Sequential Therapy for HER2+ Breast Cancer

Overseen By Heather Parsons, MD, MPH

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

Trial Summary

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.

What data supports the effectiveness of the drugs used in the Sequential Therapy for HER2+ Breast Cancer?

Research shows that combining pertuzumab with trastuzumab and docetaxel significantly improves survival outcomes in HER2-positive breast cancer patients, as demonstrated in the CLEOPATRA trial. Pertuzumab and trastuzumab work together to effectively inhibit cancer cell growth, making them a valuable part of treatment for this type of breast cancer. ^{1 2 3 4 5}

Is the combination of pertuzumab and trastuzumab safe for treating HER2-positive breast cancer?

The combination of pertuzumab and trastuzumab has been shown to be safe in treating HER2-positive breast cancer, although it may cause side effects like diarrhea. These findings are based on clinical trials and studies that evaluated their use in both early and advanced stages of the disease. ^{1 6 7 8 9}

What makes the drug combination of Pertuzumab, Trastuzumab, Trastuzumab Deruxtecan, and Tucatinib unique for treating HER2+ breast cancer?

This drug combination is unique because it uses multiple agents that target the HER2 receptor in different ways, providing a more comprehensive blockade of HER2 signaling, which can lead to better outcomes in reducing tumor growth and improving survival rates compared to using a single drug alone. ^{2 3 4 6 10}

What is the purpose of this trial?

The purpose of this study is to test the safety and effectiveness of a sequence of drugs (a Taxane plus Trastuzumab plus Pertuzumab followed by Trastuzumab Deruxtecan, followed by Tucatinib plus Ado-Trastuzumab Emtansine (T-DM1), followed by Trastuzumab plus Pertuzumab plus Tucatinib) in HER2+ Breast Cancer. The study will help investigators understand whether first intensifying therapy for a specific period and then stopping treatment is safe and effective for participants. The names of the study drugs involved in this study are: * Paclitaxel (a type of anti-microtubule agent) * Docetaxel (a type of anti-microtubule agent) * Nab-Paclitaxel (a type of anti-microtubule agent) * Trastuzumab (a type of IgG1 kappa monoclonal antibody) * Pertuzumab (a type of monoclonal antibody) * Trastuzumab Deruxtecan (a type of HER2-directed antibody drug conjugate) * Tucatinib (Tyrosine Kinase HER2 Inhibitor) * Ado-trastuzumab emtansine or T-DM1 (a type of HER2-targeted antibody-drug conjugate)

Research Team

Heather A Parsons, MD, MPH

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

References

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

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

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

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

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity. [2021]

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

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

6. 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]

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

The expanding role of pertuzumab in the treatment of HER2-positive breast cancer. [2021]

8. China 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. [2020]

10. Greece pubmed.ncbi.nlm.nih.gov

Pertuzumab: development beyond breast cancer. [2016]