Phase 1b Study of Pegylated Liposomal Doxorubicin and Pembrolizumab in Endocrine-resistant Breast Cancer

This will be a single-center phase 1b study to evaluate the tumor response and appropriate dose of combined treatment with pembrolizumab and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer (ERBC) patients. Female patients, ages 18 and above, with pathological diagnosis of breast cancer, estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2-) negative subtype, stage III non-operable, or stage IV disease, who have received at least two lines of hormonal therapy, one of which included aromatase inhibitors will be eligible for enrollment to the study. The total number of patients in the study will be 15 patients. The study diagram is shown in Figure 1. After signing the informed consent, eligible subjects will be successively assigned, in order of accrual, to a dosing cohort. Six subjects will be enrolled in the Start Cohort (Cohort S1), and receive: intravenous (IV) pembrolizumab 200 mg flat dose with IV pegylated liposomal doxorubicin (PLD) 30 mg/m2, every 3 weeks. Toxicity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Ver. 4.0 (NCI-CTCAE). If during the first 2 cycles of treatment (the first 6 weeks) in the Start Cohort (Cohort S1), up to one subject out of the 6 in the cohort will develop a dose-limiting toxicity (DLT; defined as grade-4 hematological adverse events (AEs), or grade 3 non-hematological AEs \[stomatitis, hand and foot syndrome\] in the first 2 cycles), the drug combination's safety profile will be deemed acceptable and up to 9 more subjects will be recruited in the cohort (Expanded Start Cohort S1) and will receive the same dose to help establish the rate of Tumor Response and to confirm safety. If during the first 2 cycles of treatment in the Start Cohort (Cohort S1) a DLT will be observed in 2 or more patients out of the initial 6 patients enrolled into this cohort, Cohort S1 will be discontinued, and a Reduced Dose Cohort (Cohort R1), will be accrued where the dose of PLD will be reduced by 20% to 24 mg/m2 (IV pembrolizumab 200 mg flat dose with IV PLD 24 mg/m2 every 3 weeks). Initially, 6 patients will be accrued to Cohort R1. If during the first 2 cycles of treatment (the first 6 weeks) in the Reduced Dose Cohort (Cohort R1), up to one subject out of the 6 in the cohort will develop a DLT, the drug combination's safety profile will be deemed acceptable and up to 7 more subjects will be recruited in the cohort (Expanded Reduced Cohort R1) to help establish the rate of Tumor Response and to confirm safety of the reduced dose. If during the first 2 cycles of treatment in Cohort R1, a DLT would be again observed in 2 or more subjects, the study will be terminated (refer to Figure 1 for the study diagram). Note: Only the first 2 cycles will be considered for safety clearance of any Cohort. If an additional DLT occurs in the 3rd cycle, the dose will be individually modified if the affected patient has stable disease (SD) or partial response/complete response (PR/CR), and the patient will continue to the extended phase of the study. The 3 first cycles of treatment (first 9 weeks) constitute the main phase of the study during which most of the study objectives will be reached (safe dose clearance, tumor response rate characterization of DLT's, pharmacokinetic \[PK\] analysis of PLD). Patients will return to the study center on days 7 and 14 of cycles 1, 2 and 3, for monitoring assessments and for clinical laboratory evaluations. Blood samples will be collected on study visits for measurement of PLD concentrations at various time points during cycle 1. For each subject, subsequent dosing will take place 21 days after the previous treatment, provided patients are deemed fit to be dosed again. For responding or stable patients, the extended phase of the study consists of 9 additional cycles (27 more weeks) during which further safety information, duration of response, progression-free survival (PFS) time, and other pertinent data will be collected. During both phases of the study and beyond, information on survival and post-study treatments will be collected until death. Information on potentially predictive biomarkers of treatment response (and duration of response) will be gathered all along the study. All patients receiving two or more cycles will be followed-up for survival until death. Study treatment may continue until disease progression, unacceptable toxicity, patient refusal, patient loss to follow up, or termination of the study by the Sponsor or Investigator, whichever comes first. Pembrolizumab may be continued beyond disease progression. PLD will not be continued beyond disease progression.