Background: Triple negative breast cancer (TNBC) is found in approximately 15-20% of all breast cancer, and is associated with poor prognosis, early relapse and a significantly shorter survival following recurrence. Early phase trials with immune checkpoint inhibitors have shown modest yet durable clinical responses with a tolerable safety profile. Strategies to sensitize these tumors to checkpoint inhibition will result in decreased morbidity and mortality.

Tumor infiltrating immune cells and intratumoral expression of PD-1/PD-L1/PD-L2 can predict patients' benefit from Pembrolizumab. Pre-clinical ex-vivo data show that chemokine modulating regimen consisting of Rintatolimod, IFNα and COX2 blocker (CKM), selectively attracts cytotoxic T cells into tumors, and increases intratumoral expression of PD-1/PD-L1/PD-L2, without enhancing soluble suppressive mechanisms. Furthermore, mouse data has shown safety of CKM and PD-1 blockade combination and efficacy in inducing long-term survival of mice with resistant tumors.

Clinical trials of CKM in Colon and ovarian cancer (NCT01545141, NCT02432378) demonstrated safety of Rintatolimod given with IFNα/COX2, and preliminary data show local efficacy in tumor microenvironment modulation.

Design: This is an open-label, single center, phase IIa study to test Chemokine modulating regimen (CKM) pre-treatment followed by Pembrolizumab in patients with metastatic TNBC, regardless of PD-1 expression, who progressed on ≥1 lines of therapy.

Patients are given pre-treatment CKM, which consists of Rintatolimod (200 mg IV), IFNα-2 (20 million units/m2 IV) and Celecoxib (200 mg po BID), on 3 consecutive days for a total of 2 cycles, one week apart. The patient is then treated with Pembrolizumab 200 mg IV every 3 weeks until disease progression, intolerable side effects or withdrawal from study for up to 24 months. Study includes pre- and post CKM treatment biopsies.

Eligibility: Major criteria include age ≥ 18 years, ECOG ≤ 1, histologically proven metastatic TNBC, normal organ and marrow function, no active autoimmune disease or history of transplant, no prior anti-PD1/PDL1 therapy.

Aims: Primary objective is to evaluate the overall response rate to the combination therapy per irRECIST criteria. Secondary objectives include safety profile of the combination therapy, determining progression free survival, overall survival and disease control rate. Other immune exploratory objectives will include baseline and CKM-induced predictive biomarkers of clinical activity of the combination treatment.

Statistical Methods: The study includes a safety lead-in of 6 patients and utilizes a Simon two-stage minimax design. 18 patients are enrolled into stage 1 of the study. If < 4 responses are observed, the treatment combination will not be considered promising and enrollment will be terminated. However, if ≥ 4 responses are observed, then an additional 19 patients will be enrolled into stage 2, for a total number of 37 patients. In stage 2, if ≥ 9 responses are observed, then the treatment combination will be considered promising for future study.

Citation Format: Abdou Y, Williams LE, Kalinski P, Opyrchal M. Chemokine modulation to enhance the effectiveness of pembrolizumab in patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-02.