Abstract OT2-10-05: HER2Pro: A Phase 1b dose de-escalation study of high dose prochlorperazine added to paclitaxel, trastuzumab and pertuzumab in patients with previously untreated HER2-positive metastatic breast cancer
Authors: Downton Teesha , Karlsen Emma , Cuff Katharine , Walpole Euan , Simpson Fiona , Lim Elgene 
Published: March 2023

HER2Pro: A Phase 1b dose de-escalation study of high dose prochlorperazine added to paclitaxel, trastuzumab and pertuzumab in patients with previously untreated HER2-positive metastatic breast cancer Authors Teesha Downton1,2, Emma Karlsen1, Katharine Cuff3,4, Euan Walpole3,4, Fiona Simpson3,4, Elgene Lim1,2. Affiliations 1Garvan Institute of Medical Research, Darlinghurst NSW, Australia; 2School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales Sydney, Australia; 3Diamantina Institute, University of Queensland, Woolloongabba QLD, Australia; 4Princess Alexandra Hospital, Brisbane QLD, Australia Disclosures T. Downton: None. E. Karlsen: None. K. Cuff: None. E. Walpole: None. F. Simpson: None. E. Lim. Advisory Board for Pfizer, Astra Zeneca, Lilly, Roche, Novartis, Gilead Australia. Research Funding from Pfizer, Novartis, Bayer. Abstract Background: The anti-emetic prochlorperazine reversibly inhibits dynamin-mediated endocytosis. Preclinical studies have demonstrated that through this mechanism, high dose prochlorperazine can temporarily increase tumor cell antigen presentation, enhance interaction of tumor antigens with therapeutic monoclonal antibodies, and improve antibody-dependent cellular cytotoxicity (Chew H et al. Cell 2020). High dose prochlorperazine has been well tolerated and proof of mechanism demonstrated in a pilot study (ACTRN12619001051134), and in a phase Ib trial (ACTRN12619001527156) of prochlorperazine with cetuximab in patients with EGFR-expressing advanced head and neck squamous cell carcinoma or breast cancer. Prochlorperazine potentially offers a novel approach to improve the efficacy of a range of therapeutic antibodies. This study HER2Pro (ACTRN12622000016730) aims to evaluate the feasibility and safety of high dose prochlorperazine in combination with paclitaxel, trastuzumab, and pertuzumab in patients with HER2-positive metastatic breast cancer. Trial Design: In this phase Ib single-arm trial, patients receive standard of care trastuzumab and pertuzumab 3-weekly and paclitaxel weekly. From cycle 2, patients in addition receive de-escalating doses of prochlorperazine weekly for 6 weeks, though an additional 6 weeks may be given if there are no treatment associated serious adverse events. Dose de-escalation will be evaluated using a 3+3 design, commencing at a prochlorperazine intravenous dose of 0.8mg/kg weekly. Eligibility: Eligible patients must have previously untreated HER2-positive metastatic breast cancer, Eastern Cooperative Oncology Group performance status 0-1, and baseline left ventricular ejection fraction 50%. Key exclusion criteria include current daily treatment with corticosteroids at a dose &gt;10mg prednisolone or equivalent, blood pressure &lt; 90/50 mmHg, prolonged QT interval, and Parkinson’s disease. Objectives: The primary objective is to determine the recommended phase 2 dose. Secondary objectives include determining the frequency and severity of adverse events, rates of cardiotoxicity, objective response rate, duration of response and progression free survival. Tertiary objectives include analysis of receptor trafficking and immune system activation on paired tumor biopsies obtained before and after first prochlorperazine dose. Accrual: 6-12 patients will be enrolled across 2 Australian sites. Enrollment for this trial is expected to commence late 2022.

Citation Format: Teesha Downton, Emma Karlsen, Katharine Cuff, Euan Walpole, Fiona Simpson, Elgene Lim. HER2Pro: A Phase 1b dose de-escalation study of high dose prochlorperazine added to paclitaxel, trastuzumab and pertuzumab in patients with previously untreated HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-05.