312TiP - A phase 2 randomized, double-blinded, controlled study of ONT-380 vs. placebo in combination with capecitabine (C) and trastuzumab (T) in patients...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Breast Cancer, Metastatic
Presenter Giuseppe Curigliano
Citation Annals of Oncology (2016) 27 (6): 68-99. 10.1093/annonc/mdw365
Authors G. Curigliano1, S. Loibl2, V. Müller3, X. Pivot4, A. Wardley5, D. Cameron6
  • 1Drug Development, Istituto Europeo di Oncologia, 20141 - Milano/IT
  • 2Medicine And Research, German Breast Group, 63263 - Neu-Isenburg/DE
  • 3Department Of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg/DE
  • 4Service Oncologie Medicale, CHU Besançon, Hôpital Jean Minjoz, 25030 - Besançon/FR
  • 5Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 6Oncology, Edinburgh Cancer Centre Western General Hospital, EH4 2XU - Edinburgh/GB

Abstract

Background

ONT-380 is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, ONT-380 demonstrated synergistic activity with T, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, ONT-380 was combined with C and T in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) and T. Objective response rate (ORR) was 13/ 24 (54%) in pts with measurable disease treated with ONT-380 + C + T (including 10 pts with brain mets). The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Based on these data, ONT-380 is now being evaluated in a Phase 2 study in combination with C and T.

Trial design

The primary study objective is to assess the effect of ONT-380 vs placebo given with C + T on progression-free survival (PFS) based on independent central review. Additional secondary objectives include CNS PFS, non-CNS PFS, time to CNS progression, ORR, duration of response, clinical benefit rate, and safety. The study population includes adult pts with progressive HER2+ locally advanced or MBC who have had prior treatment with a taxane, T, pertuzumab and T–DM1 but not C or lapatinib. Pts with brain mets, including untreated or progressive mets, may be enrolled. 180 pts will be enrolled in North America and Europe. Pts will receive C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and T (8 mg/kg IV loading dose; 6 mg/kg IV once every 21 days), and will be randomized in a 2:1 ratio to receive ONT–380 300 mg PO BID or placebo. Pts with isolated CNS progression may continue on study treatment after undergoing local CNS therapy. An independent Data Monitoring Committee will monitor pt safety.

Clinical trial identification

ONT-380-206

Legal entity responsible for the study

Oncothyreon Inc.

Funding

Oncothyreon Inc.

Disclosure

G. Curigliano: ESMO Faculty and ESMO Multi-Committee member. Please refer to the declaration uploaded previously. All other authors have declared no conflicts of interest.