Study of Safety and Efficacy of Durvalumab in Combination With Paclitaxel in Metastatic Triple Negative Breast Cancer Patients

Study of the Safety, Tolerability and Efficacy of the Investigational Anti PD-L1 Monoclonal Antibody Durvalumab in Combination With Paclitaxel in Patients With Metastatic Triple Negative PD-L1 Positive Breast Cancer

The expression of PD-L1 in breast cancer has been previously demonstrated (Ghebeh et al 2006). In addition, PD-L1 has been shown to work as a "molecular shield", by protecting cancer cells from cytotoxic T-cells and chemotherapy induced apoptosis (Ghebeh et al 2008) suggesting to combine PD-L1 blockade with chemotherapy.

This trial will test Durvalumab in combination with Paclitaxel on metastatic triple-negative breast cancer patients. The safety profile of Durvalumab as a monotherapy has been previously established (lu et al 2015). In this trial the safety profile and tolerability of Durvalumab given in combination of Paclitaxel will be tested. In addition, the efficacy of this combination on metastatic breast cancer will be monitored.

This open label single arm trial will involve metastatic triple negative PD-L1 positive breast cancer patients. The trial will include a dose deescalation phase where three doses of paclitaxel will be tried on 3 patients each followed by a dose expansion phase on 25 patients. Paclitaxel will be given weekly for 1 cycle followed by combination of Paclitaxel and Durvalumab. Once 6 cycles of Paclitaxel are completed, Durvalumab will be given alone until disease progression or unacceptable toxicity. The toxicity and tolerability of the combination will be the main end point while the efficacy will be a secondary end point.

Inclusion Criteria:

1. Confirmed metastatic breast cancer
2. Triple negative breast cancer (estrogen receptor (ER) negative, progesterone receptor (PR) negative and Her2/neu negative).
3. Patients had received at least 1 line of chemotherapy in metastatic setting before being enrolled in this trial.
4. Written informed consent and any locally-required authorization
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
6. Life expectancy of >12 weeks
7. Adequate normal organ and marrow functions.

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study or previous enrolment in the present study
2. Participation in another clinical study with an investigational product during the last 4 months
3. Any previous treatment with a PD-1 or PD-L1 inhibitor, including MEDI4736 or with a CTLA 4 inhibitor
4. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction
5. Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of 10 mg dexamethasone prior to paclitaxel infusion and intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
6. Active or prior documented autoimmune disease within the past 2 years
7. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
8. History of primary immunodeficiency
9. History of allogeneic organ transplant
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, interstitial lung disease (ILD), cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
11. Known history of previous clinical diagnosis of tuberculosis
12. History of leptomeningeal carcinomatosis
13. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736
14. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
15. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
16. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
17. Subjects with uncontrolled seizures.