Robin E Norris1, Elizabeth Fox2, Joel M Reid3, Andrew Ralya3, Xiaowei W Liu4, Charles Minard5, Brenda J Weigel6. 1. Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 3. Mayo Clinic, Rochester, Minnesota. 4. Children's Oncology Group Operations Center, Monrovia, California. 5. Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas. 6. University of Minnesota Medical Center/Masonic Center Minneapolis, Minneapolis, Minnesota.
Abstract
BACKGROUND: Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation. METHODS: Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation. RESULTS: Twenty-seven eligible patients (17 male, median age 15 years, range 3-21 years) were enrolled. Twenty-two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose-limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion-related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg. CONCLUSION: Ontuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults.
BACKGROUND:Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation. METHODS:Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation. RESULTS: Twenty-seven eligible patients (17 male, median age 15 years, range 3-21 years) were enrolled. Twenty-two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose-limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion-related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg. CONCLUSION:Ontuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults.
Authors: Luis A Diaz; Christina M Coughlin; Susan C Weil; Jean Fishel; Mrinal M Gounder; Susan Lawrence; Nilofer Azad; Daniel J O'Shannessy; Luigi Grasso; Jason Wustner; Wolfgang Ebel; Richard D Carvajal Journal: Clin Cancer Res Date: 2014-11-14 Impact factor: 12.531
Authors: Brian Tomkowicz; Katherine Rybinski; Denise Sebeck; Philip Sass; Nicolas C Nicolaides; Luigi Grasso; Yuhong Zhou Journal: Cancer Biol Ther Date: 2010-06-08 Impact factor: 4.742
Authors: Cecile Rouleau; Robert Smale; Yao-Shi Fu; Guodong Hui; Fei Wang; Elizabeth Hutto; Robert Fogle; Craig M Jones; Roy Krumbholz; Stephanie Roth; Maritza Curiel; Yi Ren; Rebecca G Bagley; Gina Wallar; Glenn Miller; Steven Schmid; Bruce Horten; Beverly A Teicher Journal: Int J Oncol Date: 2011-04-29 Impact factor: 5.650
Authors: Brian Tomkowicz; Katherine Rybinski; Brian Foley; Wolfgang Ebel; Brad Kline; Eric Routhier; Philip Sass; Nicholas C Nicolaides; Luigi Grasso; Yuhong Zhou Journal: Proc Natl Acad Sci U S A Date: 2007-11-06 Impact factor: 11.205
Authors: Daniel J O'Shannessy; Michael F Smith; Elizabeth B Somers; Stephen M Jackson; Earl Albone; Brian Tomkowicz; Xin Cheng; Young Park; Danielle Fernando; Andrew Milinichik; Brad Kline; Regan Fulton; Pankaj Oberoi; Nicholas C Nicolaides Journal: Oncotarget Date: 2016-10-25
Authors: Julie K Fierle; Matteo Brioschi; Mariastella de Tiani; Laureline Wetterwald; Vasileios Atsaves; Johan Abram-Saliba; Tatiana V Petrova; George Coukos; Steven M Dunn Journal: Cell Rep Med Date: 2021-08-02
Authors: Arthur Felix; Pablo Berlanga; Maud Toulmonde; Judith Landman-Parker; Sarah Dumont; Gilles Vassal; Marie-Cécile Le Deley; Nathalie Gaspar Journal: Cancer Med Date: 2021-01-15 Impact factor: 4.452
Authors: Judith Anna Delage; Silvano Gnesin; John O Prior; Jacques Barbet; Patricia Le Saëc; Séverine Marionneau-Lambot; Sébastien Gouard; Michel Chérel; Mickael Bourgeois; Niklaus Schaefer; David Viertl; Julie Katrin Fierle; Steven Mark Dunn; Alain Faivre-Chauvet Journal: Cancers (Basel) Date: 2021-11-25 Impact factor: 6.639