Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally ad
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CLINICAL TRIAL
Phase Ib clinical trial of the anti‑frizzled antibody vantictumab (OMP‑18R5) plus paclitaxel in patients with locally advanced or metastatic HER2‑negative breast cancer Jennifer R. Diamond1 · Carlos Becerra2 · Donald Richards3 · Alain Mita4 · Cynthia Osborne2 · Joyce O’Shaughnessy2 · Chun Zhang5 · Randall Henner5 · Ann M. Kapoun5 · Lu Xu5 · Bob Stagg5 · Shailaja Uttamsingh5 · Rainer K. Brachmann5 · Azeez Farooki6 · Monica Mita4 Received: 5 February 2020 / Accepted: 17 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab. Methods Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90 mg/m2 on days 1, 8 and 15 in combination with vantictumab 3.5–14 mg/kg days 1 and 15 or 3–8 mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis. Results Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS: p = 0.029 and OS: p = 0.00045, respectively). Conclusions The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer. Clinical Trial Registration: ClinicalTrials.gov registration: NCT01973309 Keywords Vantictumab · Paclitaxel · Frizzled inhibitor · Breast cancer
Introduction Metastatic breast cancer remains a leading cause of cancer-related death in women worldwide [1]. Although many agents can prolong progression-free survival (PFS), and even overall survival (OS) in some cases, acquired resistance * Jennifer R. Diamond [email protected] * Monica Mita [email protected] Extended author information available on the last page of the article
to these therapies is nearly universal and there remains a critical need for novel treatment strategies to address chemotherapy resistance [2]. The WNT/ß-catenin signaling pathway is
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