Abstract P4-15-19: A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with capecitabine and/or trastuzumab, in HER2+ metastatic breast cancer (MBC)
Authors: Hamilton Erika , Yardley Denise A , Hortobagyi Gabriel , Walker Luke , Borges Virginia F , Moulder Stacy 
Published: May 2015

Abstract
Background: ONT-380 (also known as ARRY-380) is a potent, selective small molecule inhibitor of HER2 with 500-fold selectivity compared to EGFR. Preclinical studies have demonstrated synergistic activity with ONT-380 plus chemotherapy or trastuzumab, as well as superior activity compared to lapatinib and neratinib in models of HER2+ CNS metastases. In a Phase 1 single agent study in HER2+ MBC, ONT-380 was well tolerated and provided clinical benefit with minimal EGFR-type toxicities, with an MTD of 600 mg BID using an API-in-capsule formulation. Based on the potential for dual blockade of HER2 plus a cytotoxic agent to lead to clinical benefit, ONT-380 is being evaluated in combination with capecitabine and/or trastuzumab in pts with HER2+ MBC previously treated with trastuzumab and ado-trastuzumab emtansine (T-DM1).
Methods: This parallel 3+3 dose escalation study administers ONT-380 in a new tablet formulation with either capecitabine (1000 mg/mg2 PO BID for 14 days of a 21 day cycle) (Combo 1), trastuzumab (8 mg/kg IV loading dose; then 6 mg/kg IV once every 21 days) (Combo 2), or with both capecitabine and trastuzumab (Combo 3). Prior treatment with trastuzumab and T-DM1 for metastatic disease is required. Prior therapy with lapatinib or neratinib and asymptomatic brain metastases (treated or untreated) are allowed. Study assessments include safety, ONT-380 and capecitabine PK, tumor response by RECIST 1.1, and CNS response by both modified RECIST and volumetric criteria. Dose escalation will be followed by enrollment of expansion cohorts in patients with and without CNS disease.
Results: As of 21 May 2014, 8 pts have been treated with ONT-380 at 300 mg BID in Combo 1 (n=4) for 2–7 cycles and Combo 2 (n=4) for 1–2 cycles. All pts are still active. No dose limiting toxicities (DLT) have been seen for either combination, and most toxicities have been Grade 1 or 2. The most common toxicities regardless of attribution have been nausea, diarrhea, dyspepsia, headache, and palmar-plantar erythrodysaesthesia (PPE). There has been no Grade 3 diarrhea. Two Grade 3 events have been reported, both in Combo 1: PPE and ALT/AST elevation. There have been no SAEs. ONT-380 was dose reduced in one pt (Combo 1) for persistent Grade 2 diarrhea as well as in the pt with Grade 3 ALT/AST. Capecitabine was dose reduced in three pts: diarrhea (n=2), Grade 3 PPE (n=1), and Grade 3 ALT/AST (n=1). Best response seen to date in 3 pts evaluable for response has been stable disease. Initial PK data indicate greater drug exposure is achieved with the new tablet formulation of ONT-380 compared to the earlier capsule formulation with no evidence of drug interaction with capecitabine.
Summary: ONT-380 in combination with either capecitabine or trastuzumab has been associated with an acceptable safety profile, with no DLTs seen with either combination. No Grade 3 diarrhea has been observed, including pts receiving both ONT-380 and capecitabine. Early evidence of disease control has been seen. Dose escalation continues, and evaluation of the three drug combinations is planned. Updated results will be presented for additional cohorts.
Citation Format: Erika Hamilton, Denise A Yardley, Gabriel Hortobagyi, Luke Walker, Virginia F Borges, Stacy Moulder. A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with capecitabine and/or trastuzumab, in HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-19.