Phase III Randomized, Double-Blind Study of Pembrolizumab with Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in High-Risk ER+/HER2- Breast Cancer
- Trial ID
- 2023-506921-12-00
- Protocol
- MK-3475-756
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the rate of **pathological complete response (pCR)** at the time of surgery, using the definition of ypT0/Tis ypN0 as assessed by the local pathologist, between pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies. This objective is clinically relevant as achieving pCR is associated with improved long-term outcomes in patients with high-risk early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer.
Secondary objectives include:
- Comparing overall survival (OS) following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies.
- Comparing the rate of pCR at the time of surgery, using the definition of ypT0 ypN0 as assessed by the local pathologist, between pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
- Comparing the rate of pCR at the time of surgery, using the definition of ypT0/Tis as assessed by the local pathologist, between pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
- Comparing the rate of pCR at the time of surgery, using three definitions (ypT0/Tis ypN0, ypT0 ypN0, and ypT0/Tis) as assessed by the local pathologist, between pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies in individuals with PD-L1 positive tumors (combined positive score [CPS] ≥1).
- Comparing event-free survival (EFS) as determined by the investigator and OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies in individuals with PD-L1 positive tumors (CPS ≥1).
- Evaluating the safety and tolerability of pembrolizumab combined with neoadjuvant chemotherapy and adjuvant endocrine therapy within and across the neoadjuvant and adjuvant periods.
- Evaluating health-related quality of life (QoL) assessments using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) and the EORTC Breast Cancer-specific QoL Questionnaire (QLQ-BR23) within and across the neoadjuvant and adjuvant periods.
Participants
The clinical trial involves a total of **854 participants** diagnosed with **ER+/HER2- Breast Cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having a localized invasive breast ductal adenocarcinoma confirmed by a local pathologist, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial population is characterized by adequate organ function and adherence to contraception requirements during and after the treatment period. Lifestyle considerations such as diet and physical activity are not specified. The study includes a vulnerable population, indicating a careful selection process to ensure participant safety and compliance with ethical standards.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and safety of **pembrolizumab** in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy for the treatment of high-risk early-stage **ER+/HER2- breast cancer**. The trial aims to compare the pathological complete response (pCR) rate and event-free survival (EFS) between the pembrolizumab and placebo groups. The study is expected to run from December 27, 2018, to July 30, 2031, with participants involved for a maximum treatment period of 51 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as tumor size, grade, and hormone receptor status. Following the screening, participants will be randomized to receive either pembrolizumab or placebo, both in combination with specified neoadjuvant chemotherapy agents, including **paclitaxel**, **epirubicin**, **doxorubicin**, and **anhydrous cyclophosphamide**, administered via **intravenous infusion**. The treatment phase will be followed by regular follow-up visits to monitor response and adverse events, with the primary endpoint being assessed at the time of surgery. The end-of-study visit will occur after the completion of the adjuvant therapy phase, where final assessments of efficacy and safety will be conducted.
The expected length of participant involvement is approximately 51 weeks, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study duration.
Treatment
The clinical trial involves the administration of several **experimental medications** and a **placebo**. **Paclitaxel** is administered as an intravenous infusion with a pharmaceutical form identified as PHF00016MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 80 mg/m² and a total maximum dose of 960 mg/m² over a treatment period of up to 12 weeks. **Paclitaxel** is a chemical substance, and its administration is monitored to ensure compliance with the dosing schedule.
**Epirubicin** is also administered via intravenous infusion, with a pharmaceutical form of PHF00231MIG. The maximum daily dose is 100 mg/m², and the total maximum dose is 400 mg/m² over a 12-week period. As a chemical substance, **epirubicin** requires careful monitoring to ensure adherence to the prescribed dosing regimen.
The **placebo** used in the trial is a solution of normal saline or dextrose, serving as a comparator to the active treatment, **Keytruda**. The placebo is administered in a manner consistent with the active treatment to maintain the double-blind nature of the study.
**Keytruda** (pembrolizumab) is provided as a 25 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 200 mg and a total maximum dose of 3400 mg over a 51-week period. **Pembrolizumab** is a biological substance, and its administration is closely monitored to ensure participant compliance and safety.
**Doxorubicin** is administered as an intravenous infusion with a pharmaceutical form of PHF00231MIG. The maximum daily dose is 60 mg/m², and the total maximum dose is 240 mg/m² over a 12-week period. As a chemical substance, **doxorubicin** requires adherence to the dosing schedule to ensure efficacy and minimize adverse effects.
**Anhydrous cyclophosphamide** is administered via intravenous injection, with a pharmaceutical form of PHF00231MIG. The maximum daily dose is 600 mg/m², and the total maximum dose is 2400 mg/m² over a 12-week period. Compliance with the dosing schedule is essential for the effectiveness of this chemical substance in the treatment regimen.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Pathological Complete Response (pCR) Rate** using the definition of ypT0/Tis ypN0 and **Event-Free Survival (EFS)**. These endpoints will be evaluated to compare the effects of pembrolizumab versus placebo, both in combination with protocol-specified neoadjuvant and adjuvant anticancer therapies. The pCR rate will be assessed at the time of surgery, as determined by the local pathologist.
Secondary endpoints include **Overall Survival (OS)**, various definitions of pCR rates, EFS and OS in participants with a Combined Positive Score (CPS) ≥1, and the number of participants experiencing adverse events (AEs), serious adverse events (SAEs), and immune-related AEs (irAEs). Additionally, the study will evaluate the number of study treatment discontinuations due to AEs and changes from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core 30 (QLQ-C30) and the EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) scores.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size ≥2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2. - Note: Inflammatory breast cancer is allowed.
- Has centrally confirmed ER+/HER2-, Grade 3 breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines.
- Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, grade, and PD-L1 status. - Note: Sponsor agreement is required for formalin-fixed paraffin-embedded (FFPE) tumor tissue sample or slides that were obtained greater than 60 days prior to the date that the documented informed consent was obtained.
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment.
- Male participants must agree to use contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period.
- Female participants must agree to use effective contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo.
- Has adequate organ function.
Exclusion Criteria
- Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.
- Has breast cancer with lobular histology.
- Has bilateral invasive breast cancer.
- Has metastatic (Stage IV) breast cancer.
- Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
- Has any of the following clinical lymph node staging per current American Joint Committee on Cancer (AJCC) staging criteria for breast cancer staging based on radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c.
- Has ER-, progesterone receptor positive breast cancer.
- Has undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or has undergone sentinel lymph node biopsy prior to study treatment.
- Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years. - Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, ductal breast carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
- Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
- Has a known history of active tuberculosis (Bacillus tuberculosis).
- Has an active infection requiring systemic therapy.
- Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
- Has other significant cardiac disease, such as: 1) History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months. or 2) Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has a known history of hepatitis B or known active hepatitis C virus infection
- Has received prior treatment for breast cancer.
- Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137).
- Has received a live vaccine within 30 days prior to the first dose of study treatment.
- Has severe hypersensitivity (≥Grade 3) to any of the components or excipients used in the study treatments.
- Is/was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks (12 months for an investigational agent or device with anticancer or antiproliferative properties) prior to the first dose of study treatment.
- Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 27 Dec 2018 | 16 |
 France | Not Recruiting | 27 Dec 2018 | 85 |
 Germany | Not Recruiting | 27 Dec 2018 | 73 |
 Hungary | Not Recruiting | 27 Dec 2018 | 71 |
 Ireland | Not Recruiting | 27 Dec 2018 | 7 |
 Poland | Not Recruiting | 27 Dec 2018 | 77 |
 Portugal | Not Recruiting | 27 Dec 2018 | 30 |
 Spain | Not Recruiting | 27 Dec 2018 | 65 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 51 | PRD4323105 |
EPIRUBICIN | Other | PHF00231MIG | INTRAVENOUS INFUSION | 100 | 12 | SCP1978341 |
PACLITAXEL | Other | PHF00016MIG | INTRAVENOUS INFUSION | 80 | 12 | SCP247399 |
Pacebo to Keytruda: Normal saline or dextrose | Placebo | N/A | — | — | — | N/A |
DOXORUBICIN | Other | PHF00231MIG | INTRAVENOUS INFUSION | 60 | 12 | SCP1712543 |
CYCLOPHOSPHAMIDE | Other | PHF00231MIG | INTRAVENOUS INJECTION | 600 | 12 | SCP1728208 |