PURPOSE: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. DESIGN: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. RESULTS: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. CONCLUSIONS: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.
PURPOSE: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumorpatients. DESIGN: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. RESULTS: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. CONCLUSIONS:Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.
Authors: Markus Guba; Philipp von Breitenbuch; Markus Steinbauer; Gudrun Koehl; Stefanie Flegel; Matthias Hornung; Christiane J Bruns; Carl Zuelke; Stefan Farkas; Matthias Anthuber; Karl-Walter Jauch; Edward K Geissler Journal: Nat Med Date: 2002-02 Impact factor: 53.440
Authors: Rosa Bernardi; Ilhem Guernah; David Jin; Silvia Grisendi; Andrea Alimonti; Julie Teruya-Feldstein; Carlos Cordon-Cardo; M Celeste Simon; Shahin Rafii; Pier Paolo Pandolfi Journal: Nature Date: 2006-08-17 Impact factor: 49.962
Authors: Abhik Bandyopadhyay; Yong Zhu; Shazli N Malik; Jeffrey Kreisberg; Michael G Brattain; Eugene A Sprague; Jian Luo; Fernando López-Casillas; L-Z Sun Journal: Oncogene Date: 2002-05-16 Impact factor: 9.867
Authors: Thuy L Phung; Keren Ziv; Donnette Dabydeen; Godfred Eyiah-Mensah; Marcela Riveros; Carole Perruzzi; Jingfang Sun; Rita A Monahan-Earley; Ichiro Shiojima; Janice A Nagy; Michelle I Lin; Kenneth Walsh; Ann M Dvorak; David M Briscoe; Michal Neeman; William C Sessa; Harold F Dvorak; Laura E Benjamin Journal: Cancer Cell Date: 2006-08 Impact factor: 31.743
Authors: Alan Sandler; Robert Gray; Michael C Perry; Julie Brahmer; Joan H Schiller; Afshin Dowlati; Rogerio Lilenbaum; David H Johnson Journal: N Engl J Med Date: 2006-12-14 Impact factor: 91.245
Authors: Christine C Hudson; Mei Liu; Gary G Chiang; Diane M Otterness; Dawn C Loomis; Fiona Kaper; Amato J Giaccia; Robert T Abraham Journal: Mol Cell Biol Date: 2002-10 Impact factor: 4.272
Authors: Herbert Hurwitz; Louis Fehrenbacher; William Novotny; Thomas Cartwright; John Hainsworth; William Heim; Jordan Berlin; Ari Baron; Susan Griffing; Eric Holmgren; Napoleone Ferrara; Gwen Fyfe; Beth Rogers; Robert Ross; Fairooz Kabbinavar Journal: N Engl J Med Date: 2004-06-03 Impact factor: 91.245
Authors: Abhik Bandyopadhyay; Fernando López-Casillas; Shazli N Malik; José Luis Montiel; Valentín Mendoza; Junhua Yang; L-Z Sun Journal: Cancer Res Date: 2002-08-15 Impact factor: 12.701
Authors: Fairooz Kabbinavar; Herbert I Hurwitz; Louis Fehrenbacher; Neal J Meropol; William F Novotny; Grazyna Lieberman; Susan Griffing; Emily Bergsland Journal: J Clin Oncol Date: 2003-01-01 Impact factor: 44.544