Background: Brain metastases remain an important cause of death for pts with advanced HER2+ BC. ONT-380 is an oral, potent and selective inhibitor of HER2 capable of penetrating the blood brain barrier in pre-clinical models. We evaluated the safety and preliminary efficacy of ONT-380 in combination with trastuzumab.

Methods: Open-label, dose finding, Phase I study to estimate the MTD(s) of ONT-380 + trastuzumab in pts with HER2+ BCBM. The study was conducted in parallel cohorts testing two schedules of ONT-380 (once-daily or twice-daily). The primary endpoint was determination of the MTD. A total of 15 pts were to be treated at the MTD of each schedule in order to select the best regimen for future phase 2 studies. Response was assessed by RECIST 1.1 (extracranial) and modified RECIST 1.1 (intracranial).

Results: Between Aug 2013 and March 2016, 41 pts were enrolled. Median age was 49 (range 29-65); ECOG performance status 0-1 (85%), 2 (15%). 34 (83%) patients had progressed after prior WBRT and/or SRS. Patients had a median of 2 prior treatments for metastatic breast cancer prior to enrollment. As of June 7, 2016, median number of cycles was 4 (range 1-32); 4 patients remain on active protocol therapy. 2 DLTs were observed among 5 pts treated at 450 mg BID (G3 thrombocytopenia and G3 thrombocytopenia and G3 ALT). The dose was de-escalated to 300 mg BID, and with 0/3 patients experiencing a DLT. 300mg BID was identified as the MTD and an additional 14 patients were enrolled at this dose level. 1/7 pts experienced a DLT at 750 mg QD (G3 ALT). At 900 mg QD, 2/2 pts experienced a DLT (2 patients had G3 ALT/AST). An additional 10 pts were enrolled at the MTD of 750 mg QD. The most common AEs, regardless of relationship, were fatigue, diarrhea, AST/ALT elevation, nausea, headache. Gr 3/4 AST/ALT elevation has occurred in 9/41 pts (22%), though has been reversible with dose interruption and reduction. One Gr 3 diarrhea has occurred at 450 mg BID, and 1 Gr 3 diarrhea has occurred at 750 mg QD. PK assessments showed similar exposure of ONT-380 for QD and BID regimens. Preliminary assessment CNS response is available for 19 pts in the QD cohort (5% PR, 89% SD, 5% PD) and 17 pts in the BID cohort (12% PR, 59% SD, 12% PD, 18% unknown). Preliminary non-CNS assessment for the same population is as follows: QD cohort (100% SD); BID cohort (6% PR, 71% SD and 23% unknown).

Conclusions: The combination of ONT-380 and trastuzumab is feasible. The combination has an acceptable safety profile with low incidence and severity of diarrhea and rash. Transaminase elevation was asymptomatic for all pts and resolved with drug interruption/delay. Preliminary evidence of activity was observed in CNS and non-CNS disease.

Citation Format: Metzger O, Barry W, Krop I, Guo H, Younger J, Lawler E, Walker L, Freedman R, Tolaney S, Winer E, Lin N. Phase I dose-escalation trial of ONT-380 in combination with trastuzumab in patients (pts) with HER2+ breast cancer brain metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-04.