Pembrolizumab + Standard Therapy for Breast Cancer

Recruiting at 251 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Pneumonitis, Metastatic cancer, Autoimmune, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 17

1240 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressive therapy or steroids, you may need to stop, as these are part of the exclusion criteria.

What data supports the effectiveness of the drug combination used in the Pembrolizumab + Standard Therapy for Breast Cancer trial?

Research shows that using taxane-based drugs like paclitaxel before anthracycline-based drugs like epirubicin and cyclophosphamide can lead to high response rates in breast cancer patients. Additionally, doxorubicin, a key component of the treatment, has historically been effective in treating metastatic breast cancer, especially when combined with other active agents. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and standard therapy for breast cancer safe?

Studies have shown that nab-paclitaxel, a form of paclitaxel, has a better safety profile compared to conventional paclitaxel, and pegylated liposomal doxorubicin combined with cyclophosphamide is considered safe in metastatic breast cancer. Additionally, non-pegylated liposomal doxorubicin with cyclophosphamide followed by paclitaxel showed no significant cardiac events in elderly patients. These findings suggest that components of the standard therapy have been evaluated for safety in breast cancer treatment. ^{4 6 7 8 9}

What makes the drug Pembrolizumab + Standard Therapy unique for breast cancer treatment?

Pembrolizumab combined with standard chemotherapy drugs like Cyclophosphamide, Doxorubicin, Epirubicin, and Paclitaxel offers a novel approach by incorporating an immunotherapy component (Pembrolizumab) that helps the immune system recognize and attack cancer cells, which is different from traditional chemotherapy that directly targets cancer cells. ^{10 11 12 13 14}

What is the purpose of this trial?

The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475) versus placebo in combination with neoadjuvant (pre-surgery) chemotherapy and adjuvant (post-surgery) endocrine therapy in the treatment of adults who have high-risk early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. The primary study hypotheses are: 1) pembrolizumab is superior to placebo, both in combination with the protocol-specified neoadjuvant anticancer therapy, as assessed by pathological Complete Response (pCR) rate defined by the local pathologist, and 2) pembrolizumab is superior to placebo (both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies) as assessed by Event-Free Survival (EFS) as determined by the investigator. The study is considered to have met its primary objective if pembrolizumab is superior to placebo with respect to either pCR (ypT0/Tis ypN0) or EFS.

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

Adults with high-risk early-stage ER+/HER2- breast cancer, confirmed by a pathologist, who have not received prior treatment for it. Participants must have adequate organ function and an ECOG performance status of 0 or 1. Men and women must agree to use contraception during the study and for some time after. Exclusions include those with certain heart diseases, active infections like hepatitis B/C or tuberculosis, HIV, other cancers within the last five years (except specific non-invasive types), previous immunotherapy treatments, severe allergies to study drugs' components.

Inclusion Criteria

I agree to use contraception and not donate sperm for up to 12 months after treatment.

My breast cancer is ER positive, HER2 negative, Grade 3, and of ductal type.

My breast cancer is invasive, not just on the surface, and is a certain size or has spread to nearby lymph nodes.

Exclusion Criteria

I haven't used any experimental drugs or devices within the last 4 weeks, or 12 months if they were for cancer.

I have an active tuberculosis infection.

My breast cancer is estrogen receptor-negative and progesterone receptor-positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant chemotherapy with either pembrolizumab or placebo in combination with paclitaxel, doxorubicin or epirubicin, and cyclophosphamide for 8 cycles

24 weeks

8 cycles (21 days each)

Surgery

Participants undergo surgery for breast cancer after completion of neoadjuvant treatment

Up to 6 weeks post-treatment

Adjuvant Treatment

Participants receive adjuvant therapy with either pembrolizumab or placebo for 9 cycles and variable endocrine therapy for up to 10 years

27 weeks for pembrolizumab/placebo, up to 10 years for endocrine therapy

9 cycles (21 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 12 years

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin
• Endocrine therapy
• Epirubicin
• Paclitaxel
• Pembrolizumab
• Placebo
• Radiation therapy
• Surgery

Trial Overview The trial is testing pembrolizumab's effectiveness compared to a placebo when given alongside pre-surgery chemotherapy and post-surgery endocrine therapy in treating early-stage breast cancer. Success is measured by complete response rate at surgery and event-free survival rates.

Participant Groups

Group I: Pembrolizumab+Chemotherapy (KX/KA[E]C) Experimental Treatment 8 Interventions

In the neoadjuvant setting, participants receive pembrolizumab (K) 200 mg via intravenous (IV) infusion once every 3 weeks (Q3W) + paclitaxel (X) 80 mg/m\^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by pembrolizumab 200 mg via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m\^2 or 100 mg/m\^2) via IV infusion either in Q2W or Q3W + cyclophosphamide (C) 600 mg/m\^2 via IV infusion either in Q2W or Q3W for 4 cycles (Treatment 2). At no more than 6 weeks after last cycle of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive pembrolizumab 200 mg via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long.

Group II: Placebo+Chemotherapy (PX/PA[E]C) Placebo Group 7 Interventions

In the neoadjuvant setting, participants receive placebo (P; normal saline or dextrose) via IV infusion Q3W + paclitaxel (X) 80 mg/m\^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by placebo via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m\^2 or 100 mg/m\^2) via IV infusion either in Q2W or Q3W + cyclophosphamide (C) 600 mg/m\^2 via IV infusion either in Q2W or Q3W for 4 cycles (Treatment 2). At no more than 6 weeks after last cycle of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive placebo via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

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

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

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

Merck Sharp & Dohme LLC

Lead 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

The combination of Doxil (40 mg/m2) and vinorelbine (30 mg/m2) was found to be effective in treating metastatic breast cancer in a phase I study involving 30 women, with a recommended schedule for further testing.

This combination therapy demonstrated a favorable toxicity profile, with minimal severe side effects like neutropenia and a low incidence of significant nausea, vomiting, or hair loss, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. Burstein, HJ., Ramirez, MJ., Petros, WP., et al.[2020]

In a phase II clinical trial involving 55 patients with operable breast cancer, preoperative chemotherapy using nanoparticle albumin-bound paclitaxel (nab-PTX) followed by an epirubicin and cyclophosphamide regimen achieved a pathological complete response (pCR) rate of 22.2%, indicating its efficacy in treating this condition.

The study found that HER2-positive patients had a significantly higher pCR rate of 60%, suggesting that HER2 status is an important factor in predicting treatment response, while the overall safety profile of the treatment was considered tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative neoadjuvant chemotherapy using nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide for operable breast cancer: a multicenter phase II trial. Futamura, M., Nagao, Y., Ishihara, K., et al.[2018]

The combination therapy of doxorubicin and paclitaxel (AT) showed a superior overall response rate (47%) and longer median time to treatment failure (8.0 months) compared to single-agent therapies, although the difference in survival rates was not significant.

Both doxorubicin and paclitaxel demonstrated equivalent efficacy, with median survivals of 18.9 months for doxorubicin and 22.2 months for paclitaxel, indicating that while combination therapy may enhance response rates, it does not necessarily lead to improved survival or quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). Sledge, GW., Neuberg, D., Bernardo, P., et al.[2022]

Doxorubicin has historically been the most effective treatment for metastatic breast cancer, especially when combined with other agents like 5-fluorouracil and cyclophosphamide, leading to improved patient outcomes.

New agents such as docetaxel have shown significantly higher response rates than doxorubicin in phase III trials, and importantly, docetaxel does not carry the same risk of cardiotoxicity, making it a promising option for combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining new agents with anthracyclines in metastatic breast cancer: an overview of recent findings. Aapro, MS.[2018]

In a study of 47 elderly women with high-risk breast cancer, the combination of Non-Pegylated Liposomal Doxorubicin (NPL-DOX) and Cyclophosphamide followed by weekly Paclitaxel showed a low rate of cardiac toxicity over a median follow-up of 76 months, with only one case of grade 3 congestive heart failure reported.

While there was a gradual decline in left ventricular ejection fraction (LVEF) over time, it remained above 50% and did not lead to any significant clinical symptoms, indicating that the treatment is relatively safe for cardiac health in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. Coltelli, L., Finale, C., Musettini, G., et al.[2023]

The combination of paclitaxel and doxorubicin has significantly improved clinical outcomes for breast cancer patients, particularly in neoadjuvant settings for locally advanced cases.

However, this combination therapy is associated with cardiac toxicity, highlighting the need for careful monitoring and future research to mitigate these risks while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast]. Ferrero, JM., Magné, N., Foa, C., et al.[2015]

Nab-PTX (Abraxane®) was administered to 31 breast cancer patients without any allergic reactions, indicating it is well tolerated, even in those with alcohol intolerance.

Among patients with locally advanced operable breast cancer, higher doses (260 mg/m²) resulted in a better response rate, with 10 out of 13 showing a partial response, suggesting its efficacy in treating advanced stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer]. Tauchi, Y., Kashiwagi, S., Ishihara, S., et al.[2015]

Nab-paclitaxel, a novel formulation of paclitaxel, has shown higher response rates and a better safety profile compared to conventional paclitaxel in a Phase III study, leading to its approval for treating breast cancer after prior chemotherapy failure.

Ongoing Phase II studies are investigating nab-paclitaxel's effectiveness as a first-line treatment for metastatic breast cancer and its potential use in other solid tumors, indicating its expanding role in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

nab-paclitaxel: a novel formulation of taxane for treatment of breast cancer. Vishnu, P., Roy, V.[2018]

Current cytotoxic therapies for metastatic breast cancer show low response rates, and resistance to these treatments is almost always developed, whether initially or over time.

There is a critical need for new therapies that can improve overall survival in patients who have developed resistance to standard treatments like anthracyclines and taxanes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Other options in the treatment of advanced breast cancer. Cobleigh, MA.[2019]

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]

Paclitaxel, when combined with doxorubicin, has shown a remarkable 95% objective response rate in chemotherapy-naive patients with metastatic breast cancer, indicating its high efficacy in treating this condition.

The treatment regimen demonstrated no signs of cardiac toxicity, allowing for further testing in patients with smaller tumors to potentially increase the rate of complete remission before surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future developments for paclitaxel in the treatment of breast cancer. Bonadonna, G.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. [2020]

2. Japan pubmed.ncbi.nlm.nih.gov

Preoperative neoadjuvant chemotherapy using nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide for operable breast cancer: a multicenter phase II trial. [2018]

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

Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). [2022]

4. England pubmed.ncbi.nlm.nih.gov

Pegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study. [2018]

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

Combining new agents with anthracyclines in metastatic breast cancer: an overview of recent findings. [2018]

6. Italy pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. [2023]

7. France pubmed.ncbi.nlm.nih.gov

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast]. [2015]

8. Japan pubmed.ncbi.nlm.nih.gov

[Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer]. [2015]

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

nab-paclitaxel: a novel formulation of taxane for treatment of breast cancer. [2018]

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

Other options in the treatment of advanced breast cancer. [2019]

11. 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]

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

The clinical efficacy of cytotoxic agents in locally advanced or metastatic breast cancer patients pretreated with an anthracycline and a taxane: a systematic review. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Pegylated Liposomal Doxorubicin, Docetaxel, and Trastuzumab as Neoadjuvant Treatment for HER2-Positive Breast Cancer Patients: A Phase II and Biomarker Study. [2022]

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

Future developments for paclitaxel in the treatment of breast cancer. [2015]