Very few patients with endocrine-resistant, hormone-receptor positive metastatic breast cancer respond to single agent immunotherapy. Responses to chemotherapy are usually of short duration. Combining immunotherapy with chemotherapy that has minimal immunosuppressive effect, it may be possible to achieve higher response rates while keeping the immune-associated pattern of long durations of response.
This will be a single-center phase 1b study to evaluate the tumor response and appropriate dose of a chemo-immunotherapy regime consisting of treatment with pegylated liposomal doxorubicin (PLD) and pembrolizumab-based in endocrine-resistant breast cancer (ERBC) patients.
Up to 15 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 this single arm study.
Have pathological diagnosis of breast cancer, ER positive (%ER+ cells≥1%, Allred score ≥3), Her2 negative subtype, locally advanced (stage III non-operable), or metastatic (stage IV) disease.
Have measurable disease on computed tomography (CT) or positron emission tomography-computed tomography (PET-CT) scan.
Has known hypersensitivity to the study drugs or to any of their excipients.
Has congestive heart failure (New York Heart Association [NYHA] Class IV) or left ventricular ejection fraction (LVEF) ≤40%.
Has chronic obstructive pulmonary disease (COPD) >Stage 3 (forced expiratory volume in 1 second [FEV1] <50%, forced expiratory volume 1/forced vital capacity [FEV1/FVC] <70%).
Has cirrhosis (Child-Pugh Class C score).
Single group
Chemotherapy Drugs, Cancer
DrugIV pembrolizumab 200 mg flat dose with IV PLD 30 mg/m2 (chemotherapy drugs) every 3 weeks in eligible breast cancer patients.
To establish a safe dose of PLD when delivered in combination with pembrolizumab
A dose will be considered safe when the number of Participants With Treatment-Related Adverse Events grades 3 or 4, as assessed by CTCAE v4.0, will be less than 2 per 6-patient cohort. Our hypothesis is that treatment with pembrolizumab will be compatible with the standard recommended dose of PLD,
To evaluate the Tumor Response Rate according to Response Evaluation Criteria in Solid Tumors (RECIST) after 9 weeks (3 cycles) of treatment in patients with measurable disease.
Th response rate will be evaluated after 9 weeks (3 cycles) by RECIST. Our hypothesis is that the response rate of the combination will be higher than expected from each agent alone.
To evaluate the safety and DLT of the PLD and pembrolizumab combination, as indicated by the number of study participants with treatment-related Adverse Events, and the class of Adverse Events as assessed by CTCAE v4.0.
The safety profile of PLD and pembrolizumab will be evaluated by the number of study participants with treatment-related Adverse Events, and the class of Adverse Events as assessed by CTCAE v4.0. Our hypothesis is that it will remain unchanged when given in combination, as compared to what expected for each drug alone.
To characterize the PK of PLD when delivered in combination with pembrolizumab, by measuring and comparing the Area under the curve (AUC) for doxorubicin (liposomal) obtained during Cycles 1 and 3.
The PK of PLD will be evaluated by quantitation of doxorubicin (liposomal) in plasma samples and calculation of the AUC. Hypothesis: The PK profile of PLD may be modified by pembrolizumab during the course of therapy due to indirect effects on the mononuclear-phagocyte system (MPS) which plays an important role in PLD clearance. This will translate into a decrease or increase of AUC when the results of the 1st and 3rd cycles are compared.
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