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

  • Breast Cancer Res Treat. 2020 Nov;184(1):53-62. doi: 10.1007/s10549-020-05817-w.
Jennifer R Diamond  1 ,  Carlos Becerra  2 ,  Donald Richards  3 ,  Alain Mita  4 ,  Cynthia Osborne  2 ,  Joyce O'Shaughnessy  2 ,  Chun Zhang  5 ,  Randall Henner  5 ,  Ann M Kapoun  5 ,  Lu Xu  5 ,  Bob Stagg  5 ,  Shailaja Uttamsingh  5 ,  Rainer K Brachmann  5 ,  Azeez Farooki  6 ,  Monica Mita  7
Affiliations
  • 1. University of Colorado Anschutz Medical Campus, University of Colorado Cancer Center, 12801 E 17th Ave, Mailstop 8117, Aurora, CO, 80045, USA. [email protected].
  • 2. Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA.
  • 3. Texas Oncology, US Oncology, Tyler, TX, USA.
  • 4. Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA.
  • 5. OncoMed Pharmaceuticals, Redwood City, CA, USA.
  • 6. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7. Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA. [email protected].
PMID: 32803633 DOI: 10.1007/s10549-020-05817-w
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
Breast cancer; Frizzled inhibitor; Paclitaxel; Vantictumab.
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