Abstract P6-13-21: Phase 1 study of GR antagonist mifepristone (M) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients (pts) with GR-positive triple-negative breast cancer (TNBC)
Authors: Wilks S , Modiano M , Spira A , Becerra C , Walling J , Nguyen D , Baker G , Conzen SD , Nanda R 
Published: May 2016

Abstract
Background: High tumor GR expression is associated with poor prognosis in estrogen receptor (ER) negative early-stage breast cancer. Co-treatment with M, a GR antagonist, potentiates effects of chemotherapy in ER- breast cancer xenograft studies. Herein we describe results of a phase 1 dose-escalation study of M plus E, with an ongoing dose expansion cohort in pts with GR+ TNBC.
Objectives: Determine 1) safety and tolerability, 2) recommended phase 2 dose (RP2D) of M + E, and 3) characterize pharmacokinetics (PK) and clinical activity of M in pts with GR+ TNBC.
Methods: Eligibility: 1) relapsed/refractory breast, ovarian, prostate, urothelial, sarcoma, or non-small cell lung cancer; 2) 2-5 prior chemotherapy regimens for advanced disease; 3) ECOG PS 0-1; and 4) adequate end-organ function. Study used a 3 + 3 dose escalation scheme. After a 7 day lead-in of M alone, M was administered by mouth daily in combination with E given IV on days 1 and 8 of a 21 day cycle.
Results: 13 pts in Part 1 Dose escalation with metastatic breast cancer (MBC) were treated with M+E: 5 TNBC, 8 GR+ tumors, 2 GR- tumors, and 3 of unknown GR status. Pts were treated at 3 dose levels (DL)[M mg/d, E mg/m2]: 3 at DL1 [600, 1.1] 4 at DL-1a [300, 1.4], and 6 at DL-1 [300, 1.1]. Median duration of treatment was 90+ days. Neutropenia leading to delay of E was dose limiting in 4 pts. CTAE Grade 3/4 neutropenia was observed in 10 pts over all DL, but easily managed (9 pts with growth factor support). Other grade 3+ toxicities were neuropathy (2 pts) and onycholysis (1 pt). No other significant toxicity was noted.
RP2D was determined as 300mg/d M and 1.1mg/m2 E. At this DL there were no DLTs. PK of M and E were as predicted from published literature with no evidence of drug-drug interaction (DDI). A total of 6 pts received this dose (3 TNBC; 3 MBC). All 3 TNBC were GR+. 1 had partial response, 1 had stable disease, and 1 had progressive disease.
A phase I/II study of M+E is now in progress. To date, 3 GR+ TNBC pts have been treated for a median of 28+ days.
Conclusion: M + E is a novel combination designed to improve antitumor activity. It is well tolerated with evidence of clinical activity and no evidence of DDI. RP2D is 300mg M + E 1.1mg/m2. Study is ongoing in expansion phase where recruitment is limited to pts with GR+ TNBC. Additional PK and clinical data will be presented.
Citation Format: Wilks S, Modiano M, Spira A, Becerra C, Walling J, Nguyen D, Baker G, Conzen SD, Nanda R. Phase 1 study of GR antagonist mifepristone (M) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients (pts) with GR-positive triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-21.