HER2-targeted Therapy + Immunotherapy for Breast Cancer

Recruiting at 4 trial locations

Overseen By Meredith Carter

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cedars-Sinai Medical Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Pregnancy, Autoimmune disease, Cardiovascular, others

Stay on Your Current Meds You can continue your current medications while participating

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: Unknown

Duration: 12 weeks

138 Participants Needed

Trial Summary

What is the purpose of this trial?

A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel (THP) as compared to neoadjuvant trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel (THP-pembrolizumab), or neoadjuvant trastuzumab, pembrolizumab and weekly paclitaxel (TH-pembrolizumab ) in chemo naive patients with invasive human epidermal growth factor receptor 2 (HER2) positive breast cancer whose primary tumors are \> 2 cm and/or clinically lymph node positive. Treatment will be followed by standard of care breast surgery and physician's choice adjuvant therapy per standard of care.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or have received certain treatments like live vaccines or investigational drugs recently, you may need to stop those before joining the trial.

What data supports the effectiveness of the drug combination of HER2-targeted therapy and immunotherapy for breast cancer?

Research shows that adding pertuzumab to trastuzumab and chemotherapy significantly improves survival rates in patients with HER2-positive metastatic breast cancer. This combination has been shown to increase progression-free survival and overall survival, making it a promising treatment option. ^{1 2 3 4 5}

Is the combination of HER2-targeted therapy and immunotherapy safe for humans?

The safety of pertuzumab, a drug used in HER2-targeted therapy, has been studied, and while it is effective, its cardiac (heart-related) safety needs continuous monitoring. Studies have shown that when used with trastuzumab, there are concerns about heart health, so patients should be monitored for heart-related side effects. ^{6 7 8 9 10}

What makes the HER2-targeted therapy with Paclitaxel, Pembrolizumab, Pertuzumab, and Trastuzumab unique for breast cancer?

This treatment is unique because it combines HER2-targeted therapy with immunotherapy, using drugs like trastuzumab and pertuzumab to block cancer cell growth and pembrolizumab to boost the immune system's ability to fight cancer, offering a novel approach for patients who may have developed resistance to standard HER2 therapies. ^{1 5 11 12 13}

Research Team

Heather McArthur, MD

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for adults with untreated, non-metastatic HER2-positive breast cancer that's larger than 2 cm or has spread to lymph nodes. Participants must have good organ function and performance status, not be pregnant or breastfeeding, agree to use contraception, and provide a tumor tissue sample. Exclusions include prior treatments affecting the immune system, recent vaccines, active infections like HIV/Hepatitis/TB, other cancers within 3 years, significant heart disease or mental health issues.

Inclusion Criteria

My cancer has not spread to distant parts of my body and has not been treated yet.

I can provide a sample of my tumor for testing.

I am a man and agree to use birth control and not donate sperm during treatment.

Exclusion Criteria

I have had or currently have lung inflammation treated with steroids.

I have an autoimmune disease treated with medication in the last 2 years.

I have an immune system disorder or I am on long-term steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant trastuzumab, pertuzumab, and weekly paclitaxel, with or without pembrolizumab, for four cycles followed by breast surgery

12 weeks

Weekly visits for paclitaxel administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of residual cancer burden and adverse events

4 weeks

Long-term follow-up

Participants are monitored for event-free survival, invasive disease-free survival, and overall survival

36 months

Treatment Details

Interventions

• Paclitaxel
• Pembrolizumab
• Pertuzumab
• Trastuzumab

Trial Overview The study compares three pre-surgery drug combinations for breast cancer: THP (trastuzumab + pertuzumab + paclitaxel), THP-K (THP plus pembrolizumab), and TH-K (trastuzumab + pembrolizumab + paclitaxel). It aims to see which combination is most effective and safe before standard surgery and follow-up care.

Participant Groups

Group I: Arm C: TH-Pembrolizumab Experimental Treatment 3 Interventions

Arm C: Paclitaxel weekly x12 + Trastuzumab + Pembrolizumab All subjects may receive standard of care systemic therapy after surgery per their treating physician's discretion.

Group II: Arm B: THP-Pembrolizumab Experimental Treatment 4 Interventions

Arm B: Paclitaxel weekly x12 + Trastuzumab + Pertuzumab + Pembrolizumab All subjects may receive standard of care systemic therapy after surgery per their treating physician's discretion.

Group III: Arm A: THP Active Control 3 Interventions

Arm A: Paclitaxel weekly x12 + Trastuzumab + Pertuzumab All subjects may receive standard of care systemic therapy after surgery per their treating physician's discretion.

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

Approved in United States as Taxol for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Approved in European Union as Taxol for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Approved in Canada as Paclitaxel for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Who Is Running the Clinical Trial?

Cedars-Sinai Medical Center

Lead Sponsor

Trials

523

Recruited

165,000+

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Breast Cancer Research Foundation

Collaborator

Trials

79

Recruited

40,500+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

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]

A study involving 808 patients with HER-2 positive breast cancer showed that adding pertuzumab to trastuzumab and docetaxel significantly improved overall survival, with a 3-year survival rate increase of 10% to 15%.

While pertuzumab did not worsen cardiac toxicity in patients with low cardiovascular risk, it was associated with increased side effects such as severe diarrhea and skin disorders, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

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]

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 case series of 19 patients with previously treated HER2-positive metastatic breast cancer, the combination of pertuzumab, trastuzumab, and taxane therapy resulted in a median progression-free survival of 4.1 months.

The treatment was associated with minimal adverse effects, showing only a slight decrease in left ventricular ejection fraction (-1%) and no occurrences of neutropenic fever, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination pertuzumab, trastuzumab, and taxane for metastatic breast cancer after first progression: a single institution's experience. Dao, BD., Ho, H., Quintal, LN.[2016]

A comprehensive analysis of 14,707 adverse events related to pertuzumab from the FDA Adverse Event Reporting System revealed significant safety concerns, including potential risks of myelosuppression, cardiotoxicity, and other serious conditions occurring in 12 organ systems.

Most adverse events, particularly cardiac-related issues, were reported within the first month of therapy, highlighting the need for careful monitoring and preparedness for emergency interventions, especially in elderly patients and those with pre-existing cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS). Zou, SP., Yang, HY., Ouyang, ML., et al.[2023]

In a study of 57 patients with HER2-positive breast cancer receiving neoadjuvant treatment with doxorubicin and cyclophosphamide followed by trastuzumab and pertuzumab, only 3.5% developed severe heart failure, indicating a relatively low cardiac event rate.

The study found no increased risk of cardiotoxicity from the combination of trastuzumab and pertuzumab after doxorubicin-based chemotherapy, suggesting that this treatment regimen is cardiac safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer. Yu, AF., Singh, JC., Wang, R., et al.[2018]

Pertuzumab is an effective treatment for metastatic HER2-positive breast cancer, especially when combined with trastuzumab and docetaxel, showing significant improvements in progression-free and overall survival in treatment-naive patients.

As a HER dimerization inhibitor, pertuzumab works differently than trastuzumab, allowing for a more complete blockade of HER2 signaling, and has a tolerable safety profile, making it a recommended first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab for the treatment of human epidermal growth factor receptor type 2-positive metastatic breast cancer. Chung, C., Lam, MS.[2019]

In a study of 266 patients with HER2-positive metastatic breast cancer, the majority received a treatment regimen of trastuzumab, pertuzumab, and a taxane, which aligns with the standard first-line therapy.

The median progression-free survival (PFS) for patients was 16.9 months, and the safety profile, including common side effects like fatigue and diarrhea, was consistent with findings from the pivotal CLEOPATRA trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes. Robert, NJ., Goertz, HP., Chopra, P., et al.[2020]

References

1. 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]

2. France pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

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

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

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Combination pertuzumab, trastuzumab, and taxane for metastatic breast cancer after first progression: a single institution's experience. [2016]

6. England pubmed.ncbi.nlm.nih.gov

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS). [2023]

7. England pubmed.ncbi.nlm.nih.gov

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Pertuzumab for the treatment of human epidermal growth factor receptor type 2-positive metastatic breast cancer. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes. [2020]

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

Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. [2023]

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

Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment. [2020]

12. England pubmed.ncbi.nlm.nih.gov

New treatment strategies for human epidermal growth factor receptor 2-positive breast cancer in 2023. [2023]

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

Use of pertuzumab for the treatment of HER2-positive metastatic breast cancer. [2016]