Evaluation of Capecitabine and Pembrolizumab as Adjuvant Therapy in Triple Negative Breast Cancer with Residual Disease Post-Neoadjuvant Chemoimmunotherapy

Trial ID: 2023-505291-30-01
Protocol: UC-BCG-2211, CAPPA
Sponsor: Unicancer

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Diseases & Conditions

Triple negative breast cancer

Objectives

The primary objective of this study is to evaluate the **efficacy** of post-operative **capecitabine** added to **pembrolizumab** on the invasive disease-free survival (iDFS) in subjects with **Triple Negative Breast Cancer** (TNBC) and residual disease following neoadjuvant chemotherapy associated with pembrolizumab. This is clinically relevant as it aims to improve outcomes in patients with TNBC, a subtype of breast cancer known for its aggressive nature and limited treatment options.

Secondary objectives include:

Assessing the clinical impact of the capecitabine plus pembrolizumab combination in the target population and in subgroup populations according to the Residual Cancer Burden (RCB) score, in terms of Overall Survival (OS) and Distant Disease Free Survival (DDFS). The efficacy of the experimental arm will be compared to an external cohort of patients treated with pembrolizumab as part of standard care after surgery for localized TNBC without pathological complete response (pCR) after neoadjuvant chemotherapy (NAC).
Evaluating the safety profile of the capecitabine plus pembrolizumab combination according to the use of radiation in the target population.

Participants

The clinical trial involves participants diagnosed with **Triple Negative Breast Cancer** with residual disease following neoadjuvant chemo-immunotherapy. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have undergone standard neoadjuvant chemotherapy, including a minimum of six cycles of immunochemotherapy with pembrolizumab. Participants are required to have a complete resection of the breast tumor(s) and any invaded lymph nodes, with no complete pathological response, defined as RCB Class I, II, or III. The trial population was selected based on specific inclusion criteria, such as adequate organ and bone marrow function, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or less. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations, such as diet and physical activity, are not specified. The trial includes a vulnerable population, and participants must be able to comply with study visits and procedures as per protocol.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **capecitabine** in combination with **pembrolizumab** as postoperative adjuvant therapy for patients with Triple Negative Breast Cancer (TNBC) who have residual disease following neoadjuvant chemo-immunotherapy. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the invasive disease-free survival (iDFS) as the primary endpoint, with secondary endpoints including overall survival (OS), distant disease-free survival (DDFS), and safety and tolerability as per the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0 (CTCAE v5.0).

The trial is expected to commence recruitment on October 1, 2024, and is estimated to conclude by April 30, 2028. Participants will be involved in the study for a maximum treatment period of 27 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have signed informed consent, have a histologically confirmed diagnosis of TNBC, and have undergone complete resection of the breast tumor with no complete pathological response. Participants must also have adequate organ and bone marrow function and an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator determines it is in the participant's best interest. The study will be conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

Treatment

The clinical trial involves the administration of **CAPECITABINE**, a chemotherapeutic agent, in the form of **film-coated tablets**. The active substance, capecitabine, is of chemical origin. The medication is administered orally with a maximum daily dose of 2500 mg/m² and a maximum total dose of 10000 mg/m² over a treatment period of 27 days. The administration route is specified as **infusion**, although the pharmaceutical form suggests oral intake, indicating a potential discrepancy in the data. Participant compliance with the dosing schedule will be monitored throughout the trial.

Additionally, the trial includes the administration of **PEMBROLIZUMAB**, an immunotherapeutic agent, provided as a **solution for infusion**. Pembrolizumab is a protein-based substance, specifically categorized as "Protein - Other." The maximum daily dose is set at 200 mg, with a total maximum dose of 1800 mg over the same 27-day treatment period. The administration is conducted via infusion, and adherence to the dosing regimen will be closely monitored to ensure participant compliance.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. The focus remains on evaluating the efficacy of the combination of capecitabine and pembrolizumab as postoperative adjuvant therapy for patients with **Triple Negative Breast Cancer** and residual disease following neoadjuvant chemo-immunotherapy. The trial aims to assess the impact on invasive disease-free survival (iDFS) as determined by the investigator.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the evaluation of **invasive disease-free survival (iDFS)** over a 2-year period. This primary endpoint will be measured by the time from the date of inclusion to the occurrence of invasive disease relapse or death from any cause. Secondary efficacy endpoints include Overall Survival (OS), defined as the time from inclusion to death from any cause, and Distant Disease-Free Survival (DDFS), which measures the time to distant relapse or death. For patients who are alive without distant relapse, DDFS will be censored at the date of last contact. These endpoints will also be compared to an external cohort of Triple Negative Breast Cancer (TNBC) patients without a complete pathological response after neoadjuvant chemotherapy and treated with adjuvant pembrolizumab as part of standard care post-surgery.

The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, with the primary endpoint being assessed at the 2-year mark. The trial will utilize investigator assessments to determine iDFS, while OS and DDFS will be tracked from the date of inclusion. The trial will also monitor safety and tolerability through the recording of Adverse Events (AEs) in accordance with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0 (CTCAE v5.0). The trial is designed to provide a comprehensive evaluation of the efficacy of postoperative capecitabine in combination with pembrolizumab in patients with TNBC and residual disease following neoadjuvant chemo-immunotherapy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Experimental arm : Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent;
Experimental arm : Resolution to at least grade 1 of all acute toxicities from previous therapies including immune related toxicity due to pembrolizumab, except alopecia and grade 2 immune-related endocrinopathies controlled by hormone replacement which are allowed;
Experimental arm : Minimal/maximal period for prior treatments (i.e. minimal delay from last dose of prior treatment to C1D1): breast surgery (the wound must have healed prior to C1D1) ≥2 weeks (maximum 10 weeks); last pembrolizumab injection ≥3 weeks;
Experimental arm : Women of child-bearing potential must have a negative serum pregnancy test within 7 days before C1D1;
Experimental arm : Women of child-bearing potential and male patients must agree to use 1 effective form of contraception from the time of the negative pregnancy test up to 4 months after the last dose of study drugs;
Experimental arm : Patient should be able and willing to comply with study visits and procedures as per protocol;
Experimental arm : Patients must be affiliated to a Social Security System (or equivalent).
Experimental arm : Subject ≥18 years of age on day of signing informed consent form (ICF);
Experimental arm : Histologically proven TNBC defined as follows: a. HER2 negativity (ASCO/CAP criteria) b. AND less than 10% of cells stained by immunohistochemistry (IHC) for ER and PgR;
Experimental arm : TNBC patients previously treated by standard neoadjuvant chemotherapy with a minimum of 6 cycles of immunochemotherapy containing pembrolizumab, per standard of care (and pembrolizumab label) and anthracyclines and/or taxanes (with/without carboplatin). Other drugs may be acceptable following discussion with the sponsor (with the exclusion of capecitabine);
Experimental arm : Complete resection of the breast tumor(s) (and of any invaded lymph node);
Experimental arm : No complete pathological response, defined as RCB Class I, II or III (per local assessment);
Experimental arm : Available representative formalin-fixed paraffin-embedded (FFPE) tumor block from surgery specimen with its histological report;
Experimental arm : Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2;
Experimental arm : Adequate organ and bone marrow function. All screening lab tests should be performed within 28 days before randomization;
External Cohort : Patient information prior to study entry and non-opposition to data collection
External Cohort : Subject ≥18 years of age ;
External Cohort : Histologically proven TNBC defined as follows: a. HER2 negativity (ASCO/CAP criteria) b. AND less than 10% of cells stained by immunohistochemistry (IHC) for ER and PgR;
External Cohort : TNBC patients previously treated by standard neoadjuvant chemotherapy with a minimum of 6 cycles of immunochemotherapy containing pembrolizumab, per standard of care (and pembrolizumab label) and anthracyclines and/or taxanes (with/without carboplatin). Other drugs may be acceptable following discussion with the sponsor (with the exclusion of capecitabine);
External Cohort : Complete resection of the breast tumor(s) (and of any invaded lymph node);
External Cohort : No complete pathological response, defined as RCB Class I, II or III (per local assessment);
External Cohort : Patient should have received at least one injection of pembrolizumab as post-surgery treatment (concomitantly or after radiotherapy).

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Exclusion Criteria

Experimental arm : Radiological or clinical evidence of metastatic disease documented by imaging or clinical examination performed during screening period;
Experimental arm : Has received capecitabine or other ICI than pembrolizumab in the NAC regimen;
Experimental arm : Has a known additional malignancy, excepted skin basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer or previously treated malignancy with no evidence of disease for ≥2 years;
Experimental arm : Presents a contraindication to continue pembrolizumab treatment as per respective SmPC including known hypersensitivity;
Experimental arm : Previous immune-related adverse event of any grade due to pembrolizumab that led to permanent discontinuation of pembrolizumab;
Experimental arm : Presents a contraindication to capecitabine treatment as per SmPC (See EMA website for most recent edition of SmPC);
Experimental arm : Complete DPD (Dihydropyrimidine Dehydrogenase) deficiency (a systematic screening of DPD deficiency must be performed);
Experimental arm : Patient with active infection ;
Experimental arm : Patients with history of uncontrolled or symptomatic cardiac disease ;
Experimental arm : Patients having received brivudine within 4 weeks prior to inclusion;
Experimental arm : Require the use of one of the following forbidden treatments during the study treatment period:  Any investigational anticancer therapy other than the protocol specified treatment;  Any concurrent chemotherapy, immunotherapy, biologic for cancer treatment, other than the ones stated in the protocol;
Experimental arm : Pregnant women or women who are breast-feeding;
Experimental arm : Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons;
Experimental arm : Persons deprived of their liberty or under protective custody or guardianship;
Experimental arm : Participation in another therapeutic trial within the 30 days prior to randomization.
External Cohort : Radiological or clinical evidence of metastatic disease documented by imaging or clinical examination after surgery.
External Cohort : Has received capecitabine or other ICI than pembrolizumab in the NAC regimen;
External Cohort : Has a known additional malignancy, excepted skin basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer or previously treated malignancy with no evidence of disease for ≥2 years;
External Cohort : Any investigational anticancer therapy (chemotherapy, immunotherapy, biologic for cancer treatment) other than pembrolizumab only as adjuvant treatment.