patients who had previously received multiple treatments, the combination of eribulin, pertuzumab, and trastuzumab resulted in an objective response rate of 34.8% and a median progression-free survival of 42.6 weeks.

The treatment was generally well tolerated, although 66.7% of patients experienced grade 3/4 neutropenia, leading to dose reductions in 27 patients, indicating the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer. Araki, K., Fukada, I., Yanagi, H., et al.[2018]

Trastuzumab (Herceptin) combined with endocrine therapy is a promising treatment for women with less aggressive, estrogen receptor/HER2-positive metastatic breast cancer, while for aggressive HER2-positive cases, it significantly improves survival when used with chemotherapy, particularly taxanes.

Trastuzumab has a favorable safety profile, adding little toxicity to taxane chemotherapy, and enhances quality of life compared to chemotherapy alone, making it a viable option for patients who may not tolerate cytotoxic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maximizing clinical benefit with trastuzumab. Bell, R., Verma, S., Untch, M., et al.[2019]

In a phase IIa study involving 30 patients with advanced gastric cancer, the combination of pertuzumab and trastuzumab showed a well-tolerated safety profile, with partial responses in 86% of patients receiving a specific dosing regimen.

The pharmacokinetics indicated that the serum concentration of pertuzumab was lower in this gastric cancer population compared to those with metastatic breast cancer, leading to the selection of the 840 mg q3w dose for further phase III studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Kang, YK., Rha, SY., Tassone, P., et al.[2021]

References

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

HER2-directed therapy for metastatic breast cancer. [2014]

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

Current and Future Management of HER2-Positive Metastatic Breast Cancer. [2022]

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

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. [2023]

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

Phase 2 Study of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Eribulin Mesylate With or Without Prophylactic Growth Factor for Adjuvant Treatment of Early-Stage Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer. [2023]

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

Eribulin mesylate for the treatment of patients with refractory metastatic breast cancer: use of a "physician's choice" control arm in a randomized approval trial. [2016]

6. Singapore pubmed.ncbi.nlm.nih.gov

Long-term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. [2020]

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

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers. [2019]

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

Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer. [2021]

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

Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of a third-line treatment with eribulin plus trastuzumab in a young breast cancer patient. [2016]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study. [2021]

13. Netherlands pubmed.ncbi.nlm.nih.gov

First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer. [2018]

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

Maximizing clinical benefit with trastuzumab. [2019]

15. England pubmed.ncbi.nlm.nih.gov

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. [2021]