Capecitabine Plus Pembrolizumab in Patients With Triple Negative Breast Cancer After Chemo-immunotherapy and Surgery

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical trial is to evaluate the efficacity and safety of pembrolizumab and capecitabine compare to pembrolizumab alone, on the invasive disease-free survival, in participants who have triple negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy associated with pembrolizumab.

Official Title
-----------------
A Phase III, Randomized, Open-label Study to Evaluate Capecitabine Plus Pembrolizumab vs Pembrolizumab Alone as Post-operative Therapy for Triple Negative Breast Cancer With Residual Disease After Neoadjuvant Chemo-immunotherapy

Conditions
-----------------
Triple Negative Breast Neoplasms

Intervention / Treatment
-----------------
* Drug: Pembrolizumab injection
* Drug: Capecitabine tablets
* Radiation: Local radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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; Subject ≥ 18 years of age on day of signing informed consent form; Histologically proven TNBC defined as follows: Human epidermal growth factor receptor 2 (HER2) negativity (American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) criteria), AND less than 10% of cells stained by immunohistochemistry for estrogen receptor and Progesterone receptor; 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); Complete resection of the breast tumor(s) (and of any invaded lymph node); No complete pathological response, defined as residual cancer burden (RCB) Class I, II, or III (per local assessment); Note: the final recruited population will contain no more than 25% of patients with RCB I response. Available representative formalin-fixed paraffin-embedded tumor block from surgery specimen with its histological report; Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2; Adequate organ and bone marrow function. All screening lab tests should be performed within 28 days before randomization; Resolution to at least grade 1 of all acute toxicities from previous therapies including immune related toxicity due to pembrolizumab, except alopecia, immune-related endocrinopathies receiving hormone replacement, and ≤ grade 2 of neuropathy toxicity which are allowed; Minimal/maximal period for prior treatments (i.e. minimal delay from last dose of prior treatment to cycle 1 dose 1 (C1D1)): breast surgery (the wound must have healed prior to C1D1) ≥2 weeks (maximum 10 weeks); last pembrolizumab injection ≥3 weeks; Women of child-bearing potential must have a negative serum pregnancy test within 7 days before C1D1; 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 6 months after the last dose of study drugs; Patient should be able and willing to comply with study visits and procedures as per protocol; Patients must be covered by the French medical insurance. Exclusion Criteria: Radiological or clinical evidence of metastatic disease documented by imaging or clinical examination performed during screening period; Has received capecitabine or other immune-checkpoint inhibitors (ICI) than pembrolizumab in the neoadjuvant chemotherapy (NAC) regimen; 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; Presents a contraindication to continue pembrolizumab treatment as per respective summary of product characteristics (SmPC) including known hypersensitivity; Previous immune-related adverse event of any grade due to pembrolizumab that led to permanent discontinuation of pembrolizumab; Presents a contraindication to capecitabine treatment as per SmPC; Complete Dihydropyrimidine Dehydrogenase (DPD) deficiency; 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; Pregnant women or women who are breast-feeding; Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons; Persons deprived of their liberty or under protective custody or guardianship; Participation in another therapeutic trial within the 30 days prior to randomization.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A : Pembrolizumab and capecitabine<br>Pembrolizumab will be administered at a fixed dose of 200 mg every 3 weeks (Q3W), with a total of 9 cycles at adjuvant phase of the treatment; Capecitabine will be administrated at a dose of 1250 mg/m² twice a day (BID) (14 days on / 7 days off) for a total of 8 cycles, with a dose reduction at 825 mg/m² BID during radiotherapy if indicated Local radiotherapy will be performed as per standard practice if indicated. | Drug: Pembrolizumab injection<br>* On Day 1 of each cycle for a total of 9 cycles; intravenous (IV) infusion<br>* Other names: KEYTRUDA®;Drug: Capecitabine tablets<br>* 1250 mg/m² BID, on days 1-14 of each 21-day cycle; 8 cycles Dose reduction at 825 mg/m² BID during radiotherapy if indicated<br>* Other names: Xeloda;Radiation: Local radiotherapy<br>* Local radiotherapy will be performed as per standard practice if indicated.<br>|
| Active Comparator: Arm B : Pembrolizumab alone<br>Pembrolizumab will be administered at a fixed dose of 200 mg Q3W, with a total of 9 cycles at adjuvant phase of the treatment; Local radiotherapy will be performed as per standard practice if indicated. | Drug: Pembrolizumab injection<br>* On Day 1 of each cycle for a total of 9 cycles; intravenous (IV) infusion<br>* Other names: KEYTRUDA®;Radiation: Local radiotherapy<br>* Local radiotherapy will be performed as per standard practice if indicated.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-free survival (iDFS) | Invasive disease free survival (iDFS) defined as time from randomization to the first of the following events: local, regional or distant recurrence, or second primary cancer (including contralateral) or death due to any cause. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The overall survival is the length of time from randomization that patients enrolled in the study are still alive. | From randomization to death of any cause, up to 5 years. | 
| Distant disease-free survival (DDFS) | Distant disease-free survival (DDFS) is defined as the time from the date of randomization to the date of distant relapse or death due to any cause, whichever occurs first. | Throughout study completion, up to 5 years. | 
| Acute and late toxicity during the study | The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, and 5 = death) determined by the investigator, will make it possible to assess the severity of the disorders. | Throughout study completion, up to 5 years. |