Abstract B203: Chemokine modulation to enhance the effectiveness of pembrolizumab in patients with metastatic triple-negative breast cancer
Authors: Abdou Yara , Kalinski Pawel , Opyrchal Mateusz 
Published: February 2019

Abstract
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. Preclinical ex vivo data in Dr. Kalinski’s lab 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 have 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 with IFNα/COX2, and preliminary data showed local efficacy in tumor microenvironment modulation. Design: This is an open-label, single-center, phase IIa study to test CKM pretreatment followed by pembrolizumab in patients with metastatic TNBC, regardless of PD-1 expression, who progressed on ≥1 lines of therapy. Patients are given pretreatment 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 &lt; 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. For more information: Contact Roswell Park 1-800-767-9355 or email askroswell@roswellpark.org, Dr. Opyrchal at 716-845-1486, or Mateusz.opyrchal@roswellpark.org.
Citation Format: Yara Abdou, Pawel Kalinski, Mateusz Opyrchal. Chemokine modulation to enhance the effectiveness of pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B203.