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 Mita7. 1. University of Colorado Anschutz Medical Campus, University of Colorado Cancer Center, 12801 E 17th Ave, Mailstop 8117, Aurora, CO, 80045, USA. Jennifer.diamond@cuanschutz.edu. 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. Monica.mita@cshs.org.
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.
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.
Entities:
Keywords:
Breast cancer; Frizzled inhibitor; Paclitaxel; Vantictumab
Authors: Masaki Kato; Millan S Patel; Regis Levasseur; Ivan Lobov; Benny H-J Chang; Donald A Glass; Christine Hartmann; Lan Li; Tae-Ho Hwang; Cory F Brayton; Richard A Lang; Gerard Karsenty; Lawrence Chan Journal: J Cell Biol Date: 2002-04-15 Impact factor: 10.539
Authors: Marcus M Fischer; Belinda Cancilla; V Pete Yeung; Fiore Cattaruzza; Cecile Chartier; Christopher L Murriel; Jennifer Cain; Raymond Tam; Chieh-Yang Cheng; James W Evans; Gilbert O'Young; Xiaomei Song; John Lewicki; Ann M Kapoun; Austin Gurney; Wan-Ching Yen; Timothy Hoey Journal: Sci Adv Date: 2017-06-21 Impact factor: 14.136