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

Inclusion Criteria:

1. 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.
2. Have measurable disease on computed tomography (CT) or positron emission tomography-computed tomography (PET-CT) scan.

2. Be 18 years of age on day of signing informed consent. 3. Have measurable disease based on RECIST 1.1. 4. Have Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 5. Have an estimated life expectancy of at least 3 months. 6. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 10 days of treatment initiation.

7. Have received at least two lines of hormonal therapy, one of which had included aromatase inhibitors.

8. May have received none or up to 2 lines of chemotherapy (excluding any chemotherapy given in adjuvant or pre-operative-neoadjuvant settings).

9. Have a ≥21-day treatment-free interval from chemotherapeutic treatment. 10. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2, for the course of the study through 120 days after the last dose of study medication.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

12. Understanding of study procedures and willingness to comply throughout the entire course of the study and to provide written informed consent.

Exclusion Criteria:

1. Has known hypersensitivity to the study drugs or to any of their excipients.
2. Has congestive heart failure (New York Heart Association [NYHA] Class IV) or left ventricular ejection fraction (LVEF) ≤40%.
3. 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%).
4. Has cirrhosis (Child-Pugh Class C score).
5. Has serum albumin level < 2.5 g/dl.
6. Has a known history of HIV (HIV 1/2 antibodies).
7. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
8. Has evidence of active bleeding or bleeding diathesis.
9. Concomitant use of any other chemotherapy (except for PLD) or hormonal therapy during the study
10. Uncontrolled ascites (defined as 2 or more palliative taps within 30 days of screening).
11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
12. Continuous steroid treatment for other than brain metastases requiring daily corticosteroid dose ≥ 10 mg prednisone or corticosteroid-equivalent per day.
13. Anthracycline treatment (doxorubicin, epirubicin, mitoxantrone, PLD) in metastatic setting.
14. Less than 6 months from last treatment with anthracyclines in adjuvant or neo-adjuvant setting.
15. Use of any investigational drug within 28 days prior to study entry.
16. Diagnosis of any other malignancy within 5 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, superficial melanoma, or carcinoma in situ of the breast or of the cervix.
17. Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry, or uncontrolled diarrhea in the last 4 weeks prior to enrollment.
18. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
19. Has a diagnosis of immunodeficiency or is receiving any immunosuppressive therapy (except for prednisone ≤10 mg/day or equivalent) within 7 days prior to the first dose of trial treatment.
20. Has a known history of active Bacillus Tuberculosis.
21. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.

22. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 3 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered agent.

    Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

    Note: If the subject underwent major surgery, she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

23. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin or melanoma that have undergone potentially curative therapy or in situ cervical or bladder cancer.
24. Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases are eligible for recruitment provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and may be receiving dexamethasone at a dose ≤4 mg/day prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
25. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
26. Has a known history of, or any evidence of active, non-infectious pneumonitis.
27. Has an active serious infection or an active infection requiring systemic therapy.
28. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
29. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
30. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
31. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.