Abstract P4-15-08: A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with ado-trastuzumab emtansine (T-DM1), in HER2+ metastatic breast cancer (MBC)
Authors: Borges Virginia F , Hamilton Erika , Yardley Denise A , Chaves Jorge , Aucoin Nathalie , Ferrario Cristiano , Walker Luke , Krop Ian 
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 and 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 to lead to clinical benefit, ONT-380 is being evaluated in combination with T-DM1 in patients previously treated with a taxane and trastuzumab for metastatic disease.
Methods: This 3+3 dose escalation study evaluates escalating doses of ONT-380 in a new tablet formulation combined with T-DM1 at 3.6 mg/kg IV once every 21 days. Prior treatment with trastuzumab and a taxane are required. Prior lapatinib or neratinib therapy and asymptomatic brain metastases (treated or untreated) are allowed. Previous T-DM1 is not permitted. Normal left ventricular ejection fraction and anthracycline exposure ≤ 360 mg/m2 is required. Study assessments include safety, ONT-380 and T-DM1 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, 7 patients have been treated with ONT-380 at 300 mg BID for 1–5 cycles. One dose limiting toxicity (DLT) of Grade 3 ALT/AST elevation was seen in the ONT-380 300 mg BID cohort, requiring a dose reduction for both agents with subsequent cohort expansion to 6 patients. No further DLTs have been seen in this cohort, and no other dose reductions have been required. Most toxicities have been Grade 1 or 2, with the most common regardless of attribution being nausea, fatigue, diarrhea, and thrombocytopenia. Two Grade 3 AEs have been reported, including the DLT of ALT/AST elevation, and one event of thrombocytopenia, considered related to T-DM1 but not ONT-380. There has been no Grade 3 diarrhea and no SAEs. In the four patients evaluable for response to date, best response has been 1PR, 2 SD, and 1 PD. Three patients with prior CNS radiation have had continued reduction in CNS lesions on study. Initial PK data indicate greater ONT-380 exposure is achieved with the new tablet formulation compared to the earlier capsule formulation with no evidence of drug interaction with T-DM1.
Conclusions: Treatment with ONT-380 and T-DM1 has been associated with an acceptable safety profile, with only one DLT and minimal Grade 3 toxicity, including no Grade 3 diarrhea or rash. Early evidence of disease control has been seen, including in patients with CNS metastases. Dose escalation continues, and updated results will be presented for additional cohorts.
Citation Format: Virginia F Borges, Erika Hamilton, Denise A Yardley, Jorge Chaves, Nathalie Aucoin, Cristiano Ferrario, Luke Walker, Ian Krop. A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with ado-trastuzumab emtansine (T-DM1), 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 P4-15-08.