Ph II Study of Pembrolizumab & Eribulin in Patients With HR+/HER2- MBC Previously Treated With Anthracyclines & Taxanes

Study Overview
=================
Brief Summary
-----------------
This a multicenter, open-label, phase II clinical trial to assess the efficacy of pembrolizumab in combination with eribulin in female patients older than 18 years old with hormone receptor-(HR)positive/HER2-negative metastatic breast cancer (MBC) previously treated with at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane and prior anti-hormonal therapy is mandatory. The number of patients to be included is 44 patients at 11 sites. All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle.

Detailed Description
-----------------
This a multicenter, open-label, phase II clinical trial to assess the efficacy of pembrolizumab in combination with eribulin in female patients older than 18 years old with hormone receptor-(HR)positive/HER2-negative metastatic breast cancer (MBC) previously treated with at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane in any combination or order and either in the early or metastatic disease setting unless contraindicated for a given patient. Prior anti-hormonal therapy is mandatory. The number of patients to be included is 44 patients at 11 sites. The primary objective is to assess the efficacy -as determined by the clinical benefit rate (CBR) (total number of objective responses plus stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 (pembrolizumab) in combination with eribulin. Primary endpoint is CBR based on RECIST v.1.1. All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with MK3475 (pembrolizumab) and eribulin will continue based on physician criteria. No maximum duration of treatment is specified. Study follow-up will be performed 12 months after last study dose. Available tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy since last progression of a metastatic tumor lesion not previously irradiated is requested for this study. Translational research of this protocol involves the collection, processing, temporary storage, and shipment of samples from consenting patients enrolled in centers selected for participation in the study. The study plan includes collection and initial processing of tumor tissues and blood samples to the central laboratory of Institut Hospital del Mar dInvestigacions Mèdiques (IMIM), that will be used to identify dynamic biomarkers that may be predictive of response to MK3475 (pembrolizumab) and eribulin treatment.

Official Title
-----------------
A Phase II Study of Pembrolizumab and Eribulin in Patients With HR-positive/HER2-negative Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Drug: Eribulin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent prior to beginning specific protocol procedures. Female patients ≥18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which the Investigator believes is stable at the time of screening. Life expectancy ≥ 12 weeks. Patients have a histologically and/or cytologically confirmed diagnosis of breast cancer. Patients have radiologic evidence of inoperable locally recurrent or MBC. Patients have HER2-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization (ISH) test or an immunohistochemistry (IHC) status of 0, 1+, or 2+ (if IHC 2+, a negative ISH test is required) by local laboratory testing. Patients have HR-positive breast cancer defined as estrogen receptor (ER) and/or progesterone receptor (PR) with >1% of tumor cells positive for ER and/or PR by IHC irrespective of staining intensity. Available tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy since last progression of a metastatic tumor lesion not previously irradiated. Note: Subjects for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or subject safety concern) may submit an archived metastatic tumor specimen only upon agreement from the Sponsor. Patients have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 as assessed by site Investigator and local radiology review. Patients have received at least one, but not more than two, prior chemotherapeutic regimens for locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane in any combination or order and either in the early or metastatic disease setting unless contraindicated for a given patient. Prior anti-hormonal therapy is mandatory. Patients have adequate bone marrow and organ function as defined by the following laboratory values: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L. Platelets ≥ 100 x 10^9/L. Hemoglobin ≥ 9 g/dL. Potassium, calcium (corrected for serum albumin), and magnesium within normal limits for the institution. Serum creatinine ≤ 1.5 x upper limit of normal (ULN). Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver metastases are present). Total serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present). Patients with known Gilbert disease who have serum bilirubin ≤ 3 x ULN may be enrolled. Patients must be accessible for treatment and follow-up. Exclusion Criteria: Patients have received previous treatment with eribulin and an/or anti-PD1 or anti-PD-L1 agents. Patients have a known hypersensitivity to any of the excipients of MK3475 (pembrolizumab) or eribulin. Patients who have received chemotherapy, targeted small molecule therapy, or radiotherapy within two weeks of first dose of study treatment. Patients who have received monoclonal antibodies for direct antineoplastic treatment or an investigational agent/device within four weeks of first dose of study treatment. Patients have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Known brain metastases are considered active, if any of the following criteria is applicable: Brain imaging during screening demonstrates progression of existing metastases and/or appearance of new lesions compared to brain imaging performed at least four weeks earlier. Neurological symptoms attributed to brain metastases have not returned to baseline. Steroids were used for brain metastases within 28 days of first dose of study treatment. Patients have peripheral neuropathy grade 2 or more. Patients have a concurrent malignancy or malignancy within five years of study enrollment (with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer). Patients have not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy. Patients have had a major surgical procedure within 28 days prior to starting study drug. Patients have an active cardiac disease or a history of cardiac dysfunction including any of the following: Unstable angina pectoris or documented myocardial infarction within six months prior to study entry. Symptomatic pericarditis. History of documented congestive heart failure (New York Heart Association functional classification III-IV). Patients have a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO). Patients have any of the following cardiac conduction abnormalities: Ventricular arrhythmias except for benign premature ventricular contractions. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication. Conduction abnormality requiring a pacemaker. Other cardiac arrhythmia not controlled with medication. Uncontrolled hyper/hypothyroidism or type 1 diabetes mellitus (T1DM). Patients with hypothyroidism stable on hormone replacement will not be excluded from the trial. Patients with controlled T1DM on a stable insulin regimen may be eligible for this study. Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that has required systemic treatment (steroids or immunosuppressive agents) in the past two years. Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic steroid replacement therapy (≤ 10 mg prednisone daily) for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Prior allogenic stem cell or solid organ transplantation. Active/history of pneumonitis requiring treatment with steroids or active/history of interstitial lung disease. Active uncontrolled infection at the time of screening Active tuberculosis. Current known infection with HIV. Active hepatitis B (HBV) [patients with negative hepatitis B surface antigen (HBsAg) test and a positive antibody to HBsAg (anti-HBsAg) test at screening are eligible] or hepatitis C (HCV) [patients with a positive antibody to hepatitis C (anti-HCV) are eligible only if polymerase chain reaction (PCR) is negative for virus hepatitis C RNA]. Patients have any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment contraindicate patient participation in the clinical study. Treatment with systemic steroids (standard premedication for chemotherapy/contrast reactions, inhaled steroids, and local applications are allowed) or another immunosuppressive agent within seven days prior to study treatment initiation. Has received live vaccines within 30 days prior to first dose of study treatment. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study unless they are using highly effective methods of contraception during dosing and up to 120 days after study drugs discontinuation.

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

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A phase II, multicenter, open-label study of pembrolizumab and eribulin in patients with HR- positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + eribulin<br>All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with MK3475 (pembrolizumab) and eribulin will continue based on physician criteria. No maximum duration of treatment is specified. Study follow-up will be performed 12 months after last study dose. | Drug: Pembrolizumab<br>* MK3475 (pembrolizumab) will be supplied directly as a solution for infusion in a single-use vial. Each vial contains 100 mg of MK3475 (pembrolizumab) in 4 ml of solution.<br>* Other names: MK3475;Drug: Eribulin<br>* Eribulin will be supplied as a clear and colourless aqueous solution for injection provided in glass vials containing 2 ml. Each 2 ml vial contains eribulin mesylate equivalent to 0.88 mg eribulin.<br>* Other names: Halaven;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of pembrolizumab in combination with eribulin. | The efficacy -as determined by the clinical benefit rate (CBR) (total number of objective responses plus stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 (pembrolizumab) in combination with eribulin in patients with HR-positive/HER2-negative MBC who have previously received an anthracycline and a taxane (for either early or advanced disease), unless contraindicated, and between one to two lines of chemotherapy in the metastatic setting. | At least 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The CBR in subjects with programmed death ligand-1 (PD-L1) positive tumors. | CBR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. | 24 months | 
| The progression-free survival (PFS) | PFS based on RECIST v.1.1. | 24 months | 
| The PFS in subjects with PD-L1 positive tumors. | PFS based on RECIST v.1.1 in subjects with PD-L1 positive tumors. | 24 months | 
| The overall survival OS | OS (OS will be determined at the end of the study). | 24 months | 
| The OS in subjects with PD-L1 positive tumors. | OS in subjects with PD-L1 positive tumors. | 24 months | 
| The overall response rate (ORR) | ORR based on RECIST v.1.1. | 24 months | 
| The ORR in subjects with PD-L1 positive tumors. | ORR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. | 24 months | 
| The duration of response (DoR) | DoR based on RECIST v.1.1. | 24 months | 
| The DoR in subjects with PD-L1 positive tumors. | DoR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. | 24 months | 
| Safety and tolerability of pembrolizumab in combination with eribulin | The safety and tolerability of MK3475 (pembrolizumab) in combination with eribulin according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3. | 24 months |