Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC

Study Design and Treatment (continuation): The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with an approximate 1:1 distribution between both groups. A safety dose testing or "run-in-phase", with a 6+6 design, in which toxicity will be evaluated within the first cycle, will be performed since pembrolizumab in combination with gemcitabine has not been previously tested. Initially 6 patients will be included in the study at dose level 0 (gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle): * If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be included at the current dose level. If there is a confirmation of this dose to be safe (≤ 3 patients experiencing DLT), this will be considered the RP2D and it will be used for the following recruited patients. * If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12 patients included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a dose of 1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) will be performed. In this case, a group of 12 additional patients will be included at dose level -1, if ≥ 4 experience DLT, this combination will be considered too toxic and the study will be stopped. If ≤ 3 experience DLT with this combination, this will be considered the RP2D and it will be used for the following recruited patients. Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be followed closely during the first cycle to observe the occurrence of any DLT. At the times these 3 patients are completing the first cycle, the next 3 patients will be included one by one, until the first cohort is completed. If none of these 6 patients have a DLT, up to 4 patients will be allowed for inclusion from the second cohort of 6 patients; they will follow the same procedure as in the first cohort. If one of these patients from the second cohort has a DLT, the inclusion will be in smaller groups (with a maximum number of 4 patients with DLT) and following the same procedure as in the first cohort of 6 patients. An internal committee will periodically review the safety data in order to take the decision to maintain or decrease the dose level. This internal committee will consist of the chief investigator, the Spanish Breast Cancer Research Group Scientific Director and the study statistician. The meetings will be performed by teleconference to take these decisions as quickly as possible once the last patient finishes the first cycle of treatment. Other meetings will be considered ad-hoc whenever necessary (i.e when new DLTs appear). Patients included in the run-in-phase at the same dose than that in the phase II will be considered for the phase II analysis. Study Drug/Medication: Eligible patients will be enrolled and treated with: Pembrolizumab at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle. in combination with Gemcitabine at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with pembrolizumab in the initial exploratory run-in-phase if necessary) as an intravenous (IV) infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of gemcitabine in combination with fixed doses of pembrolizumab. Primary Objective: * Run-in-phase: To determine the Recommended Phase II Dose (RP2D) of gemcitabine in combination with fixed doses of pembrolizumab. * Phase II: To assess the efficacy of pembrolizumab in combination with gemcitabine in terms of Objective Response Rate (ORR) in patients with HER2-negative ABC. Primary End-point: * Run-in-phase: To determine the incidence rate of Dose Limiting Toxicity (DLT) within the first cycle of the combination. * Phase II: Objective Response Rate (ORR) is defined as Complete Response (CR) plus Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Secondary Objectives: The following secondary objectives will be studied: * To assess other efficacy measures of the combination in patients included in the phase II (including those in the run-in-phase at the same dose that in the phase II). * To determine safety and tolerability of the combination in all patients included in the study. Secondary End-points: The following secondary end-points will be studied: * Efficacy: * Progression-Free Survival (PFS) assessed according to RECIST version 1.1 by the investigator. * Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response (PR) plus Stable Disease (SD) lasting ≥ 24 weeks according to RECIST version 1.1. * Response Duration (RD) assessed according to RECIST version 1.1. * Overall Survival (OS). With special interest on long term responders (i.e. alive and without disease progression after 24 months of study treatment). * Safety will be assessed by standard clinical and laboratory tests (haematology, serum chemistry). Adverse Events (AE) grade will be defined by the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0. Exploratory Objectives: The following exploratory objectives will be studied in all patients included in the study unless otherwise specified: * To assess other efficacy measures of the combination based on immune-related (ir) response criteria in patients included in the phase II (including those in the run-in-phase at the same dose that in the phase II). * To search for tumour tissue and peripheral blood biomarkers of clinical activity. * To compare biomarkers data from cohorts of healthy volunteers (if available) with data from patients included in the study. Exploratory End-points: The following exploratory end-points will be studied: * Efficacy: * ORR is defined as immune-related Complete Response (irCR) plus immune-related Partial Response (irPR) according to immune-related RECIST (irRECIST). * Progression-Free Survival (PFS) assessed according to irRECIST by the investigator. * Clinical Benefit Rate (CBR) defined as irCR plus irPR plus immune-related Stable Disease (irSD) lasting ≥ 24 weeks according to irRECIST. * Response Duration (RD) assessed according to irRECIST. * A set of immune biomarkers will be analysed and correlated with evolution of the disease and efficacy of pembrolizumab in combination with gemcitabine (ORR and other efficacy end-points: PFS, CBR and RD), paying special attention to long term responders. * This set of immune biomarkers will be compared with those from healthy volunteers (if available). Study population: Patients with HER2-negative advanced breast cancer. Justification of Sample size determination: A Simon's minimax two-stage design will be employed with the possibility of stopping early due to lack of response. Results from previous studies showed that gemcitabine produced a response rate of around 20%, this will be our expected H0. With the combination of pembrolizumab and gemcitabine, we expect to increase this rate to 35% what will be our H1 (an absolute increase of 15%), with an alpha error of 0.05 and a statistical power of 80%, we will need to include 53 evaluable patients in this trial. The first stage will include 31 evaluable patients, if at least 7 present a response, recruitment will continue to include the 53 evaluable patients. The null hypothesis of H0=20% will be rejected if 16 or more responses are observed in 53 patients. Statistical Analyses: Demographics and Baseline Characteristics: Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. Safety Analyses: AEs and Serious Adverse Events (SAE) will be reported in frequency tables (overall and by intensity). The safety analysis will be performed in the population that has received at least one dose of any of the study drugs/medications. Efficacy Analyses: All efficacy endpoints will be evaluated in the Per-protocol and Intent to treat (ITT) populations. Biomarker analysis:The biomarker analysis will be exploratory and descriptive. For continuous variables, mean, standard deviation, median, minimum and maximum values will be provided. Categorical variables will be summarized by numbers and proportions. Biomarker endpoints will be evaluated in all patients enrolled in the study with available samples. Study Duration: The end date of study is date of last patient´s death or the date when there is sufficient data to achieve the primary and secondary objectives and all patients have ended the study treatment, whichever comes first. Performing exploratory objectives will be independent of the date of the end of the study.