Adjuvant Pembrolizumab and Paclitaxel Versus Surveillance in Early Triple-Negative Breast Cancer with High Stromal Tumor-Infiltrating Lymphocytes
- Trial ID
- 2023-504620-26-00
- Protocol
- UC-BCG-2213
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the 5-year investigator-assessed **distant disease-free survival** (DDFS) in patients with early-stage **triple-negative breast cancer** (TNBC). This evaluation is conducted in two cohorts: Cohort 1 includes patients aged over 40 years with 30% ≤ stromal tumor-infiltrating lymphocytes (sTILs) < 50% and those aged ≤ 40 years with 30% ≤ sTILs < 75% receiving adjuvant pembrolizumab plus paclitaxel. Cohort 2 involves patients aged over 40 years with sTILs ≥ 50% and those aged ≤ 40 years with sTILs ≥ 75% who will undergo standard surveillance without adjuvant systemic treatments. The clinical relevance of this objective lies in determining the efficacy of adjuvant pembrolizumab plus paclitaxel in improving DDFS in specific subgroups of TNBC patients, which could inform treatment decisions and improve patient outcomes.
Secondary objectives include: - Efficacy: To determine the invasive-disease-free survival, distant recurrence-free survival, and overall survival, with cohorts 1 and 2 analyzed independently. - Safety: For Cohort 1, to determine the safety and tolerability of adjuvant pembrolizumab plus paclitaxel, assessed by adverse events according to the common terminology criteria for adverse events of the National Cancer Institute version 5.0. - Quality of life assessment: To determine short and long-term patient quality of life, assessed through EORTC QLQ-C30, EORTC QLQ-BR23, EORTC QLQ-FA12, and the Hospital Anxiety and Depression Scale (HADS) – anxiety subscale in the two cohorts. - Pooled analysis: To perform a pooled analysis of survival outcomes in cohort 2 together with the similar EORTC OPTIMAL study and, if feasible, other further international studies evaluating adjuvant treatment optimization in patients with early TNBC and high TILs.
Participants
The clinical trial involves participants diagnosed with **triple negative breast cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who have undergone either breast-conserving surgery or mastectomy. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals who are part of a vulnerable population, and the selection criteria ensure that participants have histologically confirmed and radically removed pT1b/c N0M0 TNBC, as defined by the AJCC TNM stage-8th version. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must demonstrate adequate organ function and have a left ventricular ejection fraction (LVEF) of ≥ 50% for cohort 1. The trial requires compliance with protocol-specified contraception methods for both men and women of childbearing potential. Participants must be willing and able to comply with the trial protocol, including treatment, scheduled visits, and follow-up examinations. The sponsor has not disclosed additional details regarding the selection process or specific lifestyle factors.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **pembrolizumab** in combination with **paclitaxel** for the treatment of early-stage **triple negative breast cancer** (TNBC) with high stromal tumor-infiltrating lymphocytes (TILs) score. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on March 1, 2024, and conclude by December 1, 2031. The study involves two cohorts: Cohort 1 will receive adjuvant pembrolizumab plus paclitaxel, while Cohort 2 will undergo standard surveillance without adjuvant systemic treatments. The primary endpoint is the 5-year investigator-assessed distant disease-free survival (DDFS).
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ECOG performance status, and histological confirmation of TNBC. Following the inclusion visit, participants in Cohort 1 will receive treatment every three weeks, with safety and tolerability assessments conducted at each visit. Follow-up visits will occur every six months for five years to monitor long-term outcomes, including DDFS, invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), and overall survival (OS). The end-of-study visit will mark the completion of the trial for each participant.
The expected length of participant involvement is up to 36 months for those receiving treatment, with additional follow-up extending to five years. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or non-compliance with the protocol. Participants must agree to use specified methods of contraception during the trial and for a defined period after the last dose of trial treatments. The trial will also include quality of life assessments and exploratory analyses of tumor tissue and blood samples to further understand the treatment's impact.
Treatment
The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for infusion, with a concentration of 25 mg/mL. The active substance, pembrolizumab, is a protein-based therapeutic agent. The maximum daily dose is 200 mg, with a total maximum dose of 1800 mg over a treatment period of up to 27 weeks. The infusion is administered intravenously, and the dosing schedule is determined by the study protocol. Compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the treatment plan.
In addition to pembrolizumab, the trial includes the administration of **PACLITAXEL**, another **concentrate for solution for infusion**. Paclitaxel is a chemical-based therapeutic agent used in the study. The maximum daily dose for paclitaxel is 80 mg/m², with a total maximum dose of 2880 mg/m² over a treatment period of up to 36 weeks. Similar to pembrolizumab, paclitaxel is administered intravenously, and the dosing schedule is aligned with the study protocol. Participant compliance with the administration schedule is closely monitored to ensure the integrity of the trial data.
The trial also includes a comparator group undergoing standard surveillance without adjuvant systemic treatments. This group serves as a control to evaluate the efficacy of the experimental treatments. The study design ensures that all participants receive appropriate monitoring and care throughout the trial duration.
Efficacy
Efficacy in this clinical trial will be assessed using several endpoints. The primary endpoint is **Distant Disease-Free Survival (DDFS)**, which is defined as the time from inclusion to the occurrence of distant recurrence of breast cancer, a second primary non-breast cancer, or death from any cause. Secondary efficacy endpoints include **Invasive Disease-Free Survival (IDFS)**, **Distant Recurrence-Free Survival (DRFS)**, and **Overall Survival (OS)**. IDFS is measured from the time of inclusion to events such as ipsilateral invasive breast tumor recurrence, regional invasive breast tumor recurrence, distant recurrence, death from any cause, or a second primary malignancy. DRFS is defined from the time of inclusion to distant recurrence of breast cancer or death from any cause. OS is measured from the time of inclusion to the date of death from any cause.
Quality of life will be assessed using validated instruments, including the EORTC QLQ-C30, EORTC QLQ-B23, EORTC QLQ-FA12, and the HADS anxiety subscale. Safety and tolerability of pembrolizumab plus paclitaxel will be evaluated every 3 weeks during treatment and every 6 months for 5 years from study entry. Exploratory endpoints will involve comprehensive analysis of tumor tissue and blood samples. The trial will include two cohorts, with efficacy assessments tailored to the specific characteristics and treatment regimens of each cohort. The study is designed to provide a robust evaluation of the efficacy of pembrolizumab in combination with paclitaxel in patients with early triple-negative breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed
- Men and women aged ≥ 18 years,
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1,
- Histologically confirmed and radically removed pT1b/c N0M0 TNBC as defined according to AJCC TNM stage-8th version, • Histologically documented TNBC (negative HER2, ER, and PgR status). HER2 negativity is defined by local laboratory assessment using in situ hybridization and immunohistochemistry assays as per ASCO/CAP criteria and ER/PgR negativity is defined by local laboratory assessment < 10% using immunohistochemistry assays, • Bilateral and/or multifocal primary tumor is allowed and the tumor with the most advanced T stage should be used to asses for eligibility. If multifocal tumor, a pathologic confirmation of TNBC is required for each focus, • Has a prior history of DCIS and/or LCIS at any time point before disease are eligible • Patients with germinal BRCA 1/2 mutation are eligible • Patient with N1 lymph node micrometastasis are not eligible
- Adequately excised breast cancer: subjects must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy.
- Have had sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) for evaluation of pathologic nodal status. Axillary nodal dissection(s) should yield a total of at least six nodes (including the axillary lymph nodes resected at the SLNB plus the lymph nodes collected at the axillary nodal dissection)
- At least 4 weeks but no more than 12 weeks between definitive breast surgery (or the last surgery with curative intent if additional resection is required for breast cancer) and treatment initiation for cohort 1 and no more than 12 weeks for cohort 2,
- Centrally assessed TILs rate from surgical FFPE tumor sample , using an H&E stained diagnostic digital slide, according to the most recent International TILs Working Group guidelines,
- Women of childbearing potential have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication for cohort 1 and within 7 days of inclusion for cohort 2,
- Women of childbearing potential must agree to use protocol-specified method(s) of contraception for 3 years after patient inclusion. Men subjects who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception during trial treatments and for at least 6 months after the last dose of trial treatments. Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year,
- Patients affiliated to the social security system (or equivalent)- France only,
- Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.
- For cohort 1 : Left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by echocardiogram or cardiac scintigraphy
- For cohort 1 : Demonstrate adequate organ function within 7 days of inclusion
Exclusion Criteria
- History of invasive malignancy, including breast cancer, ≤ 3 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer. A breast cancer occurring more than 3 years before inclusion will be eligible
- Having received prior chemotherapy or targeted therapy within the past 12 months
- Patient age ≤ 40 years with lymphovascular invasion are not eligible
- Having received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agents or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
- Treatment with systemic immunostimulatory agents (including, but not limited to, interferons, interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to inclusion
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive medications (including prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] alpha agents) within 7 days prior to inclusion
- 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). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment; subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible if: Rash must covers <10% of body surface area & Disease is well controlled at baseline and requires only low-potency topical Corticosteroids and no acute exarcerbations requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or oral corticosteroids occurred within the previous 12 months
- Has a known history of Human Immunodeficiency Virus (HIV),
- Prior allogeneic stem cell or solid organ transplant,
- Has a known history of active Bacillus Tuberculosis,
- Patients with any other disease or illness which requires hospitalisation or is incompatible with the trial treatment are not eligible,
- Pregnant women or breastfeeding or expecting to conceive within the projected duration of the study, from the inclusion visit until the end of the 3 years follow up. Men subjects who engage in heterosexual intercourse and refuse to use protocol-specified method(s) of contraception during trial treatments and for at least 6 months after the last dose of trial treatments,
- Patients unable to comply with trial obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the trial,
- Person deprived of their liberty or under protective custody or guardianship,
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- For cohort 1 : Has cardiac dysfunction as defined by any of the following prior to inclusion: - History of NCI-CTCAE v5.0 Grade > 3 symptomatic congestive heart failure or New York Heart Association (NYHA) criteria Class II, - Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease, - Significant symptoms (≥ Grade 2) relating to left ventricular dysfunction or cardiac ischemia,
- For cohort 1 : Has a known hypersensitivity (≥ Grade 3) to the components of the study therapy or its analogs,
- For cohort 1 : Has received a live vaccine or live-attenuated vaccine within 30 days of the first dose of study treatment
- For cohort 1 : Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection
- For cohort 1 : Severe infections within 4 weeks prior to initiation of study treatment, including, hospitalization for complications of infection, bacteremia, or severe pneumonia,
- For cohort 1 : Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment; subjects receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection) are eligible,
- For cohort 1 : Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during study treatment,
- For cohort 1 : Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has a current pneumonitis/interstitial lung disease
- For cohort 1 : Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 4 weeks of the first dose of treatment in this current trial.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Mar 2024 | 244 |
 Spain | Recruiting | 01 Mar 2024 | 120 |
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 |
|---|---|---|---|---|---|---|
PACLITAXEL | Test | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 80 | 36 | SUB09583MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 200 | 27 | PRD4323105 |