Sequential Therapy for HER2+ Breast Cancer

Overseen By Nancy Lin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP2C8/3A4 inhibitors/inducers

Disqualifiers: Prior breast carcinoma, Heart disease, Lung 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: 17

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether a new sequence of drugs can safely and effectively treat HER2-positive breast cancer, which grows with the help of the HER2 protein. The trial involves administering a series of medications, including Trastuzumab and Pertuzumab, in different stages to determine if stopping treatment after a period is beneficial. Suitable participants have HER2-positive breast cancer that has spread and have not tried other treatments besides a specific first-line therapy involving Trastuzumab, Pertuzumab, and a Taxane (a class of chemotherapy drugs). As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot take medications that interact with the study drugs, specifically those that affect CYP2C8 and CYP3A4 enzymes. It's best to discuss your current medications with the study team.

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

Research shows that the drugs in this trial have been studied for safety in other contexts. Here's a breakdown:

1. **Trastuzumab and Pertuzumab**: These drugs are already used together to treat HER2-positive breast cancer. Studies indicate that adding trastuzumab to chemotherapy can help prevent cancer recurrence, though it may cause side effects like heart issues. Pertuzumab can lead to reactions such as diarrhea and nausea, but these effects are usually manageable.

2. **Paclitaxel, Docetaxel, and Nab-Paclitaxel**: These chemotherapy drugs are often used with trastuzumab and pertuzumab. They can cause side effects like low blood counts and allergic reactions, but they have been safely used in many patients.

3. **Trastuzumab Deruxtecan**: This newer treatment shows promise for HER2-positive breast cancer. Some patients may experience a drop in blood cell counts and lung issues, but overall, it has a solid safety profile.

4. **T-DM1 (Ado-trastuzumab emtansine)**: This drug combines trastuzumab with a chemotherapy agent. It is considered safe, with common side effects including tiredness and low platelet counts.

5. **Tucatinib**: Often used with other HER2-targeted drugs, it has shown a good safety profile. Common side effects include diarrhea and rash, but serious reactions are rare.

These treatments have been used in breast cancer patients with varying safety profiles. Discussing potential side effects with healthcare providers before joining a trial is crucial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for HER2+ breast cancer because they combine several powerful drugs in a sequential therapy approach, aiming to target the cancer cells more effectively than standard treatments. Unlike the standard of care, which often involves individual use of drugs like Trastuzumab and Pertuzumab, this protocol includes Trastuzumab Deruxtecan, a drug conjugate that delivers a potent chemotherapy agent directly to cancer cells, and Tucatinib, a kinase inhibitor that specifically blocks HER2 signaling pathways. By using these treatments in a well-structured sequence, the approach hopes to enhance efficacy and potentially overcome resistance seen in standard therapies.

What evidence suggests that this trial's treatments could be effective for HER2+ breast cancer?

In this trial, participants will receive different sequential therapies for HER2-positive breast cancer. Research has shown that combining Trastuzumab and Pertuzumab can significantly lower the risk of death in patients with HER2-positive breast cancer. Trastuzumab alone improves survival rates and reduces the likelihood of cancer recurrence. Adding Pertuzumab further decreases the risk of death by 17%. Trastuzumab Deruxtecan, administered in Part B of the trial, effectively reduces the risk of cancer progression by 53% compared to other treatments. When Tucatinib is combined with Trastuzumab and Pertuzumab, as in Parts C and D of this trial, it enhances survival and helps control cancer spread, even to the brain. These treatments show strong promise in managing HER2-positive breast cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Nancy Lin, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals with newly diagnosed HER2+ metastatic breast cancer. Participants should be suitable for a sequence of targeted therapies, but specific inclusion and exclusion criteria are not provided in the details given.

Inclusion Criteria

I have Hepatitis B or C but meet specific health criteria.

Participants with concurrent HIV infection are eligible under specific criteria

Left ventricular ejection fraction (LVEF) ≥50%

Exclusion Criteria

I had a heart attack in the last 6 months or have heart failure symptoms.

Treatment with any other investigational agents for this condition

I have had invasive breast cancer before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person) with tumor biopsy and imaging

Treatment Part A

Participants receive a Taxane plus Trastuzumab plus Pertuzumab

12 weeks

Day 1 of 21-day cycle

Treatment Part B

Participants receive Trastuzumab Deruxtecan

18 weeks

Day 1 of 21-day cycle

Treatment Part C

Participants receive Tucatinib plus Ado-Trastuzumab Emtansine (T-DM1)

12 weeks

Day 1 of 21-day cycle

Treatment Part D

Participants receive Trastuzumab plus Pertuzumab plus Tucatinib

51 weeks

Day 1 of 21-day cycle, imaging every 9 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months to 10 years

Visits every 12 weeks with imaging every 9 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Docetaxel
• Nab-Paclitaxel
• Paclitaxel
• Pertuzumab
• T-DM1
• Trastuzumab
• Trastuzumab Deruxtecan
• Tucatinib

Trial Overview The study tests a sequential treatment regimen using various drugs including Taxanes, Trastuzumab, Pertuzumab, Trastuzumab Deruxtecan, Tucatinib, and Ado-Trastuzumab Emtansine (T-DM1) to see if intensifying therapy initially then stopping is effective.

How Is the Trial Designed?

Group I: HER2+ Breast Cancer Experimental Treatment 10 Interventions

Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Translational Breast Cancer Research Consortium

Collaborator

Trials

27

Recruited

3,100+

Published Research Related to This Trial

Pertuzumab is an effective anti-HER2 monoclonal antibody that works by preventing HER2 from forming heterodimers, which reduces tumor cell growth and survival, particularly in HER2-positive metastatic breast cancer.

In the phase III CLEOPATRA trial involving a combination of pertuzumab, trastuzumab, and docetaxel, patients experienced significantly improved progression-free survival and overall survival compared to those receiving placebo, with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer. McCormack, PL.[2021]

The novel anti-HER2 antibody 5G9 showed significantly stronger synergistic effects with trastuzumab in inhibiting cell growth compared to pertuzumab, achieving an 85% inhibition rate versus 55% (P<0.001).

In animal models, the combination of 5G9 and trastuzumab demonstrated greater antitumor efficacy than the pertuzumab and trastuzumab combination, suggesting that 5G9 could be a more effective treatment option for HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity. Ding, X., Gu, W., Zhong, Y., et al.[2021]

Pertuzumab, a new monoclonal antibody targeting HER2, has shown improved patient outcomes in clinical trials for early-stage and metastatic HER2-positive breast cancer, especially when used in combination with chemotherapy and trastuzumab.

The review highlights that while trastuzumab has improved survival for HER2-positive breast cancer, there is still a need for better treatment options, which pertuzumab aims to address, particularly for patients who continue to relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations. Lamond, NW., Younis, T.[2021]

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]

Pertuzumab is a novel monoclonal antibody that acts as a dimerization inhibitor, recently approved for treating HER2-positive breast cancer, showing significant improvement in overall survival when used with trastuzumab and docetaxel in a large phase III trial.

The drug also enhances the complete pathological response rate in the neoadjuvant setting, and ongoing research is exploring its potential effectiveness in treating other solid tumors beyond breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab: development beyond breast cancer. Barthélémy, P., Leblanc, J., Goldbarg, V., et al.[2016]

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]

In a study of 55 women with HER2-positive metastatic breast cancer, the combination of trastuzumab and pertuzumab with chemotherapy resulted in a median progression-free survival (PFS) of 10 months, indicating significant efficacy in this treatment approach.

The treatment was generally safe, with common side effects including neutropenia (40%), leukopenia (34.5%), and thrombocytopenia (32.7%), but serious adverse reactions were relatively low, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab plus pertuzumab in combination with chemotherapy in metastatic HER2-positive breast cancer: a retrospective single-armed cohort study in China. Qian, Y., Peng, Y., Zhou, H., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39825877/

Efficacy and safety of KN026 and docetaxel for HER2 ... Conclusion: KN026 plus docetaxel showed promising efficacy and a manageable safety profile in first-line treatment of HER2-positive recurrent/ ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1413513

Pertuzumab, Trastuzumab, and Docetaxel in HER2 ... First-line therapy with pertuzumab, trastuzumab, and docetaxel significantly improved overall survival among patients with HER2-positive ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)03980-6/fulltext

Are all taxanes equal in patients with HER2-positive breast ... Indeed, the practice-changing CLEOPATRA trial showed that the addition of pertuzumab to trastuzumab and docetaxel improved overall survival (OS) ...

4. e-crt.org e-crt.org/journal/view.php?number=3355

Real-World Evidence of Trastuzumab, Pertuzumab, and ... Better survival outcomes were observed in patient who received docetaxel for more than six cycles. Patients exposed to anti-HER2 directed ...

5. onclive.com onclive.com/view/kn026-plus-docetaxel-demonstrates-efficacy-in-her2-metastatic-breast-cancer

KN026 Plus Docetaxel Demonstrates Efficacy in HER2+ ... KN026 combined with docetaxel achieved a 76.4% objective response rate in HER2-positive breast cancer, with a median duration of response not ...

6. gs.amegroups.org gs.amegroups.org/article/view/135000/html

Efficacy and safety analysis of a docetaxel-plus-trastuzumab ... Conclusions: The TH regimen demonstrated promise as a novel treatment alternative for patients with early-stage HER2-positive breast cancer. It ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/taxotere-epar-product-information_en.pdf

Taxotere, INN-Docetaxel - European Medicines Agency TAXOTERE in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumours over express HER2 and who ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2059702925017211

Zanidatamab in combination with docetaxel in first-line ... Zanidatamab and docetaxel first-line treatment demonstrated efficacy and manageable safety in HER2-positive breast cancer. Background. Most patients with human ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4705087/

Based Chemotherapy in Early Breast Cancer Patients ... Docetaxel-based chemotherapy did not show any significant safety concerns for early breast cancer patients of the Asia-Pacific region.