HER2-targeted Therapy + Immunotherapy for Breast Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines new treatments for individuals with HER2-positive breast cancer. It compares three different combinations of cancer drugs to determine which is most effective before surgery. The trial focuses on patients with tumors larger than 2 cm or those that have spread to nearby lymph nodes but not beyond. Individuals with HER2-positive breast cancer who have not yet received chemotherapy may be suitable candidates for this trial. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that treatments like trastuzumab, pertuzumab, and paclitaxel are usually well-tolerated. In past studies, adding pertuzumab to trastuzumab and chemotherapy improved outcomes for patients with HER2-positive breast cancer, indicating a good safety record, though some side effects were observed.

Pembrolizumab, when combined with trastuzumab and chemotherapy, demonstrated positive effects in other cancers, such as advanced stomach cancer. This suggests it might be safe in similar combinations. However, pembrolizumab can cause immune-related side effects, which are generally manageable with proper care.

Overall, the treatments in this trial have been studied before, and evidence suggests they are generally well-tolerated. Side effects can occur, but they are usually manageable and expected. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine HER2-targeted therapy with immunotherapy, offering a potentially powerful approach against HER2-positive breast cancer. Most current treatments for this condition rely on chemotherapy and HER2-targeted drugs like Trastuzumab and Pertuzumab. However, the addition of Pembrolizumab, an immunotherapy drug, aims to boost the body's immune response to cancer cells. This combination could enhance the effectiveness of treatment, potentially improving outcomes by making the immune system more capable of attacking tumors. By integrating these therapies, there's hope for a more comprehensive assault on cancer cells, potentially leading to better long-term control of the disease.

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

Research has shown that adding pembrolizumab to the standard treatment of trastuzumab, pertuzumab, and paclitaxel (THP) can improve outcomes for patients with HER2-positive breast cancer. In this trial, participants in Arm B will receive this combination, which studies like the NeoHIP trial have shown to increase the rate of pathologic complete response (pCR), meaning no cancer was found in tissue samples after treatment. This suggests the combination might be more effective than THP alone, which is being tested in Arm A. For participants in Arm C, who will receive the TH-pembrolizumab combination, studies have demonstrated that adding pembrolizumab to trastuzumab and paclitaxel also improves treatment effectiveness. Immunotherapy with pembrolizumab has been beneficial for HER2-positive breast cancer, especially in early-stage cancer when combined with chemotherapy. These findings suggest that adding pembrolizumab could enhance the effectiveness of standard treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Heather McArthur, MD

Principal Investigator

UT Southwestern Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12293757/

Real-World Outcomes of Adjuvant Paclitaxel and ... Real-World Outcomes of Adjuvant Paclitaxel and Trastuzumab Therapy in Lymph Node-Negative, HER2-Positive Early-Stage Breast Cancer: A ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9105460/

Immunotherapy for HER2-Positive Breast Cancer Immunotherapies represent a relevant option for HER2-positive breast cancer patients, both in the adjuvant and metastatic setting.

3. nature.com nature.com/articles/s41591-024-03415-7

Pembrolizumab and chemotherapy in high-risk, early-stage ... Addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes in patients with high-risk, early-stage, triple- ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666379124002672

Emerging treatments in HER2-positive advanced breast ... This review describes the evolving treatment landscape of HER2-positive breast cancer, from the current approved therapies to the future perspectives.

5. cancertherapyadvisor.com cancertherapyadvisor.com/reports/pembrolizumab-improves-upon-thp-in-her2-breast-cancer/

Pembrolizumab Improves Upon THP in HER2+ Breast ... Adding pembrolizumab to THP improved pCR rates in patients with HER2-positive breast cancer in the phase 2 NeoHIP trial.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8914190/

Immunotherapy in HER2-Positive Breast Cancer: A Systematic ... The clinical outcome of HER2-positive breast cancer patients changed with the use of anti-Her therapies, though it still remains an aggressive and fatal ...

7. merck.com merck.com/news/keytruda-pembrolizumab-plus-trastuzumab-and-chemotherapy-significantly-improved-progression-free-survival-pfs-versus-trastuzumab-and-chemotherapy-in-first-line-her2-positive-advanced-gastric/

KEYTRUDA® (pembrolizumab) Plus Trastuzumab and ... The KEYTRUDA regimen demonstrated a statistically significant PFS improvement in advanced HER2-positive gastric or GEJ adenocarcinoma in tumors expressing PD-L ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9923093/

Review of the status of neoadjuvant therapy in HER2 ... The aim of this article is to review the continually evolving treatment strategies in the neoadjuvant setting of HER2-positive breast cancer.

9. onclive.com onclive.com/view/new-adc-data-underscore-progress-and-highlight-challenges-in-her2-breast-cancer-and-tnbc-management

New ADC Data Underscore Progress and Highlight ... During the panel discussion, breast cancer experts gathered to discuss updates in HER2-positive and triple-negative disease management that were ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT03747120

Study Details | NCT03747120 | Neoadjuvant Her2-targeted ... A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel (THP) ...